Neurocognitive Disorders in Aging,by Daniel Kempler

No abstract available for this article.     

Vitamin D,folate, and potential early lifecycle environmental origin of significant adult phenotypes

Background and objectives: Vitamin D and folate are highly UV sensitive, and critical for maintaining health throughout the lifecycle. This study examines whether solar irradiance during the first trimester of pregnancy influences vitamin D receptor (VDR) and nuclear folate gene variant occurrence, and whether affected genes influence late-life biochemical/clinical phenotypes.Methodology: 228 subjects were examined for periconceptional exposure to solar irradiance, variation in vitamin D/folate genes (polymerase chain reaction (PCR)), dietary intake (food frequency questionnaire (FFQ)) and important adult biochemical/clinical phenotypes.Results: Periconceptional solar irradiance was associated with VDR-BsmI (P = 0.0008^wk7), TaqI (P = 0.0014^wk7) and EcoRV (P = 0.0030^wk6) variant occurrence between post-conceptional weeks 6–8, a period when ossification begins. Similar effects were detected for other VDR gene polymorphisms. Periconceptional solar irradiance was also associated with 19 bp del-DHFR (P = 0.0025^wk6), and to a lesser extent C1420T-SHMT (P = 0.0249^wk6), a folate-critical time during embryogenesis. These same genes were associated with several late-life phenotypes: VDR-BsmI, TaqI and ApaI determined the relationship between dietary vitamin D and both insulin (P < 0.0001/BB, 0.0007/tt and 0.0173/AA, respectively) and systolic blood pressure (P = 0.0290/Bb, 0.0299/Tt and 0.0412/AA, respectively), making them important early and late in the lifecycle. While these and other phenotype associations were found for the VDR variants, folate polymorphism associations in later-life were limited to C1420T-SHMT (P = 0.0037 and 0.0297 for fasting blood glucose and HbA1c levels, respectively). We additionally report nutrient–gene relationships with body mass index, thiol/folate metabolome, cognition, depression and hypertension. Furthermore, photoperiod at conception influenced occurrence of VDR-Tru9I and 2R3R-TS genotypes (P = 0.0120 and 0.0360, respectively).Conclusions and implications: Findings identify environmental and nutritional agents that may interact to modify gene–phenotype relationships across the lifecycle, offering new insight into human ecology. This includes factors related to both disease aetiology and the evolution of skin pigmentation.     

Dose-response relationship for radiation-induced mutations at micro- and minisatellite loci in human somatic cells in culture

Purpose : The study was designed to determine the dose-response relationship for radiation induction of mutations at mini- and microsatellite loci in human somatic cells. Mutations induced by graded doses of gamma-irradiation were quantified by screening clones derived from single irradiated cells for micro- and minisatellite alterations following irradiation with 1, 2 or 3 Gy. Materials and methods : After irradiation, the moderately radioresistant glioma cell line UVW was seeded at low density into Petri dishes to allow formation of discrete colonies, 100 of which were examined at each dose. All the cells within a colony were presumed to have arisen from a single irradiated cell. Radiation-induced microsatellite alterations were determined at 16 different loci, by PCR amplification and visualization on polyacrylamide gels. Minisatellite alterations were identified at four different minisatellite loci by restriction enzyme digestion and Southern blotting. Results : A dose-response curve for mutation frequency was obtained by analysis of 100 clones, yielding a minisatellite mutation rate of 5.5 X 10 -3 mutations/locus/Gy/cell and a microsatellite mutation rate of 8.75 X 10 -4 mutations/locus/Gy/cell. At microsatellite loci, alterations were predominantly simple loss or gain of repeat units and loss of heterozygosity (LOH). The mutations in minisatellite loci resulted predominantly in LOH and variation in repeat number. The background instability at each locus was determined by analysis of non-irradiated clones. Only 2% and 1% of the micro- and minisatellite loci respectively showed altered bands. Conclusions : This is the first report of a dose-response relationship for radiation-induced micro- and minisatellite mutations in human somatic cells. Described is a sensitive method for analysis of low-dose radiation mutagenesis in somatic cells that may prove to be a useful tool for radiation protection and dosimetry.     

