Advances in ion mobility spectrometry-mass spectrometry reveal key insights into amyloid assembly.

Interfacing ion mobility spectrometry to mass spectrometry (IMS-MS) has enabled mass spectrometric analyses to extend into an extra dimension, providing unrivalled separation and structural characterization of lowly populated species in heterogeneous mixtures. One biological system that has benefitted significantly from such advances is that of amyloid formation. Using IMS-MS, progress has been made into identifying transiently populated monomeric and oligomeric species for a number of different amyloid systems and has led to an enhanced understanding of the mechanism by which small molecules modulate amyloid formation. This review highlights recent advances in this field, which have been accelerated by the commercial availability of IMS-MS instruments. This article is part of a Special Issue entitled: Mass spectrometry in structural biology.

Electrophoresis in nanometer inner diameter capillaries with electrochemical detection.

Separations have been achieved in 770- and 430-nm-inner diameter capillaries. The extremely low sample volumes involved in the study of biological microenvironments such as single cells has led to the desire to develop separation techniques in these ultrasmall capillaries. Total sample volumes as low as 12 fL have been injected using these nanometer inner diameter capillaries. Separations of several catecholamines have been accomplished in these submicrometer capillaries using both capillary zone electrophoresis and micellar electrokinetic chromatography with end-column amperometric detection.

The FEMA GRAS assessment of trans-anethole used as a flavouring substance. Flavour and Extract Manufacturer's Association.

This publication is the fourth in a series of safety evaluations performed by the Expert Panel of the Flavour and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of trans-anethole (i.e. 4-methoxypropenylbenzene) as a flavouring substance is critically evaluated by the FEMA Expert Panel. The evaluation uses a mechanism-based approach in which production of the hepatotoxic metabolite anethole epoxide (AE) is used to interpret the pathological changes observed in different species and sexes of laboratory rodents in chronic and subchronic dietary studies. Female Sprague Dawley rats metabolize more trans-anethole to AE than mice or humans and, therefore, are the most conservative model for evaluating the potential for AE-induced hepatotoxicity in humans exposed to trans-anethole from use as a flavouring substance. At low levels of exposure, trans-anethole is efficiently detoxicated in rodents and humans primarily by O-demethylation and omega-oxidation, respectively, while epoxidation is only a minor pathway. At high dose levels in rats, particularly females, a metabolic shift occurs resulting in increased epoxidation and formation of AE. Lower activity of the "fast" acting detoxication enzyme epoxide hydrolase in the female is associated with more pronounced hepatotoxicity compared to that in the male. The continuous intake of high dose levels of trans-anethole (i.e. cumulative exposure) has been shown in dietary studies to induce a continuum of cytotoxicity, cell necrosis and cell proliferation. In chronic dietary studies in rats, hepatotoxicity was observed when the estimated daily hepatic production of AE exceeded 30 mg AE/kg body weight. In female rats, chronic hepatotoxicity and a low incidence of liver tumours were reported at a dietary intake of 550 mg trans-anethole/kg body weight/day. Under these conditions, daily hepatic production of AE exceeded 120 mg/kg body weight. Additionally, neither trans-anethole nor AE show any evidence of genotoxicity. Therefore, the weight of evidence supports the conclusion that hepatocarcinogenic effects in the female rat occur via a non-genotoxic mechanism and are secondary to hepatotoxicity caused by continuous exposure to high hepatocellular concentrations of AE. trans-Anethole was reaffirmed as GRAS (GRASr) based on (1) its low level of flavour intake (54 microg/kg body weight/day); (2) its metabolic detoxication pathway in humans at levels of exposure from use as a flavouring substance; (3) the lack of mutagenic or genotoxic potential; (4) the NOAEL of 120 mg trans-anethole/kg body weight/day in the female rat reported in a 2 + -year study which produces a level of AE (i.e. 22 mg AE/kg body weight/day) at least 10,000 times the level (0.002 mg AE/kg body weight day) produced from the intake of trans-anethole from use as a flavouring substance; and (5) the conclusion that a slight increase in the incidence of hepatocellular tumours in the high dose group (550 mg trans-anethole/kg body weight/day) of female rats was the only significant neoplastic finding in a 2+ -year dietary study. This finding is concluded to be secondary to hepatotoxicity induced by high hepatocellular concentrations of AE generated under conditions of the study. Because trans-anethole undergoes efficient metabolic detoxication in humans at low levels of exposure, the neoplastic effects in rats associated with dose-dependent hepatotoxicity are not indicative of any significant risk to human health from the use of trans-anethole as a flavouring substance.

