Investigational drugs for the treatment of AD: what can we learn from negative trials?

Given the level of interest and activity in the race to find a treatment for Alzheimer's disease, it is expected that a reasonably safe and effective drug will be identified within the next decade. It may be worthwhile to pause periodically during the course of this race to take stock of what we have learned. Over the past few years, a number of trials have been conducted with promising new compounds (including some with novel mechanisms of action) that failed to meet primary endpoints and so were discontinued from clinical development. This article reviews a set of molecules with a range of mechanisms that have been trialed but with negative results. This article also examines the reasons for the negative findings and summarizes some of what we have learned from these experiences

Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote

Objective: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) epsilon 2/epsilon 2 homozygote. Background: Apo epsilon 2/epsilon 2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE epsilon 2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo epsilon 2/epsilon 2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. Results: The clinical course is typical of AD, with progressive cognitive and functional decline. Conclusion: Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur. Copyright (C) 2010 S. Karger AG, Base

Reductive Decomposition of A Diazonium Intermediate by Dithiothreitol Affects The Determination of NOS Turnover Rates

Accurate determination of nitrite either as such or as the breakdown product of nitric oxide (NO) is critical in a host of enzymatic reactions in various settings addressing structure–function relationships, as well as mechanisms and kinetics of molecular operation of enzymes. The most common way to quantify nitrite, for instance in nitric oxide synthase (NOS) mechanistic investigations, is the spectrophotometric assay based on the Griess reaction through external standard calibration. This assay is based on a two-step diazotization reaction, in which a cationic diazonium derivative of sulfanilamide is formed as intermediate before the final absorbing azo-product. We show that this intermediate is very sensitive to reducing agents that may be transferred from the reaction media under investigation. The interaction of this vital intermediate with the reducing agent, dithiothreitol (DTT), which is widely used in NOS reactions, is characterized by both electrochemical and spectroscopic means. The effect of DTT on the performance of external calibration, both in sample recovery studies and in actual NOS reactions, is presented. Finally an alternative method of standard additions, which partially compensates for the accuracy and sensitivity problems of external calibration, is proposed and discussed

Increasing Precision of Clinical Diagnosis of Alzheimer\u27s Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data

Establishing the in vivo diagnosis of Alzheimer€™s disease (AD) or other dementias relies on clinical criteria; however, the accuracy of these criteria can be limited. The diagnostic accuracy is 77% for a clinical diagnosis of AD, even among experts. We performed a review through PubMed of articles related to specific diagnostic modalities, including APOE genotyping, cerebrospinal fluid (CSF) testing, fludeoxyglucose F 18 positron emission tomography (PET), amyloid PET, tau PET, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and B12 and thyroid-stimulating hormone screening, to determine the specificity and sensitivity of each test used in the clinical diagnosis of AD. We added a novel immunomagnetic reduction assay that provides ultrasensitivity for analyzing the levels of plasma tau and beta amyloid 42 (Aβ42). The sensitivity and specificity of the current diagnostic approach (structural CT or MRI with screening labs) remain low for clinical detection of AD and are primarily used to exclude other conditions. Because of limited diagnostic capabilities, physicians do not feel comfortable or skilled in rendering a clinical diagnosis of AD. Compounding this problem is the fact that inexpensive, minimally invasive diagnostic tests do not yet exist. Biomarkers (obtained through CSF testing or PET imaging), which are not routinely incorporated in clinical practice, correlate well with pathologic changes. While PET is particularly costly and difficult to assess, CSF measures of tau and beta amyloid are not costly, and these tests may be worthwhile when the tiered approach proposed here warrants further testing. There is a need for developing bloodborne biomarkers that can aid in the clinical diagnosis of AD. Here we present a streamlined questionnaire-enriched, biomarker-enriched approach that is more cost-effective than the current diagnosis of exclusion and is designed to increase clinical confidence for a diagnosis of dementia due to AD

Low disordered, stable, and shallow germanium quantum wells: a playground for spin and hybrid quantum technology

