The Relationship Between Grain Hardness, Dough Mixing Parameters and Bread-Making Quality in Winter Wheat

The influence of grain hardness, determined by using molecular markers and physical methods (near-infrared (NIR) technique and particle size index—PSI) on dough characteristics, which in turn were determined with the use of a farinograph and reomixer, as well as bread-making properties were studied. The material covered 24 winter wheat genotypes differing in grain hardness. The field experiment was conducted at standard and increased levels of nitrogen fertilization. Results of molecular analyses were in agreement with those obtained by the use of physical methods for soft-grained lines. Some lines classified as hard (by physical methods) appeared to have the wild-type Pina and Pinb alleles, similar to soft lines. Differences in dough and bread-making properties between lines classified as hard and soft on the basis of molecular data appeared to be of less significance than the differences between lines classified as hard and soft on the basis of physical analyses of grain texture. Values of relative grain hardness at the increased nitrogen fertilization level were significantly higher. At both fertilization levels the NIR parameter determining grain hardness was significantly positively correlated with the wet gluten and sedimentation values, with most of the rheological parameters and bread yield. Values of this parameter correlated with quality characteristics in a higher degree than values of particle size index

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients

Alloimmunisation to Donor Antigens and Immune Rejection Following Foetal Neural Grafts to the Brain in Patients with Huntington's Disease

BACKGROUND: The brain is deemed “immunologically privileged” due to sparse professional antigen-presenting cells and lymphatic drainage, and to the blood-brain barrier. Although the actual extent of this privilege is controversial, there is general consensus about the limited need in intracerebral neural grafts for immunosuppressive regimens comparable to those used in other cases of allotransplantation. This has led over the past fifteen years to the use of either short-term or even no immunosuppression in most clinical trials with foetal neural transplant in patients with Parkinson's and Huntington's disease. METHODOLOGY/PRINCIPAL FINDINGS: We report biological demonstration of alloimmunisation without signs of rejection in four grafted patients out of 13 studied during the course of a clinical trial involving fetal neural transplantation in patients with Huntington's Disease. Biological, radiological and clinical demonstration of an ongoing rejection process was observed in a fifth transplanted patient. The rejection process was, however, fully reversible under immunosuppressive treatment and graft activity recovered within six months. CONCLUSIONS/SIGNIFICANCE: There had been, up to date, no report of documented cases that could have cast a doubt on those procedures. Our results underline the need for a reconsideration of the extent of the so-called immune privilege of the brain and of the follow-up protocols of patients with intracerebral grafts. It also suggests that some of the results obtained in past studies with foetal neural transplants may have been biased by an unrecognized immune response to donor cells

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington\u27s disease. METHODS: Ninety-six patients with early-stage Huntington\u27s disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington\u27s disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society

Human Mesenchymal Stem Cells Prolong Survival and Ameliorate Motor Deficit through Trophic Support in Huntington's Disease Mouse Models

We investigated the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in Huntington's disease (HD) mouse models. Ten weeks after intrastriatal injection of quinolinic acid (QA), mice that received hBM-MSC transplantation showed a significant reduction in motor function impairment and increased survival rate. Transplanted hBM-MSCs were capable of survival, and inducing neural proliferation and differentiation in the QA-lesioned striatum. In addition, the transplanted hBM-MSCs induced microglia, neuroblasts and bone marrow-derived cells to migrate into the QA-lesioned region. Similar results were obtained in R6/2-J2, a genetically-modified animal model of HD, except for the improvement of motor function. After hBM-MSC transplantation, the transplanted hBM-MSCs may integrate with the host cells and increase the levels of laminin, Von Willebrand Factor (VWF), stromal cell-derived factor-1 (SDF-1), and the SDF-1 receptor Cxcr4. The p-Erk1/2 expression was increased while Bax and caspase-3 levels were decreased after hBM-MSC transplantation suggesting that the reduced level of apoptosis after hBM-MSC transplantation was of benefit to the QA-lesioned mice. Our data suggest that hBM-MSCs have neural differentiation improvement potential, neurotrophic support capability and an anti-apoptotic effect, and may be a feasible candidate for HD therapy

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation