bluuebunny/crossref_metadata_2025 huggingface dataset:
Consideration of Pharmacokinetics and Temporal Sensitivity for Hydroxyurea in Relation to Teratogenic Potential
Authors: Beliles R. P. , Makris N. G. , Scott W. J.
Published: November 2007

A compartmental pharmacokinetic-mathematical model for the time-dependent distribution of hydroxyurea (HU) in both the maternal plasma and embryonic fluids of pregnant rats and rhesus monkeys was developed. Across species scaling was based on maternal plasma clearance rates and compartmental sizes as a percent of the body weight of the dam. Mathematical optimization provided the compartmental transfer rates. The estimated maternal and embryonic concentrations of HU correlated well with the experimental pharmacokinetic data regarding both time and quantity for both the rat and the monkey. When the biological effective dose was considered to be the embryonic HU concentration over time (AUC), the dose to the individual embryos was higher in the monkeys (392 mg HU hr/L/day) than in the rats (69 mg HU hr/L/day) at an applied dose of 100 mg HU/kg administered to the dams. The AUC doses are consistent with the evaluation of the embryos of both species for teratogenic changes and embryonic death. The effect of repeated doses as compared with a single dose given only on one day of gestation was examined in the rat. Because of the rapid maternal clearance the carryover of embryonic HU concentration from one day to the next was minimal. A single treatment on Day 9 only was estimated to be sufficient to produce the adverse embryonic effects of HU on Days 9 through 12 as reported by Wilson et al. The sensitivity of the embryo to HU decreased with increasing embryonic age. The implications of the pharmacokinetic simulation and the temporal susceptibility for ongoing clinical trials of HU in the treatment of sickle cell anemia were reviewed. A human embryo dose of 69 mg HU hr/L/day was estimated to result from an i.v. dose of 10 mg/kg to the mother. This concentration produced no effect in the rat. An i.v. dose of 50 mg HU/mg was estimated to result in a human embryo dose of 353 mg HU hr/L/day which approaches a Rhesus monkey embryo dose that produced adverse effects in all embryos.
Chronic Inhalation Study Findings as a Basis for Proposing a New Occupational Dust Exposure Limit
Authors: Morrow P. E. , Muhle H. , Mermelstein R.
Published: November 2007

This article briefly reviews the history of the current threshold limit value and the permissible exposure limit for occupational dusts derived originally from the Nuisance Dust standard. Chronic inhalation studies of appropriate design are described in terms of their key findings and potential impact on the dust standards, especially modern, experimental studies which have been affected by the problem of dust overloading. Many studies show that dust overloading produces a significant and progressive retardation of macrophage-mediated dust removal leading to various dysfunctional and pathologic changes which confound the interpretation of chronic toxicity study findings. Assuming that there may be a human counterpart to this condition at the same milligram dust per gram lung concentration, extrapolation modeling can be used to show that the current occupational dust limits do not protect worker lungs from this eventuality. Several bases for substantially reducing the current occupational standards are discussed.
Subchronic Toxicity of Orally Administered Beta-Cyclodextrin in Rats
Authors: Olivier Philippe , Verwaerde Francoise , Hedges Allan R.
Published: November 2007

Beta-cyclodextrin (BCD) was administered in the diet to male and female OFA rats derived from a Sprague-Dawley strain. Rats were fed a standard semisynthetic diet, UAR 210, containing 1.25% BCD, 2.5% BCD, 5% BCD, 10% BCD, and 10% lactose. Twenty animals/sex/group were dosed for 90 consecutive days. One animal died in the course of the study, but there was no indication that the death was compound-related. There were no dose-related adverse effects pertaining to hematology, blood, or urine chemistry. A small fraction of BCD was recovered in the urine of animals fed 5% or 10% BCD, amounting to 0.1–0.3% of the highest administered dose. The absolute and relative filled cecal weights of the rats that were fed BCD or lactose were increased in both the males and females, which is common in rats receiving slowly digestible fermentable carbohydrates due to incomplete digestion in the small intestine. No treatment-related effects indicative of a toxicologic response were found from the histopathologic examination. Based on these findings, BCD appears to lack toxicologic activity.
The Subacute and Subchronic Oral Toxicity of 1,3-Dichloropropane in the Rat
Authors: Terrill James B. , Robinson Merrel , Wolfe Gary W. , Billups Leonard H.
Published: November 2007

1,3-Dichloropropane (DCP) was administered by gavage for 14 and 90 days to male and female Sprague-Dawley-derived rats (10/sex/group). In the 14-day study using dose levels of 200, 600, and 1800 mg/kg/day, all high-dose group animals died, and none died in the other two treatment groups. Other signs associated with treatment in high-dose animals included languid behavior, salivation (also seen in middose group animals), dyspnea, and prostration. No differences were found between animals in the low-dose or middose groups compared to the control animals for body weight, food consumption, hematology, and gross postmortem and histopathology data. Total protein and albumin blood levels were increased for low-dose and middose females, and middose females, respectively. The clinical chemistry findings appeared to be treatment-related, since they were accompanied by significantly increased liver weights (absolute and relative; both sexes of middose animals) and kidney weights (absolute and relative; middose males). The dose levels used in the 90-day study, chosen on the results of the 14-day study, were 50, 200, and 800 mg/kg/day. All animals survived to termination. Males in the high-dose group exhibited a significant decrease in body weight, whereas females in this group exhibited urine-stained fur. No treatment-related effects were found in food consumption or hematology data. Alkaline phosphatase, alanine aminotransferase (males only), albumin, and total protein for high-dose group animals were increased. These findings were accompanied by increases in liver weight for low-dose (females only), middose, and high-dose animals and kidney weights for middose and high-dose group animals. Microscopic evaluations revealed centrilobular hepatocellular hypertrophy for the high-dose group animals and an exacerbation of chronic progressive nephropathy for middose (males only) and high-dose animals.
The Limitations of Scientific Testimony in Chronic Disease Litigation
Authors: Davidson Michael S.
Published: November 2007

Questions raised by scientists about the relationship between chronic diseases and environmental exposures have formed the basis for numerous lawsuits seeking to obtain compensation for diseases claimed to be caused by those exposures. Scientists, as a result, are sought by the legal system to provide expert testimony on these topics. This article attempts to describe for scientists the legal system into which they are being asked to enter, to review the various ways in which courts have responded to the uncertainties in this area, and to suggest some cautions to scientists about their role in this system.
Updating Developmental Toxicity Testing Guidelines for the Safety Assessment of Direct Food Additives and Color Additives Used in Food: Results of a Survey
Authors: Collins Thomas F.X. , Black Thomas N. , Graham Stuart L. , Jackson Benjamin A. , Welsh John J.
Published: November 2007

In 1982, the Food and Drug Administration (FDA) issued guidelines for testing the effects of direct food additives and color additives on developing embryos and for longer monitoring during several generations. In 1984, an FDA task force began a review of testing procedures for reproductive and developmental toxicity. The Developmental Toxicity Committee was formed specifically to evaluate the current guidelines and to propose revisions. As part of the evaluation, a two-part questionnaire was devised and sent to about 800 members of the Teratology Society and the Reproductive and Developmental Toxicity Specialty Section of the Society of Toxicology. The questionnaire included questions on multigeneration reproduction and developmental toxicity. A total of 132 responses (16.5%) were received, and they are discussed in detail in this report. The responses to the multigeneration reproduction questions were concerned with the optimum number of generations and litters, reduction of litter size for standardization, selection of offspring to produce the next generation, parameters to be measured, indices to be calculated, length of premating exposure, additional protocols, and microscopic examination of the offspring. Responses to the developmental toxicity questions were concerned with dose levels, diet variations, route of administration, examination of the offspring, and control of bias.
Acute, Subchronic, and Reproductive Toxicity of a Linear Alcohol Ethoxylate Surfactant in the Rat
Authors: Gingell Ralph , Lu Cheryle C.
Published: November 2007

The mammalian toxicity of a C9–11 linear primary alcohol 6-mole ethoxylate, used in aqueous cleaning formulations, has been evaluated. The rat acute oral LD50 was 1.4 g/kg, and the rabbit acute dermal LD50 was greater than 2 g/kg. Undiluted material was severely irritating to the skin, but a 1% w/v aqueous dilution was not a skin sensitizer. There was no evidence of mutagenicity in the Ames assay. In a rat dermal subchronic study, there were no treatment-related effects at 1% and 10% aqueous concentrations, but at 25%, there was flaking of the skin and microscopic evidence of hyperkeratosis at the treatment site as the only compound-related effect. Potential reproductive toxicity was evaluated in a two-generation study in Fischer rats exposed similarly to the subchronic study. No compound-related effects on the reproductive performance or on the growth and development of the offspring were detected. It is concluded that this ethoxylate is typical of the more widely used alcohol ethoxylates with alkyl chains in the C12–18 range, being moderately acutely toxic by the oral route. By the dermal route—the relevant route of human exposure—it is not expected to produce skin irritation or systemic or reproductive toxicity at concentrations used in formulated cleaning products.
Subchronic Studies of Tripelennamine in B6C3F1 Mice
Authors: Jackson Carlton D. , Blackwell Boon-Nam
Published: November 2007

The subchronic toxicity of tripelennamine hydrochloride was determined to provide data for selecting dose levels for a 2-year study in mice. Male and female B6C3F1 mice were administered the drug in their feed at dose levels of 0, 150, 300, 600, 1200, and 2400 ppm (calculated as free amine) for 14 days or 0, 300, 600, 1200, 2400, and 4800 ppm for 90 days. Little toxicity was observed in the 14-day study. In the 90-day study, final body weights of males and females of the 4800 ppm groups were reduced 14% and 4%, respectively. Clinical observations and necropsy findings were unremarkable in the 90-day study. Decreased heart weight/brain weight ratios in males and increased liver weight/brain weight ratios in females were seen at dose levels as low as 600 ppm. Histologically, changes consisting of cytomegaly, karyomegaly, and cytoplasmic vacuolization of the liver, mild to severe cytomegaly and necrosis of parotid salivary gland acinar cells, and a mild degree of vacuolar degeneration of the bronchial epithelium of the lung were observed. The results indicate that an oral dose level of 2000 ppm tripelennamine would not be life-shortening in male or female B6C3F, mice in a 2-year study.
Endocrine Toxicity of Drinking Water Disinfectants. I. In Vivo Dehalogenation and Clearance of Iodinated Nutrients
Authors: Bercz J. P.
Published: November 2007

Ingestion of aqueous chlorine-based disinfectants has been shown earlier to cause decreased serum thyroxine levels and increased 131-I thyroid uptake in nonhuman primates. Disinfectants also were shown to immobilize iodine on gastric mucosa and cause covalent binding of dietary iodide to gastrointestinal contents in laboratory rodents. It has been demonstrated that nutrients in the presence of chlorine oxides, under conditions simulating the alimentary tract, effectively organify I- in vitro. A logical consequence of these is that traces of iodinated organics are absorbed after ingestion of drinking water disinfectants. Since over 100 million consumers receive a daily dose of about 0.4 mM of free chlorine, the pharmacotoxicology of such modified nutrient molecules is of public health interest. Therefore, we examined the in vivo deiodination of randomly in vitro iodinated organic mixtures prepared from different nutrients. Using adult female rats, we determined the 24-hour thyroid uptake of 125-I liberated from nutrients administered by gavage, relative to simultaneously ip-injected I131-. Also, 24-hour fecal and urinary clearances of the iodinated organics as well as tissue distributions were determined. The results showed that although various iodinated nutrient classes widely differed in their in vivo fate, most were dehalogenated effectively. Thus, their iodine content was returned as inorganic I- for thyroid uptake. It was also shown that tissue (blood, liver, intestinal, adipose, and muscle) distribution of the two isotopes did not differ significantly, suggesting that at 24 hours, the originally organic iodine existed in the tissues as inorganic I-. It is likely that oral exposure to chlorine-based disinfectants did not disturb the bioavailability of I-, and any thyroid effects caused were due to mechanisms other than I- deficiency.
Endocrine Toxicity of Drinking Water Disinfectants. II. Inhibition of Hepatic 5'-Thyroxine Deiodinase by Halogenated Nutrients
Authors: Bercz J. P. , Garner L.
Published: November 2007

Administration of drinking water treated with chlorine-based disinfectants was shown in prior studies to interfere with thyroid function of laboratory animals. One possible mechanism is that intraalimentary redox interactions between chlorine oxides and organic and inorganic contents of the gastrointestinal tract cause formation of iodinated and chlorinated nutrients. Several halogenated organic molecules generated by this route were shown to vary in their in vivo dehalogenation and clearance. In seeking clues to the etiology of the thyroid effect, the influence of several iodinated and chlorinated amino and fatty acid isomers on 5-deiodination of thyroxine (T4) to triiodothyronine (T3) was studied using rat liver homogenates in this study. Several of the compounds tested inhibited conversion of T4 to T3, with effective concentration comparable to the known inhibitor of the type I 5'-thyroxine deiodinase (5'-TDI). Unexpectedly, iodinated isomers of histidine, and chlorotyrosine appeared to activate rather than decrease T3 formation. Effective molar concentrations indicated that even if all of the chlorine dose ingested via drinking water would be converted into such halogenated analogs, their levels in body fluids would be too small to cause clinically detectable thyroid changes.
Morphometric Analysis of Rat Trigeminal Ganglion Cells and Their Vibrissa Follicle Nerve Axons Following Multiple Low-Dose Exposure to the Carbamate Insecticide Aldicarb
Authors: Klein Bradley G. , Mccain Wilfred C. , Ehrich Marion
Published: November 2007

Chronic carbamate exposure is reported to cause somatosensory dysfunction in humans. The limited experimental literature on neuropathic effects of repeated, low-level carbamate exposure is equivocal and does not address effects on well-defined somatosensory pathways. In this study, adult Sprague-Dawley rats were given 0.2 mg/kg/day of aldicarb, by oral gavage, for 90–114 days. The daily dose was below that capable of inducing clinical signs of cholinergic poisoning but inhibited acetylcholinesterase in spinal cord and blood. Aldicarb was evaluated for its ability to cause death or morphologic alteration of sensory neurons innervating C1 mystacial vibrissa follicles. Light and electron microscopy were used to examine the number of myelinated axons in C1 vibrissa follicle nerves and the respective areas of these axons and their myelin sheaths. Retrograde axonal transport was used with fluorescence microscopy to examine the number and diameter of the cell bodies of C1 vibrissa follicle nerve axons. No differences were observed between aldicarb-treated and control groups for any of these dependent variables. This study indicates that repeated exposure to aldicarb, at a dose below that causing sufficient acetylcholinesterase inhibition to elicit clinical signs, does not produce an anatomic correlate for somatosensory dysfunction in rats.
Behavioral Toxicology of Volatile Organic Solvents V. Comparisons of the Behavioral and Neuroendocrine Effects Among n-Alkanes
Authors: Glowa John R.
Published: November 2007

Four homologous n-alkanes were compared for their ability to impair performance and stimulate hypothalamic-pituitary activity in mice. Performance was assessed using operant responding maintained under a fixed interval 60-sec schedule of milk presentation. Cumulative concentration-effect functions for octane, heptane, hexane, and pentane were obtained by incrementally increasing exposure concentrations until responding was abolished. Recovery from these rate-decreasing effects was determined 30 min after exposure to the highest concentration. Rate-decreasing potency (EC50) was greatest for octane (2474 ppm), and progressively less for heptane (3872 ppm), hexane (7051 ppm), and pentane (36130 ppm). Responding recovered completely 30 min after exposure for pentane and hexane, to 75% of pre-exposure levels for heptane, but to only 15% of pre-exposure levels for octane. The risk of obtaining a small effect with these agents (the concentration expected to decrease performance 10% in 1 out of 1000 mice) exhibited a similar order. The effect was predicted to occur at 227 ppm for octane, 331 ppm for heptane, and 1429 ppm for pentane. However, this prediction occurred at an unusually low dose for hexane (68 ppm). These n-alkanes also stimulated up to 2000-fold increases in adrenocorticotropin hormone (ACTH) release. n-Hexane was slightly more potent and produced larger effects. These studies demonstrate a direct relationship between aliphatic carbon chain length and the potency of n-alkanes in impairing performance.
Applications of a Neurobehavioral Screening Battery
Authors: Moser Virginia Clayton
Published: November 2007

With the growing awareness of the neurological effects of many environmental chemicals, there is considerable emphasis being placed on the detection of neurotoxic potential at the screening, or first-tier, level of testing. We have developed a neurobehavioral screening battery consisting of a functional observational battery (FOB) and an automated measure of motor activity which can be incorporated into neuropathological studies as well as general toxicity assessments of new and existing chemicals in rats. This approach has been recommended by several expert national and international panels, and recently has been recommended by the U.S. Environmental Protection Agency for testing pesticides and industrial chemicals. The FOB consists of a series of home-cage, open-field, and interactive assessments of the rat's behavior and neurological functions. Motor activity provides an objective apical measure of the rat's neurobehavioral function. In order to assess validity, sensitivity, and specificity, we have utilized these test methods to determine dose-response and time-course characteristics of a wide variety of chemicals including pesticides, metals, solvents, and industrial compounds. We currently are developing approaches to provide profiles of effect for different types of neurotoxicants, which can then be used to make decisions concerning neurotoxic potential and provide direction for more in-depth, second-tier testing.
Strategy for and Experience with Neurotoxicity Testing of New Pharmaceuticals
Authors: Haggerty Gillian C.
Published: November 2007

In response to present and anticipated regulatory needs for routine screening of pharmaceuticals for assessment of their neurotoxic potential, a primary tier screen for rodents, consisting of a functional observational battery (FOB) and an automated test of motor activity, has been developed at Searle. Additionally, an FOB for dogs currently is being developed. The rodent FOB assess such functions as home cage and open field activity, stimulus reactivity, and neuromuscular function. The dog FOB emphasizes evaluation of gait, postural reactions, and reflex function. The strategy taken has been to incorporate the primary rodent tier screen into repeated dose preclinical studies. Positive findings would trigger a secondary tier of testing, which would involve the use of more complex and integrated tests of neurobehavioral function. The methodologies for both rodent and nonrodent primary tier screens, validation study results, and the scientific criteria that would trigger secondary tier testing are discussed.
Neuropathology As a Screen for Neurotoxicity Assessment
Authors: Broxup B.
Published: November 2007

Pathology has been a cornerstone of toxicity testing for many years and is an integral part of the primary tier screen in the testing of drugs and chemicals for neurotoxicity. Because of the special nature of nervous tissue and its anatomical complexity, the approach to the evaluation can influence in a major way the effectiveness of the task. This report discusses issues which may account for variation in the degree of neuropathological assessment between laboratories. Both systematic and flexible approaches to the evaluation of neuropathology are discussed.
Computer Pattern Recognition: Spontaneous Motor Activity Studies of Rats Following Acute Exposure to Triethyltin
Authors: Kernan W. J. , Hopper D. L. , Bowes M. P.
Published: November 2007

A computer pattern recognition system, RAPID, was used to measure the spontaneous activity of male Sprague-Dawley rats during six observational periods distributed over 11 days after a single oral dose of triethyltin bromide (TET) at 3 or 5 mg/kg. These observational periods were distributed between those taken under red light conditions during the animals normal dark cycle (Days 2, 7, and 10 after exposure) and those taken under white light conditions during the animals normal light cycle (Days 3, 6, and 11 after exposure). Significant disruption of the normal behavioral patterns were observed on Days 2 and 7 for the 3 mg/kg-exposed group and on Days 2, 3, 6, 7, and 10 for the 5 mg/kg-exposed group.
The Use of Glial Fibrillary Acidic Protein in First-Tier Assessments of Neurotoxicity
Authors: O'Callaghan James P.
Published: November 2007

Diverse neurotoxic insults result in proliferation and hypertrophy of astrocytes, a subtype of central nervous system glia. The hallmark of this response, often termed “reactive gliosis,” is the enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). These morphological observations suggest that GFAP may be a useful biochemical indicator of neurotoxicity. To investigate this possibility we have administered prototype neurotoxicants to experimental animals and then assessed the effects of these agents on the tissue content of GFAP, as determined by radioimmunoassay. We found that assays of GFAP reveal dose-, time-, and region-dependent patterns of neurotoxicity at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. No false positives have been seen following exposure to a variety of pharmacological agents. By using regional assessments of GFAP in a first-tier evaluation, it should be possible to localize areas of damage. A second-tier evaluation, using assays of proteins or transmitters associated with cells in the affected region, may reveal the cellular targets of neurotoxicity. This two-tiered approach should serve as a foundation for guiding studies aimed at determining mechanisms of neurotoxicity.
Caprenin 2. Short-Term Safety and Metabolism in Rats and Hamsters
Authors: Webb D. R. , Peters J. C. , Jandacek R. J. , Fortier N. E.
Published: November 2007

A series of short-term feeding studies was undertaken to evaluate the biological effects of three behenic medium-chain triglycerides (BMCTs), including caprenin (CAP). All three triglycerides were composed primarily of caprylic (C8:0), capric (C10:0), and behenic (C22:0) acids, although total fatty acids compositions differed slightly. In the first experiment, adult male rats were maintained for 23 days on semipurifled diets containing 26% (w/w) of a BMCT, medium-chain triglyceride (MCT) oil or corn oil. Each triglyceride was assessed for its effects on growth, feed efficiency, calcium and iron balance, fat balance, and carcass fatty acid composition. A 28-day study of similar design evaluated the nutritive properties of chow diets that were supplemented with 15% of a BMCT or MCT when consumed by adult male golden Syrian hamsters. Finally, a 28-day feeding study in weanling male and female rats was conducted to assess the potential oral toxicity of CAP. CAP was administered in semipurifled diet at 0, 5, 10, and 15%. Corn oil was added at 18, 13, 8, and 3%, respectively, to maintain total dietary fat content at 18% and provide a source of essential fatty acids. The overall results of these experiments demonstrated that (1) BMCTs, including CAP, provided usable energy to sustain growth in rats and hamsters, although these triglycerides had lower calorie values than typical fats and oils, (2) up to 75–82% of the behenic acid content of BMCTs was unabsorbed by both species and excreted in the feces, (3) increased fecal excretion of BMCT-derived behenic acid did not significantly affect calcium and iron balance in rats, (4) behenic acid was metabolized readily by both rats and hamsters as indicated by recovery of only 3–15 % of the absorbed fatty acid in total carcass fat at the end of the studies, and (5) CAP was nontoxic to rats when consumed for 28 consecutive days at levels of up to 15% in the diet (83% of total dietary fat).
Application of the Principles of Total Quality Will Improve Science and Compliance
Authors: Siconolfi Richard M.
Published: November 2007

The scientific method was developed over a long period of time by many scientists from different disciplines. The procedure starts with an observation and the defining of a problem. This lead to postulating a hypothesis, conducting an experiment, and formulating a theory. The theory is then retested. Good Laboratory Practice (GLP) compliance was the first imposition of quality on top of the normal science process. To date, this improved compliance has contributed to documentation of science, but it has not done much to improve science itself. By learning and practicing the principles of total quality, both science and compliance can improve. The result of using the total quality principles is conducting toxicology studies right the first time. This goes beyond the GLPs and is not in opposition to them. Total quality requires planning, proper project execution, unbiased analysis of data, and reviewing and improving the process by capturing the good points and improving the weak ones. This process is very similar to the scientific method and consistent with good science. To use these principles in the management of a toxicology study, we must be good communicators and develop a common understanding with all professionals involved.
Who Are the Players, and What Do They Bring to the Science and Compliance Teams?
Authors: Pomerleau Patricia O'Brien
Published: November 2007

The aim of a Good Laboratory Practice (GLP) toxicology study is to provide useful information on the toxicity of a compound to a multiplicity of internal and external groups. Using the principles of total quality management (TQM), a multidisciplinary team is formed to plan the strategy for either an improvement or a change in a GLP toxicology study. The team members use their respective expertise to clarify their expectations and jointly define a common goal. Through carrying out the planned improvement or change, assessing the results, and replanning a GLP toxicology study, the stage is set for a continual improvement process. At the heart of the process is the willingness of team members to openly communicate and work together toward a common goal. The end result of using a dynamic TQM approach is that a GLP toxicology setting can result in continual improvements, better study planning, and a decrease in defects. Science and GLP compliance become members of the same team and a winning combination for successful management of GLP toxicology studies.
Study-Planning with Science and Compliance as the Driving Forces
Authors: Christian Mildred S.
Published: November 2007