Buried-channel semiconductor heterostructures are an archetype material platform to fabricate gated semiconductor quantum devices. Sharp confinement potential is obtained by positioning the channel near the surface, however nearby surface states degrade the electrical properties of the starting material. In this paper we demonstrate a two-dimensional hole gas of high mobility ($5\times 10^{5}$ cm$^2$/Vs) in a very shallow strained germanium channel, which is located only 22 nm below the surface. This high mobility leads to mean free paths $\approx6 \mu m$, setting new benchmarks for holes in shallow FET devices. Carriers are confined in an undoped Ge/SiGe heterostructure with reduced background contamination, sharp interfaces, and high uniformity. The top-gate of a dopant-less field effect transistor controls the carrier density in the channel. The high mobility, along with a percolation density of $1.2\times 10^{11}\text{ cm}^{-2}$, light effective mass (0.09 m$_e$), and high g-factor (up to $7$) highlight the potential of undoped Ge/SiGe as a low-disorder material platform for hybrid quantum technologies

Three-month outcomes from a patient-centered program to treat opioid use disorder in Iowa, USA

Background: Opioid use disorder (OUD), a chronic disease, is a major public health problem. Despite availability of effective treatment, too few people receive it and treatment retention is low. Understanding barriers and facilitators of treatment access and retention is needed to improve outcomes for people with OUD. Objectives: To assess 3-month outcomes pilot data from a patient-centered OUD treatment program in Iowa, USA, that utilized flexible treatment requirements and prioritized engagement over compliance. Methods: Forty patients (62.5% female: mean age was 35.7 years, SD 9.5) receiving medication, either buprenorphine or naltrexone, to treat OUD were enrolled in an observational study. Patients could select or decline case management, counseling, and peer recovery groups. Substance use, risk and protective factors, and recovery capital were measured at intake and 3 months. Results: Most participants reported increased recovery capital. The median Assessment of Recovery Capital (ARC) score went from 37 at enrollment to 43 (p < 0.01). Illegal drug use decreased, with the median days using illegal drugs in the past month dropping from 10 to 0 (p < 0.001). Cravings improved: 29.2% reported no cravings at intake and 58.3% reported no cravings at 3 months (p < 0.001). Retention rate was 92.5% at 3 months. Retention rate for participants who were not on probation/parole was higher (96.9%) than for those on probation/parole (62.5%, p = 0.021). Conclusion: This study shows preliminary evidence that a care model based on easy and flexible access and strategies to improve treatment retention improves recovery capital, reduces illegal drug use and cravings, and retains people in treatment.Fil: Lynch, Alison C.. University of Iowa; Estados UnidosFil: Weber, Andrea N.. University of Iowa; Estados UnidosFil: Hedden, Suzy. University of Iowa; Estados UnidosFil: Sabbagh, Sayeh. University of Iowa; Estados UnidosFil: Arndt, Stephan. University of Iowa; Estados UnidosFil: Acion, Laura. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; Argentin

Ag-Functionalized CuWO₄/WO₃ nanocomposites for solar water splitting

Ag-Functionalized CuWO 4 /WO 3 heterostructures were successfully prepared via a polyvinyl pyrrolidone (PVP)-assisted sol-gel (PSG) route. Thin films prepared via electrophoretic deposition were used as photoanodes for photoelectrochemical (PEC) water splitting. Compared to pristine CuWO 4 and WO 3 films, a significant enhancement of the photocurrent (3-4 times) at the thermodynamic potential for oxygen evolution (0.62 V vs. Ag/AgCl, pH 7) was obtained for the Ag-functionalized CuWO 4 /WO 3 photoanodes. The obtained enhancement is shown to be derived from a synergic contribution of heterostructure formation (CuWO 4 /WO 3 ) and improvements of light utilization by Ag-induced surface plasmon resonance (SPR) effects. Accordingly, a photocurrent of 0.205 mA cm -2 at 0.62 V vs. Ag/AgCl under neutral conditions (without hole scavengers) under front-side simulated AM1.5G illumination was achieved. A detailed analysis of the obtained PEC data alongside performed impedance measurements suggests that charge seperation is significantly improved for the prepared Ag-functionalized CuWO 4 /WO 3 photoanodes. Our work offers beneficial insights to design new plasmonic metal/heterostructured nanocomposites for energy conversion applications

Synthesizing attractors of Hindmarsh-Rose neuronal systems

In this paper a periodic parameter switching scheme is applied to the Hindmarsh-Rose neuronal system to synthesize certain attractors. Results show numerically, via computer graphic simulations, that the obtained synthesized attractor belongs to the class of all admissible attractors for the Hindmarsh-Rose neuronal system and matches the averaged attractor obtained with the control parameter replaced with the averaged switched parameter values. This feature allows us to imagine that living beings are able to maintain vital behavior while the control parameter switches so that their dynamical behavior is suitable for the given environment.Comment: published in Nonlinear Dynamic