comments and reactions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68187/2/10.1177_074171365500600102.pd

Noninvasive stress testing of myocardial perfusion defects: head-to-head comparison of thallium-201 SPECT to MRI perfusion

Background: To evaluate the diagnostic value of magnetic resonance imaging (MRI) of myocardial perfusion in the assessment of flow-limiting epicardial stenosis in a head-to-head comparison with abnormal thallium-201 (201TI) single photon emission tomography (SPECT) studies in patients with predominantly known coronary artery disease (CAD). Methods and Results: Twenty-one patients (mean age 65±10years) with reversible myocardial perfusion defects on 201TI-SPECT images during dipyridamole-stimulated hyperemia were recruited for study purpose. Within 5days of the 201TI-SPECT study, myocardial perfusion was studied again with MRI during dipyridamole stimulation and at rest. Overall, 201TI-SPECT identified 30 reversible regional perfusion defects. The sensitivity to detect hypoperfused segments was 70% (21/30) with the GRE-MRI perfusion analysis with 201TI-SPECT as reference. When patients were subgrouped according to the extent of regional reversible perfusion defects on 201TI-SPECT, mild- (SDS: 2-4), moderate- (SDS: 5-8), and severe- (SDS>8) perfusion defects were also identified by GRE-MRI perfusion analysis in 75% (6/8), in 56% (9/16) and 100% (6/6), respectively. Conclusions: GRE-MRI first-pass stress perfusion imaging may not identify up to 30% of mild-to-moderate perfusion defects in a group of preselected patients with predominantly known CAD and abnormal 201TI-SPECT studie

First passage time statistics of Brownian motion with purely time dependent drift and diffusion

Systems where resource availability approaches a critical threshold are common to many engineering and scientific applications and often necessitate the estimation of first passage time statistics of a Brownian motion (Bm) driven by time-dependent drift and diffusion coefficients. Modeling such systems requires solving the associated Fokker-Planck equation subject to an absorbing barrier. Transitional probabilities are derived via the method of images, whose applicability to time dependent problems is shown to be limited to state-independent drift and diffusion coefficients that only depend on time and are proportional to each other. First passage time statistics, such as the survival probabilities and first passage time densities are obtained analytically. The analysis includes the study of different functional forms of the time dependent drift and diffusion, including power-law time dependence and different periodic drivers. As a case study of these theoretical results, a stochastic model for water availability from surface runoff in snowmelt dominated regions is presented, where both temperature effects and snow-precipitation input are incorporated

A preliminary investigation of norms and relationships for the Stern Fixation Test in the elementary school population

The Stern Fixation Test was investigated for its usefulness as a screening test for detecting visual problems associated with reading. Preliminary norms were established based on age and reading level, significant relationships between these norms and subject reading level for certain groups were found, and correlations between Stern Fixation Teat scores and the 21-point examination were found to be of low order. While the Stern Fixation Test cannot be expected to screen for all visual factors involved in reading, it can serve as a useful screening tool for many visual factors related to reading difficulties

Expressing the human proteome for affinity proteomics: optimising expression of soluble protein domains and in vivo biotinylation

The generation of affinity reagents to large numbers of human proteins depends on the ability to express the target proteins as high-quality antigens. The Structural Genomics Consortium (SGC) focuses on the production and structure determination of human proteins. In a 7-year period, the SGC has deposited crystal structures of >800 human protein domains, and has additionally expressed and purified a similar number of protein domains that have not yet been crystallised. The targets include a diversity of protein domains, with an attempt to provide high coverage of protein families. The family approach provides an excellent basis for characterising the selectivity of affinity reagents. We present a summary of the approaches used to generate purified human proteins or protein domains, a test case demonstrating the ability to rapidly generate new proteins, and an optimisation study on the modification of >70 proteins by biotinylation in vivo. These results provide a unique synergy between large-scale structural projects and the recent efforts to produce a wide coverage of affinity reagents to the human proteome

Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys

Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu- CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000- fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/ injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted.This research was supported in part by the Intramural Research Program of the NIH, National Institute on Drug Abuse

CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer\u27s disease

Aggregated insoluble tau is one of two defining features of Alzheimer\u27s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ 

Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection

SummarySexual intercourse is the major route of HIV transmission. To identify endogenous factors that affect the efficiency of sexual viral transmission, we screened a complex peptide/protein library derived from human semen. We show that naturally occurring fragments of the abundant semen marker prostatic acidic phosphatase (PAP) form amyloid fibrils. These fibrils, termed Semen-derived Enhancer of Virus Infection (SEVI), capture HIV virions and promote their attachment to target cells, thereby enhancing the infectious virus titer by several orders of magnitude. Physiological concentrations of SEVI amplified HIV infection of T cells, macrophages, ex vivo human tonsillar tissues, and transgenic rats in vivo, as well as trans-HIV infection of T cells by dendritic or epithelial cells. Amyloidogenic PAP fragments are abundant in seminal fluid and boost semen-mediated enhancement of HIV infection. Thus, they may play an important role in sexual transmission of HIV and could represent new targets for its prevention

Hard x-ray optics for the HEFT balloon-borne payload: prototype design and status

We report on the current status and performance of prototype hard x-ray optics we are producing for use on the high energy focusing telescope (HEFT) experiment. The baseline substrates are thermally formed glass mirrors that are overcoated with multilayers to provide good performance throughout the 20-80 keV bandpass. Progress made in the thermal forming process as well as in the multilayer performance has allowed production of optics that meet or exceed all HEFT requirements. We present metrology on the substrates and result from x-ray characterization. A novel mounting scheme for the individual telescope shells is currently being tested. If successful the mounting technique will produce a monolithic, extremely stiff and robust optic