The effect of bleach duration and age on the ERG photostress test

Background: The ERG photostress test assesses the recovery of the focal 41 Hz ERG following exposure to a bright light that bleaches a significant proportion of photopigment. The aims of this study were: 1) to compare the repeatability of the ERG photostress test recovery time constant following long and short duration light exposure, and 2) to determine the effect of age on the ERG photostress test recovery time constant. Methods: Focal 41 Hz ERGs were recorded from 23 participants (age range 20–71 years) at 20-second intervals for 5 minutes following either a short-duration (photoflash) or long-duration (equilibrium) light exposure. After a 5-minute wash-out period, the procedure was repeated using the second bleach modality. The time constant of cone recovery was determined by fitting an exponential model to the amplitude recovery data. The whole procedure was repeated on a second occasion. The co-efficient of repeatability (CoR) was calculated for each bleaching technique. The relationship between the time constant of recovery and age was investigated (Pearson’s correlation coefficient). Results: The time constant of recovery following an equilibrium bleach was more repeatable than recovery following a photoflash (CoR = 85s and 184s respectively). Eight trials (from seven participants) failed to show a reduction in amplitude following the photoflash, suggesting that a blink or fixation loss had occurred. All participants were reliably light-adapted by the equilibrium bleach. For the equilibrium bleach data, the time constant of recovery increased with age at a rate of 27 seconds per decade. Conclusions: The equilibrium bleach was more reliable and repeatable than the photoflash. Increasing participant age was shown to result in a lengthening of the recovery time constant, of a magnitude comparable to previously published psychophysical data

Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis

Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis

Therapeutic effects of guggul and its constituent guggulsterone: Cardiovascular benefits

Oleogum resin (known as guggul) from the guggul tree, Commiphora mukul, found in India, Bangladesh, and Pakistan, has been used to treat various diseases including hyper-cholesterolemia, atherosclerosis, rheumatism, and obesity over several thousands of years. Guggulsterone isolated from guggul has been identified as the bioactive constituent responsible for guggul\u27s therapeutic effects. Since the first study demonstrating the therapeutic effects of guggul in an animal model in 1966, numerous preclinical and clinical trails have been carried out. Although differences in study design, methodological quality, statistical analysis, sample size, and subject population result in certain inconsistencies in the response to therapy, the cumulative data from in vitro, preclinical, and clinical studies largely support the therapeutic claims for guggul described in the ancient Ayurvedic text. However, future clinical studies with much larger size and longer term are required to confirm these claims. The cardiovascular benefits of the therapy are derived from the multiple pharmacological activities associated with guggul or guggulsterone, notably its hypolipidemic, antioxidant, and antiinflammatory activities. It has been established that guggulsterone is an antagonist at farnesoid x receptor (FXR), a key transcriptional regulator for the maintenance of cholesterol and bile acid homeostasis. The FXR antagonism by guggulsterone has been proposed as a mechanism for its hypolipidemic effect. A recent study demonstrates that guggulsterone upregulates the bile salt export pump (BSEP), an efflux transporter responsible for removal of cholesterol metabolites, bile acids from the liver. Such upregulation of BSEP expression by guggulsterone favors cholesterol metabolism into bile acids, and thus represents another possible mechanism for its hypolipidemic activity. Guggulsterone has been found to potently inhibit the activation of nuclear factor-κB (NF-κB), a critical regulator of inflammatory responses. Such repression of NF-κB activation by guggulsterone has been proposed as a mechanism of the antiinflammatory effect of guggulsterone. © 2007 The Authors

Time Delay Estimation in Room Acoustic Environments: An Overview

<p/> <p>Time delay estimation has been a research topic of significant practical importance in many fields (radar, sonar, seismology, geophysics, ultrasonics, hands-free communications, etc.). It is a first stage that feeds into subsequent processing blocks for identifying, localizing, and tracking radiating sources. This area has made remarkable advances in the past few decades, and is continuing to progress, with an aim to create processors that are tolerant to both noise and reverberation. This paper presents a systematic overview of the state-of-the-art of time-delay-estimation algorithms ranging from the simple cross-correlation method to the advanced blind channel identification based techniques. We discuss the pros and cons of each individual algorithm, and outline their inherent relationships. We also provide experimental results to illustrate their performance differences in room acoustic environments where reverberation and noise are commonly encountered.</p