Evaluating Response to High-Dose 13.3 mg/24 h Rivastigmine Patch in Patients with Severe Alzheimer's Disease

AIMS: To identify factors predicting improvement/stabilization on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and investigate whether early treatment responses can predict long-term outcomes, during a trial of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Logistic regression was used to relate Week 24 ADCS-CGIC score to potential baseline predictors. Additional analyses based on receiver-operating characteristic curves were performed using Week 8/16 ADCS-CGIC scores to predict response (13.3 mg/24 h patch) at Week 24. ADCS-CGIC score of (1) 1-3 = "improvement," (2) 1-4 = "improvement or no change". RESULTS: "Treatment" (13.3 mg/24 h patch) and increased age were significant predictors of "improvement" (P = 0.01 and P = 0.003, respectively), and "treatment" (P = 0.001), increased age (P = 0.002), and prior AD treatment (P = 0.03) for "improvement or no change". At Week 8 and 16, ADCS-CGIC scores of 4 and 5 were optimal thresholds in predicting "improvement," and "improvement or no change," respectively, at Week 24. CONCLUSIONS: A significant therapeutic effect of high-dose rivastigmine patch on ADCS-CGIC response was observed. The 13.3 mg/24 h patch was identified as a predictor of "improvement" or "improvement or no change". Patients with minimal worsening/improvement/no change after treatment initiation may be more likely to respond following long-term therapy

Mount St. Helens aerosol evolution

Stratospheric aerosol samples were collected using a wire impactor during the year following the eruption of Mount St. Helens. Analysis of samples shows that aerosol volume increased for 6 months due to gas-to-particle conversion and then decreased to background levels in the following 6 months

Evaluating High-Dose Rivastigmine Patch in Severe Alzheimer’s Disease: Analyses with Concomitant Memantine Usage as a Factor

Background: ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer’s disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale–Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. Methods: Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. Results: Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. Conclusion: These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (−4.6; SD=8.7) and SIB (−7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (−3.9; SD=8.0 and −4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch

The Role of Choroid Plexus In IVIG-induced Beta-Amyloid Clearance

We have shown that intravenous immunoglobulin (IVIG) contains anti-Aβ autoantibodies and IVIG could induce beta amyloid (Aβ) efflux from cerebrospinal fluid (CSF) to blood in both Multiple Sclerosis (MS) and Alzheimer disease (AD) patients. However, the molecular mechanism underlying IVIG-induced Aβ efflux remains unclear. In this study, we used amyloid precursor protein (AβPP) transgenic mice to investigate if the IVIG could induce efflux of Aβ from the brain and whether low-density lipoprotein receptor-related protein-1 (LRP1), a hypothetic Aβ transporter in blood-cerebrospinal fluid barrier (BCB); could mediate this clearance process. We currently provide strong evidence to demonstrate that IVIG could reduce brain Aβ levels by pulling Aβ into the blood system in AβPP transgenic mice. In the mechanistic study, IVIG could induce Aβ efflux through the in-vitro BCB membrane formed by cultured BCB epithelial cells. Both RAP (receptor-associated protein; a functional inhibitor of LRP1), and LRP1 siRNA were able to significantly inhibit the Aβ efflux. Should Aβ prove to be the underlying cause of AD, our results strongly suggest that IVIG could be beneficial in the therapy for Alzheimer's disease (AD) by inducing efflux of Aβ from the brain through the LRP1 in the BCB

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

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

Spatial repellents: from discovery and development to evidence based validation

International public health workers are challenged by a burden of arthropod-borne disease that remains elevated despite best efforts in control programmes. With this challenge comes the opportunity to develop novel vector control paradigms to guide product development and programme implementation. The role of vector behaviour modification in disease control was first highlighted several decades ago but has received limited attention within the public health community. This paper presents current evidence highlighting the value of sub-lethal agents, specifically spatial repellents, and their use in global health, and identifies the primary challenges towards establishing a clearly defined and recommended role for spatial repellent products in disease control

Intra-guild competition and its implications for one of the biggest terrestrial predators, Tyrannosaurus rex

Identifying tradeoffs between hunting and scavenging in an ecological context is important for understanding predatory guilds. In the past century, the feeding strategy of one of the largest and best-known terrestrial carnivores, Tyrannosaurus rex, has been the subject of much debate: was it an active predator or an obligate scavenger? Here we look at the feasibility of an adult T. rex being an obligate scavenger in the environmental conditions of Late Cretaceous North America, given the size distributions of sympatric herbivorous dinosaurs and likely competition with more abundant small-bodied theropods. We predict that nearly 50 per cent of herbivores would have been within a 55–85 kg range, and calculate based on expected encounter rates that carcasses from these individuals would have been quickly consumed by smaller theropods. Larger carcasses would have been very rare and heavily competed for, making them an unreliable food source. The potential carcass search rates of smaller theropods are predicted to be 14–60 times that of an adult T. rex. Our results suggest that T. rex and other extremely large carnivorous dinosaurs would have been unable to compete as obligate scavengers and would have primarily hunted large vertebrate prey, similar to many large mammalian carnivores in modern-day ecosystems

DINOSAUR FOOTPRINTS FROM THE GLEN ROSE FORMATION (PALUXY RIVER, DINOSAUR VALLEY STATE PARK, SOMERVELL COUNTY, TEXAS)

Dinosaur footprints are found in the Glen Rose Formation and other Lower Cretaceous stratigraphic units over much of central Texas (Pittman, 1989; Rogers, 2002; Farlow et al., 2006). Dinosaur tracks were discovered in the rocky bed of the Paluxy River, near the town of Glen Rose, Texas, early in the 20th Century (Jasinski, 2008; Farlow et al., 2012b). Ellis W. Shuler of Southern Methodist University did pioneering studies on the dinosaur tracks (Shuler 1917, 1935, 1937), and Langston (1974) summarized much of the early literature. What really put the dinosaur footprints of the Paluxy River on the map, though, were the herculean efforts that Roland T. Bird of the American Museum of Natural History made to secure trackway slabs for display at that institution and at the Texas Memorial Museum in Austin (Bird, 1985; Jasinski, 2008). In 1970 Dinosaur Valley State Park was created to protect the dinosaur footprints. This guidebook briefly summarizes earlier work, and also serves as an interim report of research of our group still in progress, concerned with identifying the makers of the Paluxy River footprints, and determining what those animals were up to as they made their tracks. We will offer some comparisons of the dinosaur tracks of the Glen Rose Formation with those from other ichnofaunas around the world. The last quarter-century has seen an explosive increase in the technical literature dealing with dinosaur footprints, and we cannot possibly cite all of the relevant studies. For the sake of brevity we will emphasize publications from the present century, and summary papers and books, as much as possible. Even with this restriction, however, the literature is so vast that the literature-cited “tail” of this report starts to wag the “dog” of the text