Ageing and dementia in low and middle income countries - Using research to engage with public and policy makers

Abstract While two thirds of the 24 million people with dementia worldwide live in low and middle income countries, very little research has been conducted to support policy making in these regions. Among the non-communicable diseases, dementia (in common with other chronic NCDs linked more to long-term disability than to mortality) has been relatively under-prioritized. International agreements, plans and policy guidelines have called for an end to ageist discrimination and a focus upon reducing disadvantage arising from poverty and the consequences of ill health. Social protection, access to good quality age-appropriate healthcare and addressing the problem of disability are all key issues. However, as yet, little progress has been made in addressing these concerns. In this review we outline the current international policy agenda for older individuals, and its specific relevance to those with dementia and other disabling non-communicable diseases. We consider the potential for epidemiological research to raise awareness, refine the policy agenda, and promote action, using the example of the dissemination strategy developed by the 10/66 Dementia Research Group

The 10/66 Dementia Research Group's fully operationalised DSM-IV dementia computerized diagnostic algorithm, compared with the 10/66 dementia algorithm and a clinician diagnosis: a population validation study

<p>Abstract</p> <p>Background</p> <p>The criterion for dementia implicit in DSM-IV is widely used in research but not fully operationalised. The 10/66 Dementia Research Group sought to do this using assessments from their one phase dementia diagnostic research interview, and to validate the resulting algorithm in a population-based study in Cuba.</p> <p>Methods</p> <p>The criterion was operationalised as a computerised algorithm, applying clinical principles, based upon the 10/66 cognitive tests, clinical interview and informant reports; the Community Screening Instrument for Dementia, the CERAD 10 word list learning and animal naming tests, the Geriatric Mental State, and the History and Aetiology Schedule – Dementia Diagnosis and Subtype. This was validated in Cuba against a local clinician DSM-IV diagnosis and the 10/66 dementia diagnosis (originally calibrated probabilistically against clinician DSM-IV diagnoses in the 10/66 pilot study).</p> <p>Results</p> <p>The DSM-IV sub-criteria were plausibly distributed among clinically diagnosed dementia cases and controls. The clinician diagnoses agreed better with 10/66 dementia diagnosis than with the more conservative computerized DSM-IV algorithm. The DSM-IV algorithm was particularly likely to miss less severe dementia cases. Those with a 10/66 dementia diagnosis who did not meet the DSM-IV criterion were less cognitively and functionally impaired compared with the DSMIV confirmed cases, but still grossly impaired compared with those free of dementia.</p> <p>Conclusion</p> <p>The DSM-IV criterion, strictly applied, defines a narrow category of unambiguous dementia characterized by marked impairment. It may be specific but incompletely sensitive to clinically relevant cases. The 10/66 dementia diagnosis defines a broader category that may be more sensitive, identifying genuine cases beyond those defined by our DSM-IV algorithm, with relevance to the estimation of the population burden of this disorder.</p

Overfeeding Reduces Insulin Sensitivity and Increases Oxidative Stress, without Altering Markers of Mitochondrial Content and Function in Humans

BACKGROUND: Mitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered. METHODOLOGY AND PRINCIPAL FINDINGS: Forty (37±2 y) non-obese (25.6±0.6 kg/m2) sedentary men (n = 20) and women (n = 20) were overfed (+1040±100 kcal/day, 46±1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6±0.1 and 2.7±0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5 mmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P,<.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1a) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO2 production at either time point. CONCLUSIONS: Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.Dorit Samocha-Bonet, Lesley V. Campbell, Trevor A. Mori, Kevin D. Croft, Jerry R. Greenfield, Nigel Turner and Leonie K. Heilbron

The protocols for the 10/66 dementia research group population-based research programme

