Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years

BACKGROUND: Rivastigmine, a butyl- and acetylcholinesterase inhibitor, is approved for symptomatic treatment of Alzheimer's disease (AD). Data supporting the safety and efficacy of second-generation cholinesterase inhibitors, such as rivastigmine, are available for treatment up to 1 year, with limited data up to 2 1/2 years. The purpose of this report is to present safety and effectiveness data for rivastigmine therapy in patients with mild to moderately severe AD receiving treatment for up to 5 years. METHODS: An observational approach was used to study 37 patients with originally mild to moderate AD receiving rivastigmine as a therapy for AD in an open-label extension (ENA713, B352 Study Group, 1998). RESULTS: The initial trial demonstrated rivastigmine was well-tolerated and effective in terms of cognition, global functioning and activities of daily living. In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period. Two thirds of the participants still enrolled at week 234 were in the original high-dose rivastigmine group during the double-blind phase, suggesting that early therapy may confer some benefit in delaying long-term progression of symptoms. CONCLUSIONS: Long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period. Early initiation of treatment, with titration to high-dose therapy, may have an advantage in delaying progression of the illness

Neither bones nor feet: track morphological variation and “preservation quality”

As purely sedimentary structures, fossil footprints are all about shape. Correctly interpreting the significance of their surface topography requires understanding the sources of morphological variation. Differences among specimens are most frequently attributed to either taxonomy (trackmaker) or to preservation quality. “Well-preserved” tracks are judged more similar to pedal anatomy than “poorly preserved” ones, but such broad-brush characterizations confound two separate episodes in a track’s history. Current evaluations of track quality fail to distinguish among behavioral, formational, intravolumetric, and post-formational sources of variation. Based on analogy with body fossils, we recommend restricting assessments of track preservation quality to modifications that take place only after a track is created. Ichnologists need to try to parse the relative influence of factors affecting disparity, but we currently lack an adequate vocabulary to describe the overall shapes and specific features of formational variants

A survey of partial differential equations in geometric design

YesComputer aided geometric design is an area where the improvement of surface generation techniques is an everlasting demand since faster and more accurate geometric models are required. Traditional methods for generating surfaces were initially mainly based upon interpolation algorithms. Recently, partial differential equations (PDE) were introduced as a valuable tool for geometric modelling since they offer a number of features from which these areas can benefit. This work summarises the uses given to PDE surfaces as a surface generation technique togethe

Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

BACKGROUND: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. METHODS: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. RESULTS: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. CONCLUSIONS: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. FUNDING: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer's Association (SG-20-690363-DIAN)

Characterization method of dielectric properties of free falling drops in a microwave processing cavity and its application in microwave internal gelation

[EN] Microwave internal gelation (MIG) is a chemical process proposed for the production of nuclear particle fuel. The internal gelation reaction is triggered by a temperature increase of aqueous droplets falling by gravity by means of non-contact microwave heating. Due to the short residence time of a solution droplet in a microwave heating cavity, a detailed knowledge of the interaction between microwaves and chemical solution (shaped in small drops) is required. This paper describes a procedure that enables the measurement of the dielectric properties of aqueous droplets that freely fall through a microwave cavity. These measurements provide the information to determine the optimal values of the parameters (such as frequency and power) that dictate the heating of such a material under microwaves.This work is a part of the PINE (Platform for Innovative Nuclear FuEls) project which targets the development of an advanced production method for Sphere-Pac fuel and is financed by the Swiss Competence Center for Energy and Mobility. The work has been also financed by the European Commission through contract no 295664 regarding the FP7 PELGRIMM Project, as well as contract no 295825 regarding the FP7-ASGARD Project. MC-S would like to thank the ITACA research team (UPV Valencia, Spain) and the EMPA Thun (Switzerland) for their support in the measurements and Carl Beard (PSI, Switzerland) for the help provided in respect with CST simulations. The work of FLP-F was supported by the Conselleria d'Educacio of the Generalitat Valenciana for economic support (BEST/2012/010).Cabanes Sempere, M.; Catalá Civera, JM.; Penaranda-Foix, FL.; Cozzo, C.; Vaucher, S.; Pouchon, MA. (2013). Characterization method of dielectric properties of free falling drops in a microwave processing cavity and its application in microwave internal gelation. Measurement Science and Technology. 24(9). https://doi.org/10.1088/0957-0233/24/9/095009S24

AluY-mediated germline deletion, duplication and somatic stem cell reversion in <i>UBE2T</i> defines a new subtype of Fanconi anemia

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.</p

Nonsense-Mediated Decay Enables Intron Gain in Drosophila

Intron number varies considerably among genomes, but despite their fundamental importance, the mutational mechanisms and evolutionary processes underlying the expansion of intron number remain unknown. Here we show that Drosophila, in contrast to most eukaryotic lineages, is still undergoing a dramatic rate of intron gain. These novel introns carry significantly weaker splice sites that may impede their identification by the spliceosome. Novel introns are more likely to encode a premature termination codon (PTC), indicating that nonsense-mediated decay (NMD) functions as a backup for weak splicing of new introns. Our data suggest that new introns originate when genomic insertions with weak splice sites are hidden from selection by NMD. This mechanism reduces the sequence requirement imposed on novel introns and implies that the capacity of the spliceosome to recognize weak splice sites was a prerequisite for intron gain during eukaryotic evolution

Impact of physical activity on activity of daily living in moderate to severe dementia: a critical review

The objectives of this study were to describe the different modalities of physical activity programs designed for moderate to severe dementia and to identify their impact on functional independence in activities of daily living (ADL). A critical review of randomized controlled trials related to the impact of physical activity programs in moderately to severely demented persons on ADL performance and meta-analysis of the identified studies were performed. Among the 303 identified articles, five responded to the selection criteria. Four out of the five studies demonstrated limited methodological quality. In one high-quality study, physical activity programs significantly delayed deterioration of ADL performance. The program components and ADL assessment tools vary widely across studies. Although the proposed treatments have not proven their efficiency in improving the ADL status of the patients, they were able to limit the decline in ADL functioning. Future research is warranted in order to identify clinically relevant modalities for physical activity programs for people with moderate to severe dementia