Study protocol of the multi-site randomised controlled REDALI-DEM trial - The effects of structured Relearning methods on Daily Living task performance of persons with Dementia

<p>Abstract</p> <p>Background</p> <p>Evidence from pilot trials suggests that structured learning techniques may have positive effects on the performance of cognitive tasks, movement sequences or skills in patients with Alzheimer's disease. The purpose of this trial is to evaluate whether the usual method of learning by trial and error or the method of errorless learning demonstrate better effects on the performance of two selected daily living tasks six weeks after the intervention in people with mild to moderate dementia.</p> <p>Methods/Design</p> <p>A seven-centre single-blind, active-controlled design with a 1:1 randomisation for two parallel groups will include 175 persons diagnosed with Alzheimer's disease or mixed type dementia (MMSE 14-24), living at home, showing at least moderate need for assistance in instrumental activities of daily living; primary carer available and informed consent of patient and primary carer. Patients of both study arms will receive 15 one-hour-sessions at home by trained interventionists practising two daily living tasks individually selected. In one group the trial and error technique and in the other group the errorless learning method will be applied. Primary outcome is the task performance measured with the Task Performance Scale six weeks post treatment.</p> <p>Discussion</p> <p>The trial results will inform us to improve guidelines for instructing individuals with memory impairments. A user-friendly practice guideline will allow an efficient implementation of structured relearning techniques for a wide range of service providers in dementia care.</p> <p>Trial registration</p> <p>DRKS00003117</p

Cross-Sectional Dating of Novel Haplotypes of HERV-K 113 and HERV-K 115 Indicate These Proviruses Originated in Africa before Homo sapiens

The human genome, human endogenous retroviruses (HERV), of which HERV-K113 and HERV-K115 are the only known full-length proviruses that are insertionally polymorphic. Although a handful of previously published papers have documented their prevalence in the global population; to date, there has been no report on their prevalence in the United States population. Here, we studied the geographic distribution of K113 and K115 among 156 HIV-1+ subjects from the United States, including African Americans, Hispanics, and Caucasians. In the individuals studied, we found higher insertion frequencies of K113 (21%) and K115 (35%) in African Americans compared with Caucasians (K113 9% and K115 6%) within the United States. We also report the presence of three single nucleotide polymorphism sites in the K113 5′ long terminal repeats (LTRs) and four in the K115 5′ LTR that together constituted four haplotypes for K113 and five haplotypes for K115. HERV insertion times can be estimated from the sequence differences between the 5′ and 3′ LTR of each insertion, but this dating method cannot be used with HERV-K115. We developed a method to estimate insertion times by applying coalescent inference to 5′ LTR sequences within our study population and validated this approach using an independent estimate derived from the genetic distance between K113 5′ and 3′ LTR sequences. Using our method, we estimated the insertion dates of K113 and K115 to be a minimum of 800,000 and 1.1 million years ago, respectively. Both these insertion dates predate the emergence of anatomically modern Homo sapiens

Microarray-Based Sketches of the HERV Transcriptome Landscape

Human endogenous retroviruses (HERVs) are spread throughout the genome and their long terminal repeats (LTRs) constitute a wide collection of putative regulatory sequences. Phylogenetic similarities and the profusion of integration sites, two inherent characteristics of transposable elements, make it difficult to study individual locus expression in a large-scale approach, and historically apart from some placental and testis-regulated elements, it was generally accepted that HERVs are silent due to epigenetic control. Herein, we have introduced a generic method aiming to optimally characterize individual loci associated with 25-mer probes by minimizing cross-hybridization risks. We therefore set up a microarray dedicated to a collection of 5,573 HERVs that can reasonably be assigned to a unique genomic position. We obtained a first view of the HERV transcriptome by using a composite panel of 40 normal and 39 tumor samples. The experiment showed that almost one third of the HERV repertoire is indeed transcribed. The HERV transcriptome follows tropism rules, is sensitive to the state of differentiation and, unexpectedly, seems not to correlate with the age of the HERV families. The probeset definition within the U3 and U5 regions was used to assign a function to some LTRs (i.e. promoter or polyA) and revealed that (i) autonomous active LTRs are broadly subjected to operational determinism (ii) the cellular gene density is substantially higher in the surrounding environment of active LTRs compared to silent LTRs and (iii) the configuration of neighboring cellular genes differs between active and silent LTRs, showing an approximately 8 kb zone upstream of promoter LTRs characterized by a drastic reduction in sense cellular genes. These gathered observations are discussed in terms of virus/host adaptive strategies, and together with the methods and tools developed for this purpose, this work paves the way for further HERV transcriptome projects

Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Env and other proteins are encoded by some transcriptionally active HML-2 loci. However, more detailed information is required regarding which HML-2 loci are transcribed in ALS, which of their proteins are expressed, and differences between the disease and non-disease states. Methods For brain and spinal cord tissue samples from ALS patients and controls, we identified transcribed HML-2 loci by generating and mapping HML-2-specific cDNA sequences. We predicted expression of HML-2 env gene-derived proteins based on the observed cDNA sequences. Furthermore, we determined overall HML-2 transcript levels by RT-qPCR and investigated presence of HML-2 Env protein in ALS and control tissue samples by Western blotting. Results We identified 24 different transcribed HML-2 loci. Some of those loci are transcribed at relatively high levels. However, significant differences in HML-2 loci transcriptional activities were not seen when comparing ALS and controls. Likewise, overall HML-2 transcript levels, as determined by RT-qPCR, were not significantly different between ALS and controls. Indeed, we were unable to detect full-length HML-2 Env protein in ALS and control tissue samples despite reasonable sensitivity. Rather our analyses suggest that a number of HML-2 protein variants other than full-length Env may potentially be expressed in ALS patients. Conclusions Our results expand and refine recent publications on HERV-K(HML-2) and ALS. Some of our results are in conflict with recent findings and call for further specific analyses. Our profiling of HML-2 transcription in ALS opens up the possibility that HML-2 proteins other than canonical full-length Env may have to be considered when studying the role of HML-2 in ALS disease

Effects of restricted feeding on physiological stress parameters in growing broiler breeders

In previous studies, a lack of agreement in measurements of plasma corticosterone concentrations and heterophil:lymphocyte (H/L) ratio as physiological indices of stress, caused by hunger and frustration in restricted-fed broiler breeders, was observed. It could be suggested that the differences between previous studies were caused by differences in duration of restriction and time of the day of the measurements. Therefore, in the present study the plasma corticosterone concentration and the H/L ratio were again determined in restricted- and ad libitum-fed growing broiler breeders, taking possible causes of disagreement between previous studies into account. In addition, we measured the daily rhythm in body temperature and heart rate, and the corticosterone responses to an acute stressor as physiological indices of stress. 2. Female broiler breeders (64 per treatment, housed in groups of 4 birds) were used in the experiment. Behaviour, baseline plasma corticosterone concentrations and H/L ratio were determined at 21 d of age (immediately after the start of food restriction), and at 42 and 63 d of age. Body temperature, heart rate and activity were measured by radiotelemetry for 36 h at 49 and 70 d of age. In addition, the plasma corticosterone response to acute stress (5 min manual restraint) was measured at 77 or 78 d of age. 3. Restricted broiler breeders had higher plasma corticosterone concentrations at 42 and 63 d of age, but no differences in H/L ratio were found between restricted birds and unrestricted control birds. Restricted broiler breeders had a higher corticosterone response to 5 min manual restraint than unrestricted birds. Restricted birds displayed a clear day-night rhythm in body temperature, heart rate and activity whereas such a rhythm was blunted in ad libitum-fed birds. 4. It is discussed that some physiological differences (plasma corticosterone concentrations, body temperature and heart rate) between ad libitum-fed and restricted broiler breeders may have been caused by differences in metabolic rate as well as by differences in the level of stress.

Effects of restricted feeding on physiological stress parameters in growing broiler breeders

In previous studies, a lack of agreement in measurements of plasma corticosterone concentrations and heterophil:lymphocyte (H/L) ratio as physiological indices of stress, caused by hunger and frustration in restricted-fed broiler breeders, was observed. It could be suggested that the differences between previous studies were caused by differences in duration of restriction and time of the day of the measurements. Therefore, in the present study the plasma corticosterone concentration and the H/L ratio were again determined in restricted- and ad libitum-fed growing broiler breeders, taking possible causes of disagreement between previous studies into account. In addition, we measured the daily rhythm in body temperature and heart rate, and the corticosterone responses to an acute stressor as physiological indices of stress. 2. Female broiler breeders (64 per treatment, housed in groups of 4 birds) were used in the experiment. Behaviour, baseline plasma corticosterone concentrations and H/L ratio were determined at 21 d of age (immediately after the start of food restriction), and at 42 and 63 d of age. Body temperature, heart rate and activity were measured by radiotelemetry for 36 h at 49 and 70 d of age. In addition, the plasma corticosterone response to acute stress (5 min manual restraint) was measured at 77 or 78 d of age. 3. Restricted broiler breeders had higher plasma corticosterone concentrations at 42 and 63 d of age, but no differences in H/L ratio were found between restricted birds and unrestricted control birds. Restricted broiler breeders had a higher corticosterone response to 5 min manual restraint than unrestricted birds. Restricted birds displayed a clear day-night rhythm in body temperature, heart rate and activity whereas such a rhythm was blunted in ad libitum-fed birds. 4. It is discussed that some physiological differences (plasma corticosterone concentrations, body temperature and heart rate) between ad libitum-fed and restricted broiler breeders may have been caused by differences in metabolic rate as well as by differences in the level of stress.