The FEMA GRAS assessment of furfural used as a flavour ingredient. Flavor and Extract Manufacturers' Association.

The Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA) has assessed the safety of furfural for its continued use as a flavour ingredient. The safety assessment takes into account the current scientific information on exposure, metabolism, pharmacokinetics, toxicology, carcinogenicity and genotoxicity. Furfural was reaffirmed as GRAS (GRASr) as a flavour ingredient under conditions of intended use based on: (1) its mode of metabolic detoxication in humans; (2) its low level of flavour use compared with higher intake levels as a naturally occurring component of food; (3) the safety factor calculated from results of subchronic and chronic studies, (4) the lack of reactivity with DNA; and (5) the conclusion that the only statistically significant finding in the 2-year NTP bioassays, an increased incidence of hepatocellular adenomas and carcinomas in the high-dose group of male mice, was secondary to pronounced hepatotoxicity. Taken together, these data do not indicate any risk to human health under conditions of use as a flavour ingredient. This evidence of safety is supported by the occurrence of furfural as a natural component of traditional foods, at concentrations in the diet resulting in a 'natural intake' that is at least 100 times higher than the intake of furfural from use as a flavour ingredient.

The FEMA GRAS assessment of alicyclic substances used as flavour ingredients.

For over 35 years, an independent panel of expert scientists has served as the primary body for evaluating the safety of flavour ingredients. This group, the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA), has achieved international recognition from the flavour industry, government regulatory bodies including the Food and Drug Administration, and the toxicology community for its unique contributions. To date, the Expert Panel has evaluated the safety of more than 1700 flavour ingredients and determined the vast majority to be "generally recognized as safe" (GRAS). Elements that are fundamental to the safety evaluation of flavour ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavour ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. The elements of the GRAS assessment program as they have been applied by the Expert Panel to the group of 119 alicyclic substances used as flavour ingredients, and the relevant scientific data which provide the basis for the GRAS status of these substances, are described herein.

Decreased incidence of scoliosis in hearing-impaired children. Implications for a neurologic basis for idiopathic scoliosis.

STUDY DESIGN: A retrospective survey of the incidence of positive scoliosis screenings in schools for the hearing impaired was performed. OBJECTIVES: The incidence rate of scoliosis in a population with a high incidence of vestibular dysfunction was compared with the national normative incidence rate. The comparison was done to investigate the contribution of the vestibular system to scoliosis. SUMMARY OF BACKGROUND DATA: Several reports have emphasized a possible neural etiology to idiopathic scoliosis. Based on the experimental hypothesis that an altered vestibular processing is critical for the production of scoliosis, 100 schools for the hearing impaired were surveyed to determine their incidence of positive screenings for scoliosis. Because it is known that hearing-impaired children have a high incidence of vestibular dysfunction, it was hypothesized that their screening incidence would change if the vestibular system contributed to idiopathic scoliosis. METHODS: Surveys were sent to 100 schools for the hearing impaired asking for their most recent scoliosis screening data. RESULTS: Of the 40 surveys returned, 28 schools for the hearing impaired conducted routine scoliosis screenings, of which 17 had demographics representative of the national norms. Of the 3127 students screened at these 17 schools, 1.2% of the students screened positive for scoliosis. This is significantly less than national incidence rate of 4%-10%. CONCLUSION: The results suggested that hearing-impaired students may be a population that is protected from idiopathic scoliosis by a neural dysfunction. These data strongly suggest that idiopathic scoliosis has a neural etiology.