BACKGROUND: Latin America, China and India are experiencing unprecedentedly rapid demographic ageing with an increasing number of people with dementia. The 10/66 Dementia Research Group's title refers to the 66% of people with dementia that live in developing countries and the less than one tenth of population-based research carried out in those settings. This paper describes the protocols for the 10/66 population-based and intervention studies that aim to redress this imbalance. METHODS/DESIGN: Cross-sectional comprehensive one phase surveys have been conducted of all residents aged 65 and over of geographically defined catchment areas in ten low and middle income countries (India, China, Nigeria, Cuba, Dominican Republic, Brazil, Venezuela, Mexico, Peru and Argentina), with a sample size of between 1000 and 3000 (generally 2000). Each of the studies uses the same core minimum data set with cross-culturally validated assessments (dementia diagnosis and subtypes, mental disorders, physical health, anthropometry, demographics, extensive non communicable disease risk factor questionnaires, disability/functioning, health service utilisation, care arrangements and caregiver strain). Nested within the population based studies is a randomised controlled trial of a caregiver intervention for people with dementia and their families (ISRCTN41039907; ISRCTN41062011; ISRCTN95135433; ISRCTN66355402; ISRCTN93378627; ISRCTN94921815). A follow up of 2.5 to 3.5 years will be conducted in 7 countries (China, Cuba, Dominican Republic, Venezuela, Mexico, Peru and Argentina) to assess risk factors for incident dementia, stroke and all cause and cause-specific mortality; verbal autopsy will be used to identify causes of death. DISCUSSION: The 10/66 DRG baseline population-based studies are nearly complete. The incidence phase will be completed in 2009. All investigators are committed to establish an anonymised file sharing archive with monitored public access. Our aim is to create an evidence base to empower advocacy, raise awareness about dementia, and ensure that the health and social care needs of older people are anticipated and met

Novel Primate-Specific Genes, RMEL 1, 2 and 3, with Highly Restricted Expression in Melanoma, Assessed by New Data Mining Tool

Melanoma is a highly aggressive and therapy resistant tumor for which the identification of specific markers and therapeutic targets is highly desirable. We describe here the development and use of a bioinformatic pipeline tool, made publicly available under the name of EST2TSE, for the in silico detection of candidate genes with tissue-specific expression. Using this tool we mined the human EST (Expressed Sequence Tag) database for sequences derived exclusively from melanoma. We found 29 UniGene clusters of multiple ESTs with the potential to predict novel genes with melanoma-specific expression. Using a diverse panel of human tissues and cell lines, we validated the expression of a subset of three previously uncharacterized genes (clusters Hs.295012, Hs.518391, and Hs.559350) to be highly restricted to melanoma/melanocytes and named them RMEL1, 2 and 3, respectively. Expression analysis in nevi, primary melanomas, and metastatic melanomas revealed RMEL1 as a novel melanocytic lineage-specific gene up-regulated during melanoma development. RMEL2 expression was restricted to melanoma tissues and glioblastoma. RMEL3 showed strong up-regulation in nevi and was lost in metastatic tumors. Interestingly, we found correlations of RMEL2 and RMEL3 expression with improved patient outcome, suggesting tumor and/or metastasis suppressor functions for these genes. The three genes are composed of multiple exons and map to 2q12.2, 1q25.3, and 5q11.2, respectively. They are well conserved throughout primates, but not other genomes, and were predicted as having no coding potential, although primate-conserved and human-specific short ORFs could be found. Hairpin RNA secondary structures were also predicted. Concluding, this work offers new melanoma-specific genes for future validation as prognostic markers or as targets for the development of therapeutic strategies to treat melanoma

Efficacy of high-intensity, low-volume interval training compared to continuous aerobic training on insulin resistance, skeletal muscle structure and function in adults with metabolic syndrome: study protocol for a randomized controlled clinical trial (Intraining-MET)

ABSTRACT: Evidence of the efficacy of high-intensity, low-volume interval training (HIIT-low volume) in treating insulin resistance (IR) in patients with metabolic disorders is contradictory. In addition, it is unknown whether this effect is mediated through muscle endocrine function, which in turn depends on muscle mass and fiber type composition. Our aims were to assess the efficacy of HIIT-low volume compared to continuous aerobic exercise (CAE) in treating IR in adults with metabolic syndrome (MS) and to establish whether musclin, apelin, muscle mass and muscle composition are mediators of the effect. Methods: This is a controlled, randomized, clinical trial using the minimization method, with blinding of those who will evaluate the outcomes and two parallel groups for the purpose of showing superiority. Sixty patients with MS and IR with ages between 40 and 60 years will be included. A clinical evaluation will be carried out, along with laboratory tests to evaluate IR (homeostatic model assessment (HOMA)), muscle endocrine function (serum levels of musclin and apelin), thigh muscle mass (by dual energy x-ray absorptiometry (DXA) and thigh muscle composition (by carnosine measurement with proton magnetic resonance spectroscopy (H–MRS)), before and after 12 weeks of a treadmill exercise program three times a week. Participants assigned to the intervention (n = 30) will receive HIIT-low volume in 22-min sessions that will include six intervals at a load of 90% of maximum oxygen consumption (VO2 max) for 1 min followed by 2 min at 50% of VO2 max. The control group (n = 30) will receive CAE at an intensity of 60% of VO2 max for 36 min. A theoretical model based on structural equations will be proposed to estimate the total, direct and indirect effects of training on IR and the proportion explained by the mediators. Discussion: Compared with CAE, HIIT-low volume can be effective and efficient at improving physical capacity and decreasing cardiovascular risk factors, such as IR, in patients with metabolic disorders. Studies that evaluate mediating variables of the effect of HIIT-low volume on IR, such as endocrine function and skeletal muscle structure, are necessary to understand the role of skeletal muscle in the pathophysiology of MS and their regulation by exercise. Trial registration: NCT03087721. High-intensity Interval, Low Volume Training in Metabolic Syndrome (Intraining-MET). Registered on 22 March 2017, retrospectively registered

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Clinicaltrials.gov NCT00126672

Quasispecies Theory and the Behavior of RNA Viruses

A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy

Direct Interaction between Two Viral Proteins, the Nonstructural Protein 2CATPase and the Capsid Protein VP3, Is Required for Enterovirus Morphogenesis

In spite of decades-long studies, the mechanism of morphogenesis of plus-stranded RNA viruses belonging to the genus Enterovirus of Picornaviridae, including poliovirus (PV), is not understood. Numerous attempts to identify an RNA encapsidation signal have failed. Genetic studies, however, have implicated a role of the non-structural protein 2CATPase in the formation of poliovirus particles. Here we report a novel mechanism in which protein-protein interaction is sufficient to explain the specificity in PV encapsidation. Making use of a novel “reporter virus”, we show that a quasi-infectious chimera consisting of the capsid precursor of C-cluster coxsackie virus 20 (C-CAV20) and the nonstructural proteins of the closely related PV translated and replicated its genome with wild type kinetics, whereas encapsidation was blocked. On blind passages, encapsidation of the chimera was rescued by a single mutation either in capsid protein VP3 of CAV20 or in 2CATPase of PV. Whereas each of the single-mutation variants expressed severe proliferation phenotypes, engineering both mutations into the chimera yielded a virus encapsidating with wild type kinetics. Biochemical analyses provided strong evidence for a direct interaction between 2CATPase and VP3 of PV and CAV20. Chimeras of other C-CAVs (CAV20/CAV21 or CAV18/CAV20) were blocked in encapsidation (no virus after blind passages) but could be rescued if the capsid and 2CATPase coding regions originated from the same virus. Our novel mechanism explains the specificity of encapsidation without apparent involvement of an RNA signal by considering that (i) genome replication is known to be stringently linked to translation, (ii) morphogenesis is known to be stringently linked to genome replication, (iii) newly synthesized 2CATPase is an essential component of the replication complex, and (iv) 2CATPase has specific affinity to capsid protein(s). These conditions lead to morphogenesis at the site where newly synthesized genomes emerge from the replication complex