Aged Residential Care Health Utilisation Study (ARCHUS): a randomised controlled trial to reduce acute hospitalisations from residential aged care

ABSTRACT: BACKGROUND: For residents of long term care, hospitalisations can cause distress and disruption, and often result in further medical complications. Multi-disciplinary team interventions have been shown to improve the health of Residential Aged Care (RAC) residents, decreasing the need for acute hospitalisation, yet there are few randomised controlled trials of these complex interventions. This paper describes a randomised controlled trial of a structured multi-disciplinary team and gerontology nurse specialist (GNS) intervention aiming to reduce residents' avoidable hospitalisations. METHODS: This Aged Residential Care Healthcare Utilisation Study (ARCHUS) is a cluster- randomised controlled trial (n = 1700 residents) of a complex multi-disciplinary team intervention in long-term care facilities. Eligible facilities certified for residential care were selected from those identified as at moderate or higher risk of resident potentially avoidable hospitalisations by statistical modelling. The facilities were all located in the Auckland region, New Zealand and were stratified by District Health Board (DHB).InterventionThe intervention provided a structured GNS intervention including a baseline facility needs assessment, quality indicator benchmarking, a staff education programme and care coordination. Alongside this, three multi-disciplinary team (MDT) meetings were held involving a geriatrician, facility GP, pharmacist, GNS and senior nursing staff.OutcomesHospitalisations are recorded from routinely-collected acute admissions during the 9-month intervention period followed by a 5-month follow-up period. ICD diagnosis codes are used in a pre-specified definition of potentially reducible admissions. DISCUSSION: This randomised-controlled trial will evaluate a complex intervention to increase early identification and intervention to improve the health of residents of long term care. The results of this trial are expected in early 2013.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN 12611000187943.     

Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses

Epitopes of the circumsporozoite (CS) protein of Plasmodium falciparum, the most pathogenic species of the malaria parasite, have been shown to elicit protective immunity in experimental animals and human volunteers. The mechanisms of immunity include parasite-neutralizing antibodies that can inhibit parasite motility in the skin at the site of infection and in the bloodstream during transit to the hepatocyte host cell and also block interaction with host cell receptors on hepatocytes. In addition, specific CD4+ and CD8+ cellular mechanisms target the intracellular hepatic forms, thus preventing release of erythrocytic stage parasites from the infected hepatocyte and the ensuing blood stage cycle responsible for clinical disease. An innovative method for producing particle vaccines, layer-by-layer (LbL) fabrication of polypeptide films on solid CaCO₃ cores, was used to produce synthetic malaria vaccines containing a tri-epitope CS peptide T1BT* comprising the antibody epitope of the CS repeat region (B) and two T-cell epitopes, the highly conserved T1 epitope and the universal epitope T*. Mice immunized with microparticles loaded with T1BT* peptide developed parasite-neutralizing antibodies and malaria-specific T-cell responses including cytotoxic effector T-cells. Protection from liver stage infection following challenge with live sporozoites from infected mosquitoes correlated with neutralizing antibody levels. Although some immunized mice with low or undetectable neutralizing antibodies were also protected, depletion of T-cells prior to challenge resulted in the majority of mice remaining resistant to challenge. In addition, mice immunized with microparticles bearing only T-cell epitopes were not protected, demonstrating that cellular immunity alone was not sufficient for protective immunity. Although the microparticles without adjuvant were immunogenic and protective, a simple modification with the lipopeptide TLR2 agonist Pam₃Cys increased the potency and efficacy of the LbL vaccine candidate. This study demonstrates the potential of LbL particles as promising malaria vaccine candidates using the T1BT* epitopes from the P. falciparum CS protein.     

The Effect of Residential Aged Care Size,Ownership Model,and Multichain Affiliation on Resident Comfort and Symptom Management at the End of Life

Context

In most resource-rich countries, a large and growing proportion of older adults with complex needs will die while in a residential aged care (RAC) facility.