A Novel Implantable Glaucoma Valve Using Ferrofluid

Purpose To present a novel design of an implantable glaucoma valve based on ferrofluidic nanoparticles and to compare it with a well-established FDA approved valve. Setting: Massachusetts Eye & Ear Infirmary, Boston, USA. Methods: A glaucoma valve was designed using soft lithography techniques utilizing a water-immiscible magnetic fluid (ferrofluid) as a pressure-sensitive barrier to aqueous flow. Two rare earth micro magnets were used to calibrate the opening and closing pressure. In-vitro flow measurements were performed to characterize the valve and to compare it to Ahmed™ glaucoma valve. The reliability and predictability of the new valve was verified by pressure/flow measurements over a period of three months and X-ray diffraction (XRD) analysis over a period of eight weeks. In vivo assessment was performed in three rabbits. Results: In the in vitro experiments, the opening and closing pressures of the valve were 10 and 7 mmHg, respectively. The measured flow/pressure response was linearly proportional and reproducible over a period of three months (1.8 µl/min at 12 mmHg; 4.3 µl/min at 16 mmHg; 7.6 µl/min at 21 mmHg). X-ray diffraction analysis did not show oxidization of the ferrofluid when exposed to water or air. Preliminary in vivo results suggest that the valve is biocompatible and can control the intraocular pressure in rabbits. Conclusions: The proposed valve utilizes ferrofluid as passive, tunable constriction element to provide highly predictable opening and closing pressures while maintaining ocular tone. The ferrofluid maintained its magnetic properties in the aqueous environment and provided linear flow to pressure response. Our in-vitro tests showed reliable and reproducible results over a study period of three months. Preliminary in-vivo results were very promising and currently more thorough investigation of this device is underway

One-Pot Synthesis of Cationic Gold Nanoparticles by Differential Reduction

The size-controlled synthesis of cationic particles by differential reduction of HAuCl precursor in the presence of NaBH and 1-aminoundecane-12-thiol (AUT) is reported. The number of seed particles is determined by the fraction of the initially Au precursor reduced by NaBH present in the reaction mixture, which are then grown larger by the AUT, acting as both weak reducing agent and stabilizing surfactant. By this methodology, size controlled synthesis is achieved in a two-step one-pot synthesis at room temperature

Reduced bioavailability of Au and isotopically enriched ¹⁰⁹Ag nanoparticles transformed through a pilot wastewater treatment plant in Hyalella azteca under environmentally relevant exposure scenarios

Wastewater Treatment Plants (WWTP) are a major repository and entrance path of nanoparticles (NP) in the environment and hence play a major role in the final NP fate and toxicity. Studies on silver nanoparticles (AgNP) transport via the WWTP system and uptake by aquatic organisms have so far been carried out using unrealistically high AgNP concentrations, unlikely to be encountered in the aquatic environment. The use of high AgNP concentrations is necessitated by both the low sensitivity of the detection methods used and the need to distinguish background Ag from spiked AgNP. In this study, isotopically enriched 109AgNP were synthesized to overcome these shortcomings and characterized by a broad range of methods including transmission electron microscopy, dynamic and electrophoretic light scattering. 109AgNP and gold NP (AuNP) were spiked to a pilot wastewater treatment plant fed with municipal wastewater for up to 21 days. AuNP were used as chemically less reactive tracer. The uptake of the pristine and transformed NP present in the effluent was assessed using the benthic amphipod Hyalella azteca in fresh- and brackish water exposures at environmentally relevant concentrations of 30 to 500 ng Au/L and 39 to 260 ng Ag/L. The unique isotopic signature of the 109AgNP allowed to detect the material at environmentally relevant concentrations in the presence of a much higher natural Ag background. The results show that the transformations reduce the NP uptake at environmentally relevant exposure concentrations. For 109Ag, lower accumulation factors (AF) were obtained after exposure to transformed NP (250–350) compared to the AF values obtained for pristine 109AgNP (750–840). The reduced AF values observed for H. azteca exposed to effluent from the AuNP-spiked WWTP indicate that biological transformation processes (e.g. eco-corona formation) seem to be involved in addition to chemical transformation.publishedVersio

Microwave dielectric heating of non-aqueous droplets in a microfluidic device for nanoparticle synthesis

We describe a microfluidic device with an integrated microwave heater specifically designed to dielectrically heat non-aqueous droplets using time-varying electrical fields with the frequency range between 700 and 900 MHz. The precise control of frequency, power, temperature and duration of the applied field opens up new vistas for experiments not attainable by conventional microwave heating. We use a non-contact temperature measurement system based on fluorescence to directly determine the temperature inside a single droplet. The maximum temperature achieved of the droplets is 50 °C in 15 ms which represents an increase of about 25 °C above the base temperature of the continuous phase. In addition we use an infrared camera to monitor the thermal characteristics of the device allowing us to ensure that heating is exclusively due to the dielectric heating and not due to other effects like non-dielectric losses due to electrode or contact imperfection. This is crucial for illustrating the potential of dielectric heating of benzyl alcohol droplets for the synthesis of metal oxides. We demonstrate the utility of this technology for metal oxide nanoparticle synthesis, achieving crystallization of tungsten oxide nanoparticles and remarkable microstructure, with a reaction time of 64 ms, a substantial improvement over conventional heating methods.Engineering and Applied SciencesPhysic

High-Throughput Single-Cell Labeling (Hi-SCL) for RNA-Seq Using Drop-Based Microfluidics

The importance of single-cell level data is increasingly appreciated, and significant advances in this direction have been made in recent years. Common to these technologies is the need to physically segregate individual cells into containers, such as wells or chambers of a micro-fluidics chip. High-throughput Single-Cell Labeling (Hi-SCL) in drops is a novel method that uses drop-based libraries of oligonucleotide barcodes to index individual cells in a population. The use of drops as containers, and a microfluidics platform to manipulate them en-masse, yields a highly scalable methodological framework. Once tagged, labeled molecules from different cells may be mixed without losing the cell-of-origin information. Here we demonstrate an application of the method for generating RNA-sequencing data for multiple individual cells within a population. Barcoded oligonucleotides are used to prime cDNA synthesis within drops. Barcoded cDNAs are then combined and subjected to second generation sequencing. The data are deconvoluted based on the barcodes, yielding single-cell mRNA expression data. In a proof-of-concept set of experiments we show that this method yields data comparable to other existing methods, but with unique potential for assaying very large numbers of cells

Clinical and biomarker changes in dominantly inherited Alzheimer\u27s disease

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer\u27s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer\u27s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant\u27s age at baseline assessment and the parent\u27s age at the onset of symptoms of Alzheimer\u27s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent\u27s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ) 42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer\u27s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer\u27s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer\u27s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.

Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer\u27s disease

The relationship between body-mass index (BMI) and Alzheimeŕs disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time

Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated A beta compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by gamma-secretase and the generation of toxic beta-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression