Assessing membrane aerated biofilm reactor configurations in mainstream anammox applications.

Partial nitritation anammox (PNA) membrane aerated biofilm reactors (MABRs) have the potential to be employed in mainstream wastewater treatment and can drastically decrease the energy and carbon requirements for nitrogen removal. Previous PNA MABR studies have looked at 1-stage systems, but no study has holistically compared the performance of different MABR configurations. In this study, a PNA MABR was mechanistically modelled to determine the impact of the reactor configuration (1-stage, hybrid, or 2-stage system) on the location of the preferred niche for anammox bacteria and the overall nitrogen removal performance. Results from this study show that the 2-stage configuration, which used an MABR with a thin biofilm for nitritation and a moving bed biofilm reactor for anammox, had a 20% larger nitrogen removal rate than the 1-stage or hybrid configurations. This suggests that an MABR should focus on maximizing nitrite production with anammox implemented in a second-stage biofilm reactor to achieve the most cost-effective nitrogen removal. However, the optimal configuration will likely be facility specific, as each facility differs in operating costs, construction costs, footprint, and effluent limits. Additional experimentation is required to confirm these results, but this work narrows the number of viable configurations that need to be tested. The results of this study will inform researchers and engineers how to best implement PNA MABRs in mainstream nitrogen removal at larger scales.

The FEMA GRAS assessment of phenethyl alcohol, aldehyde, acid, and related acetals and esters used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of phenethyl alcohol, aldehyde, acid, and related acetals and esters as flavoring ingredients is evaluated. The group of phenethylalcohol, aldehyde, acid, and related acetals and esters was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food, their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of phenethyl alcohol, aldehyde, acid, and related acetals and esters as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

The FEMA GRAS assessment of benzyl derivatives used as flavor ingredients.

This publication is the eighth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of benzyl derivatives as flavoring ingredients is evaluated. The group of benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

The FEMA GRAS assessment of hydroxy- and alkoxy-substituted benzyl derivatives used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of hydroxy- and alkoxy-substituted benzyl derivatives as flavoring ingredients is evaluated. The group of hydroxy- and alkoxy-benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of hydroxy- and alkoxy-substituted benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

A procedure for the safety evaluation of natural flavor complexes used as ingredients in food: essential oils.

A scientifically based guide has been developed to evaluate the safety of naturally occurring mixtures, particularly essential oils, for their intended use as flavor ingredients. The approach relies on the complete chemical characterization of the essential oil and the variability of the composition of the oil in the product intended for commerce. Being products of common plant biochemical pathways, the chemically identified constituents are organized according to a limited number of well-established chemical groups called congeneric groups. The safety of the intake of the each congeneric group from consumption of the essential oil is evaluated in the context of data on absorption, metabolism, and toxicology of members of the congeneric group. The intake of the group of unidentified constituents is evaluated in the context of the consumption of the essential oil as a food, a highly conservative toxicologic threshold, and toxicity data on the essential oil or an essential oil of similar chemotaxonomy. The flexibility of the guide is reflected in the fact that high intake of major congeneric groups of low toxicologic concern will be evaluated along with low intake of minor congeneric groups of significant toxicological concern (i.e., higher structural class). The guide also provides a comprehensive evaluation of all congeneric groups and constituents that account for the majority of the composition of the essential oil. The overall objective of the guide is to organize and prioritize the chemical constituents of an essential oil in order that no reasonably possible significant risk associated with the intake of essential oil goes unevaluated. The guide is, however, not intended to be a rigid checklist. The Flavor and Extract Manufacturers Association (FEMA) Expert Panel will continue to evaluate each essential oil on a case by case basis applying their scientific judgment to insure that each natural flavor complex is exhaustively evaluated.

Tachyphylaxis in 12-0-tetradecanoylphorbol acetate- and arachidonic acid-induced ear edema.

12-0-Tetradecanoylphorbol acetate (TPA) applied to mouse ears rapidly induces an edema which is maximal by 6 hr but has substantially waned by 24 hr. (This is in contrast to many inflammatory agents that cause a prolonged edema lasting many days.) Reapplication of TPA at 16-24 hr will not provoke a second edematous response although increased erythema is evident. Arachidonic acid (AA) applied to mouse ears (4 mg) provokes an even more rapid edema which is maximal at 1 hr and has substantially waned by 6 hr. Reapplication of AA at 3-24 hr also will not provoke a second edematous response although, again, increased erythema does result. Pretreatment of ears with AA results in inhibition of the edema response to subsequent application of TPA, and TPA pretreatment moderately inhibits a subsequent response to AA. TPA-induced edema can be delayed by agents such as naproxen, an inhibitor of AA cyclooxygenase. In contrast, AA-induced edema is inhibited only by agents, such as phenidone, that inhibit both cyclooxygenase and lipoxygenase. The data suggest that the edemas result from interaction of the products of the cyclooxygenase and lipoxygenase pathways of AA metabolism. The lack of secondary edema response appears to be related to the inability of TPA or AA to reinduce vascular permeability. The effect is specific to AA and TPA; responses to xylene or anthralin are unaffected by TPA or AA pretreatment. It is postulated that the tachyphylactic effects observed involve lipoxygenase metabolites of AA.

Corticosteroid-induced dermal atrophy in the rat.

Corticosteroid-induced dermal atrophy has been studied in the rat using daily application of ethanolic solutions to small areas of flank skin. After 12 days of treatment, the degree of atrophy was determined by comparing the weights of skin plugs (16 mm diameter) taken from the treated areas with contralaterally paired control areas. Doses can be adjusted so that systemic effects are minimized and only local effects are observed. Hydrocortisone, hydrocortisone butyrate, dexamethasone, betamethasone, desonide and triamcinolone acetonide all produce atrophy in the rat, and the degree of thinning is dose dependent. Potencies in the dermal atrophy assay compare directly with topical anti-inflammatory potencies in the rat, and the presence of fluorine in the steroid molecule is not a determining factor in the production of atrophy.

Anthralin inhibition of mouse epidermal arachidonic acid lipoxygenase in vitro.

Epidermal strips, free of sebaceous gland and hair follicle contamination, were prepared from mouse tail skin. Epidermal homogenates synthesized prostaglandins and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) from exogenously added [1-14C]arachidonic acid. The effects of pH, assay time, substrate concentration, and several selective inhibitors upon the lipoxygenase and cyclooxygenase pathways were determined. Ultracentrifugation of the crude homogenate at 105,000 g sedimented both activities, and pellet 12-HETE synthesis increased 2-fold relative to the crude homogenate. Recombination of the 105,000 g pellet and supernatant gave yields of prostaglandins and 12-HETE essentially equivalent to that of crude homogenate. When tested in homogenate with 4.5 microM arachidonic acid, anthralin specifically inhibited 12-HETE production with IC50 of 50.0 microM; no significant effect against cyclooxygenase was observed over the dose range of 2-200 microM. 1,8-Dihydroxy-9,10-anthraquinone (DHAQ) also specifically inhibited 12-HETE synthesis, but the dose response curve was flatter and maximum inhibition was only 55% at 200 microM. 6-Chloro-2,3-dihydroxy-1,4-naphthoquinone (CDNQ), an agent with topical antipsoriatic activity, also inhibited 12-HETE synthesis with an IC50 of 25 microM, but simultaneously stimulated prostaglandin production, up to 2.5-fold at 200 microM. When tested with washed human platelets, anthralin again specifically inhibited 12-HETE production with an IC50 of 10 microM, while DHAQ inhibited lipoxygenase activity by only 40% at 25 microM. When tested in platelets, CDNQ gave 33% inhibition of 12-HETE production at 200 microM, although prostaglandin synthesis was stimulated over the range of 25-200 microM. It is proposed that certain antipsoriatic agents may exert their action through modulation of arachidonic acid metabolism.

Family risk factors for child and adolescent suicidal behavior.

In this review, the author evaluates the empirical support for the claims that various aspects of family dysfunction are risk factors for completed suicide or suicidal symptoms in childhood or adolescence. There is consistent evidence that a history of physical or sexual abuse is a risk factor and some evidence for other risk factors, including poor family or parent-child communication, loss of caregiver to separation or death, and psychopathology in first-degree relatives. However, the researchers of the vast majority of studies did not attend to whether the putative risk factors preceded the development of suicidal symptoms; thus, most of the claims regarding family risk factors are not justified by their research designs and findings.

In vivo inhibition of cathepsin B by peptidyl (acyloxy)methyl ketones.

Peptidyl (acyloxy)methyl ketones, previously established as potent irreversible inhibitors of the cysteine proteinase cathepsin B in vitro, were investigated and optimized for their inhibitory activity in vivo. Incorporation of polar or charged functional groups in the inhibitor structure afforded effective cathepsin B inhibition, following dosing to rats. The most effective inhibitor, Z-Phe-Lys-CH2OCO-(2,4,6-Me3)Ph (8), was found to give ED50 values of 18 mg/kg po (orally) and 5.0 mg/kg ip (intraperitoneally) at 4-5 h postdose, and 2.4 mg/kg sc (subcutaneously) at 24 h postdose, for liver cathepsin B inhibition (measured ex vivo). The subcutaneous route of administration of (acyloxy)methyl ketone 8 also provided potent cathepsin B inhibition in certain peripheral tissues (e.g., ED50 1.0 mg/kg for skeletal muscle, 0.1 mg/kg for heart). These investigations demonstrate that peptidyl (acyloxy)methyl ketones such as 8 have promise as tools for the characterization of in vivo biochemical processes and as therapeutic agents.

The necessary role of the autopsy in cardiovascular epidemiology.

The autopsy rate in the United States today is remarkably low, with proportionally fewer autopsies for natural causes of death. Consequently, most cardiovascular epidemiology studies do not use autopsy data and rely on death certificates, medical records, questionnaires, and family interviews as sources of mortality information. These practices introduce a high degree of variability and uncertainty regarding cause of death. This review illustrates the necessity for increased use of autopsies in cardiovascular epidemiology by critically evaluating other measures of cardiovascular disease (CVD) incidence. We evaluated the literature regarding CVD as cause of death and conducted discussions with cardiologists, pathologists, and epidemiologists. No attempt was made for meta-analysis. This review shows the limited reliability of death certificates, medical records, and interviews as sources of mortality statistics. In addition, the autopsy's role in clearly indicating the presence of CVD is illustrated. The autopsy used in conjunction with medical records is the only reliable means for establishing cause of death from CVD. There is an urgent need to reassess the current dependence of statistical mortality data on death certificates and other inadequate sources of CVD incidence. Death certificates, in general, are inadequately monitored for quality control and appropriate administrative oversight. With an increase in the number of hospitals performing no autopsies to investigate cause of death, a uniform national autopsy database is needed.

Drug related vasculitis. Clinicopathologic correlations in 30 patients.

Drug related vasculitis has variously been described as necrotizing hypersensitivity or allergic angiitis or microscopic panarteritis nodosa. We reviewed tissue sections from 30 patients with validated drug hypersensitivity and vasculitis in order to precisely define this entity. No evidence of necrotizing vascular lesions or of fibrinoid associated with necrosis was found. The vascular lesions in all 30 patients involved small arteries, arterioles, capillaries, and venules. The inflammatory infiltrate consisted primarily of mononuclear cells and prominent numbers of eosinophils and was present in all three layers of the involved vessel walls. Clinically the patients developed either localized or systemic vasculitis, which could not be predicted on the basis of the associated drug. The findings of a skin rash, fever, or eosinophilia and the development of symptoms consistent with a hypersensitivity reaction while medication was being taken were all suggestive of the diagnosis of drug related vasculitis.

Maximal power across the lifespan.