Science and compliance are not competing forces. Only by simultaneous application of scientific principles and compliance requirements can appropriate, replicable safety evaluations be produced. Our organization has developed a system, identified as Telstar, by which teams that include members from each department are assigned to each study before its initiation and continue to be involved with the study until issue of the final report. This team is identified on the basis of appropriate expertise and experience and representation of appropriate areas. The Telstar team for each study includes the study director/report coordinator, the principal technician, the animal care technician, the data specialist, the information specialist, and the quality assurance auditor. Start and end times are assigned to each study period, including protocol approval, the various phases of study conduct and critical phase audits, specific raw data audits, beginning and ending of the in-life phase meetings, preparation of intermediate and final tables, review of tables, review of report results with senior staff, report writing by the study director, submission of report to senior staff, revision times, submission of report to quality assurance for audit, final review by study director after the quality assurance audit, final review by management (including review of the quality assurance audit results for the report), and report issue. Throughout the study, various team members interact with the study director, and scheduling is checked at twice-weekly management meetings, allowing study design and milestones to be modified if necessary. Use of this project team, with the study director coordinating specialists from each area, results in a quality product that meets all needs.
Use of Total Quality Principles Can Result in Faster, Clearer, and More Accurate Reports That Are of Greater Value to the User
Authors: Nixon Gerald A.
Published: November 2007

Successful completion of any study is the timely preparation and distribution of an accurate, understandable, and useful report. The report should include all details of study procedures and results plus conclusions based on thoughtful consideration of the data. Overall, responsibility for a study report should belong to the study director. Contributing scientists and scientific writers should work closely with the study director in establishing timing and format. Review by one or more peers is an effective means of assuring that the report is scientifically valid and that conclusions drawn are sound and accurate. Review by the quality assurance unit (QAU) helps assure that the report accurately reflects the raw data and that all pertinent data are included in the report. However, although the foregoing are necessary, they are not sufficient. It is crucial that the study director and other report contributors have a clear understanding of the expectations and needs of the sponsor before the report is assembled. A total quality approach to planning and preparing the report will result in a high-quality document.
Science Versus Compliance Equals Less Than Total Quality
Authors: King Helen M. , Snyder Frederick G.
Published: November 2007

The scope of this presentation is to discuss why a Total Quality System is a fundamental and essential entity of the scientific planning, conduct, reporting, and overall management of a research study or program. Inclusive of a total quality system is the partnership realized between science and compliance both from the end product perspective, e.g., meeting testing guidelines/standards, IND and NDA requirements, as well as administrative or regulatory perspective e.g., GLPs, GMPs, or the various clinical regulations/standards. AH study participants interact continually as customers and suppliers and as such must know the requirements of others. The roles often change during this process so communication is key to keeping this conduit open and productive. If, however, interaction is minimal or nonexistent and individuals work in isolation, this will be perceived as an antagonistic and even adversarial state. In the latter, problems which evolve will not be resolved but will manifest themselves in another form. Rarely is the cause of the problem brought to the surface. In this situation, the process still has flaws and the individuals involved feel frustrated, because they were never considered as an integral part of the solution; some may not feel part of the process. This process exists because of the adversarial relationship created and, therefore, someone has to win when, in fact, everyone loses. The cost of rework is also a major consideration since this is an add on to the product or service with no value added. In this scenario this is always a given. A total quality program builds personnel interaction and management involvement into the process; stresses continual communication, and, assures that all requirements are clear and are in harmony with the common goal. For a TQM program to be successful, it must be driven from the top down with all individuals completely involved in the process. Only when science and compliance are in harmony can total quality be achieved.
From conceptual intention to utterance: A study of impaired language output in a child with developmental dysphasia
Authors: Chiat Shula , Hirson Allen
Published: November 2007

This is a psycholinguistic case study of a child whose linguistic output is often unintelligible or ungrammatical, and who has been diagnosed as developmental dysphasic. It explores the conceptual intentions expressed in the child's spontaneous utterances, and her linguistic mapping of these intentions. Analysis of the scope and limits of her output reveal:

a variety and complexity of conceptual intentions which exceed her ability to map these intentions linguistically;

constituent structures which are intact from a gross syntactic, semantic, and phonological (prosodic) point of view;

omissions and substitutions which affect syllables within words and words within sentences according to their place within the prosodic structure of the word or sentence, those items which occur pre‐stress being most vulnerable;

lexical substitutions affecting words which are semantically and syntactically contingent on the head they modify.