Name that tone. The proliferation of alarms in the intensive care unit.

The proliferation of alarms on equipment in ICUs contributes to a level of noise that can disturb both patient and staff. To determine whether these alarms are identifiable by sound alone to our ICU staff, we recorded 33 audio signals commonly heard on the ward, 10 of which we defined as critical alarms. One hundred subjects (25 physicians, 41 nurses, and 34 respiratory therapists) listened individually in a quiet room to the tape recording that consisted of 10 s of audible followed by a 10-s pause for a written response. Only 50 percent of the critical alarms and only 40 percent of the noncritical sounds were correctly identified. By occupation, registered respiratory therapists scored highest, followed by nurses, nonregistered therapists, and physicians. Those with > 1 year ICU work experience scored higher than those with less than 1 year. We conclude that the myriad of alarms that regularly occur in the ICU are too much for even experienced ICU staff to quickly discern. Patient and caregiver alike could benefit by a graded system in which only urgent problems have audible alarms, and these should be covered by regular in-service training.

GRAS evaluation of flavoring substances by the Expert Panel of FEMA.

The review describes the evolution of the process of GRAS evaluation of flavoring substances by the Expert Panel of FEMA during the past 30 years. These materials possess prominent olfactory and gustatory effects and, therefore, are added to foods in very small quantities. The procedures used and criteria employed for GRAS determinations are noted. Attention is called to the process for the re-review of the GRAS status of flavoring substances.

Isotope dilution technique for the estimation of l-alpha-[2-3H]-acetylmethadol and its metabolites in biological samples.

An isotope dilution technique for the determination of l-alpha-(2-3H)-acetylmethadol and its metabolites from biological samples is described. The parent drug and metabolites were extracted from biological samples with chlorobutane after the addition of unlabeled internal standards. The extracts were purified by two-dimensional thin-layer chromatography for quantification by gas-liquid chromatography and scintillation counting. Dinoracetylmethadol (NNAM) was found to be converted to 6-acetamido-4,4-diphenyl-3-heptanol (AMIDE) during the extraction procedure. The conversion of NNAM to AMIDE was confirmed by gas chromatography-mass spectrometry.

An information service for practicing veterinarians.

Many Indiana veterinarians are relatively isolated from colleagues and information sources. Their information needs cannot be easily met by public or medical libraries. The Veterinary Medical Information Center (VMIC) at Purdue University, which began operation in the fall of 1977, offers information services designed to meet the specific needs of veterinary medical practitioners in the state of Indiana. Questions received by the center have covered all facets of animal medicine and management. After two years of free service, VMIC will begin charging clients for services and will consider expansion of the service to other states. VMIC operations will be evaluated through data collected by the center and follow-up surveys.

Brown pelicans: improved reproduction off the southern California coast.

Although still about 30 percent too low for population stability, productivity of California brown pelicans at their two northern colonies has improved significantly since 1971. Numbers of adults breeding probably reflect food supplies and recruitment from more successful colonies to the south, but improving fledging rates (up to 0.9 young per nest in 1974) reflect better egg survival and improving eggshell condition, with declining DDE contamination in anchovies, their major food source.

Accuracy of the Bing and Rinne tuning fork tests.

Fifty children seen in an ENT clinic received the Bing and Rinne tuning fork tests, otoscopic examination, and puretone audiometry to determine the accuracy of the tuning fork tests in predicting otoscopic abnormality or conductive hearing loss. Neither tuning fork test showed high accuracy. The Bing test overidentified by yielding negative results (conductive loss) for many ears with normal hearing or sensorineural loss. It correctly identified conductive loss or otoscopic abnormality only slightly better than chance57% to 66% of the time. The Rinne test identified with high accuracy those ears with a 40 dB or greater air-bone gap. For air-bone gaps of 10-35 dB, only 27% of the ears gave negative results, meaning correct identification. However, when a negative Rinne occurred, the result was in error only 2% of the time.