BACKGROUND: Previous investigators have reported that maximal power increases during growth and decreases with aging. These age-related differences have been reported to persist even when power is scaled to body mass or muscle size. We hypothesized that age-related differences in maximal power were primarily related to differences in muscle size and fiber-type distribution rather than to age per se. METHODS: Maximum cycling power (Pmax) and optimal pedaling rate (Vopt, a surrogate measure for muscle fiber type) were determined for 195 boys and men, 8-70 years of age, by using inertial load cycle ergometry. Anthropometric dimensions were used to estimate lean thigh volume (LTVest) of all subjects, and magnetic resonance imagery was used to determine thigh and hip muscle volume (MRIvol) for 24 subjects. RESULTS: Pmax was highly related to the product of LTVest and Vopt (LTVest X Vopt; r2 = .83). Multiple regression revealed that Pmax was significantly related to both LTVest x Vopt and age (R2 = .84). Power scaled by LTVest X Vopt was stable during growth and exhibited a small but significant decrease with aging. MRIvol was highly correlated with LTVest, and the ratio of LTVest to MRIvol was independent of age. CONCLUSIONS: These results suggest that muscle volume and optimal pedaling rate are the main determinants of maximal power across the lifespan and that the contractile properties of muscle are developed early in childhood and remain nearly intact late into the lifespan.

Parents' reactions to adolescents' suicide attempts.

OBJECTIVES: To examine parents' emotional and verbal reactions to adolescents' suicide attempts and to test models of the interpersonal functions of suicide attempts. METHOD: Thirty-four mothers and fathers of 23 adolescent suicide attempters were assessed shortly after the attempt regarding their emotional reactions the day before, upon discovering, and the day after the suicide attempt, using both open-ended and structured interviews. RESULTS: Feelings of caring, sadness, and anxiety increased from before the attempt to the point of discovery, and for mothers they remained higher through the following day. Hostile feelings were present in approximately 50% of mothers across the time points; however, upon discovering the suicide attempt, parents were less likely to verbalize hostility than they were to verbalize support and to be careful what they said. CONCLUSIONS: The findings have implications for clinical interventions with parents of recent suicide attempters.

Inertial-load method determines maximal cycling power in a single exercise bout.

A cycle ergometer was modified to measure power (P) with resistance provided solely by the moment of inertia (I) of the flywheel. P was calculated as the product of I, angular velocity (omega), and angular acceleration (alpha). Flywheel omega and alpha were determined by means of an optical sensor and a micro-controller based computer interface which measured time (+/- 1 microsecond) and allowed P to be calculated instantaneously (PI) every 3 degrees of pedal crank rotation or averaged over one complete revolution of the pedal cranks (PREV). Values for maximum P were identified from each bout (PI max and PREV max). Mechanical calibration of torque via a resistive strap proved this method to be both valid and accurate. Thirteen active male subjects performed four bouts of maximal acceleration lasting approximately 3-4 s with 2 min resting recovery. The mean coefficient of variation for PREV max was 3.3 +/- 0.6% and the intraclass correlation was 0.99. PREV max averaged 1317 +/- 66 W at 122 +/- 2 rpm, and PI max averaged 2137 +/- 101 W at 131 +/- 2 rpm. PREV max and PI max were highly correlated (r = 0.86 and r = 0.80 respectively, P < 0.002) with estimated lean thigh volume. Therefore, the inertial-load method provides a valid and reliable determination of cycling power in one short exercise bout.

Hamster costovertebral organ lipogenesis in vitro and in vivo: effects of cerulenin.

An assay for lipid synthesis by hamster costovertebral organ (CVO) in vivo is described. When sodium [1-14C]acetate is injected intraperitoneally into male hamsters, maximum labeling of CVO lipids occurs after 5 min and remains constant for more than 40 min following injection. The major products of in vivo labeling are polar lipids, triglycerides, and sterols. The distribution of radiolabeled lipid products in vivo is similar to that obtained from incubation of CVO punch biopsy specimens with [1-14C]acetate in vitro. Castration results in an greater than 80% inhibition of CVO lipid synthesis as measured using in vitro or in vivo techniques. Cerulenin inhibited de novo fatty acid synthesis by the 100,000 X g supernatant of a CVO homogenate and the incorporation of [1-14C]acetate into fatty acids by CVO biopsies in vitro. Topical application of cerulenin to the CVO did not inhibit synthesis of radiolabelled lipids from [1-14C]acetate in vivo. The in vivo assay provides a necessary means of determining the physiological significance of in vitro results obtained when assaying for inhibitors of sebaceous gland lipogenesis.

Safety evaluation of natural flavour complexes.

Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.

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 pyrazine derivatives used as flavor ingredients. Flavor and Extract Manufacturers Association.

This is the fifth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of pyrazine derivatives as flavoring ingredients is evaluated.