It is suggested that phonological constraints, which limit the processing of phonological detail within a rhythmic structure, and which may be affected by certain semantic factors, are responsible for the child's impaired output. These conclusions are discussed in relation to current research in the field, raising specific questions for further psycholinguistic investigation into developmental dysphasia.
The basis of language impairment in children: A comment on Chiat and Hirson
Authors: Fletcher Paul
Published: November 2007

Pinpointing the source of a gap in a child's linguistic repertoire, as revealed by a surface profiling approach, is not straightforward. For any one syntactic category deficit, for example, there may he a number of possible sources. To begin to conceptualise the potential bases of language impairment it is helpful to make explicit a structure‐process distinction (as Chiat and Hirson implicitly do), and to modularise the various components of a model that takes this distinction seriously. It may then he possible to locate the source of impairment more reliably. While it is conceded, with reference to an outline modular framework, that the Chiat & Hirson case study does show problems which for the most part can be located in a phonological processing component, it is suggested that this is unlikely to be true of all, or even the majority, of complex language impairments. The proposed framework, if it can be properly specified, may assist in the delineation of a more successful typology of language impairment.
Coexisting psychogenic and neurogenic dysphonia: A source of diagnostic confusion
Authors: Sapir Shimon , Aronson Arnold E.
Published: November 2007

Four patients are described who had neurologic disease and accompanying dysphonia that proved to he partially or entirely psychogenic. The findings suggest that the association of a speech disorder with organic disease does not necessarily imply a causal relationship, even when the speech signs seem to arise from the site or organ system affected by disease. The potential for psychogenic factors to confuse the differential neurologic diagnosis of speech disorders is emphasised.
Paediatric speech and language therapy referral in Singapore: implications for multilingual language disability
Authors: Gupta Anthea Fraser , Chandler Helen
Published: November 2007

Abstracts

Singapore is extremely multilingual, a situation that presents many difficulties for speech and language therapists. A prevalent attitude of tolerance of language use appears to mask language disability in children, and referral rates are low.

Singapour est caracterisé par un multilinguisme extrème, qui pose plusieurs types de difficultés aux orthophonistes. Il est possible que l'attitude générale de tolérance envers les langues parlées masque l'existence de troubles linguistiques chez les enfants, ce qui serait en partie la cause d'une taux bas de consultation.

Singapur ist eine vielsprachige Stadt, ein Zustand, der für den Sprech‐ und Sprachtherapeuten viele Probleme mit sich bringt. Die vorherrschende Toleranz gegenüber unterschiedlichem Sprachgebrauch scheint Sprachbehinderung in Kindern zu maskieren, und Überweisungen für Therapie sind relativ selten.
Speech pattern audiometry for clinical use
Authors: Hazan V. , Wilson G. , Howells D. , Miller D. , Abberton E. , Fourcin A.
Published: November 2007

ABSTRACTS

A new PC‐based speech perception testing system (‘speech pattern audiometer’) is described which aims to provide a simple and efficient clinical tool to assess patients' ability to make use of the acoustic speech pattern information which is fundamental to speech perception. The speech pattern audiometer is likely to find its main application in audiology and speech and language therapy clinics with those who are deaf or who have developmental or acquired speech‐perceptual disorders. This system constitutes a module of a complete speech and hearing assessment and teaching/therapy workstation.

Un système de tests par logiciel de la perception de la parole (‘Audiomètre des Types de Parole’) est décrit; ce système a pour but de fournir un outil clinique simple et efficace pour mesurer la capacité des patients d'utiliser l'information, provenant des types acoustiques de la parole, qui est fondamentale pour la perception de celle‐ci. Il est probable que l'Audiomètre des Types de Parole trouvera son utilité principale en audiologie et dans les cliniques de thérapie du langage et de la parole, chez ceux qui sont atteints de surdité ou qui souffrent de troubles de perception de la parole qui apparaissent lors de la croissance ou qui sont acquis plus tard. Ce système constitue un module d'une station complet d'évaluation et d'enseignement et thérapie de la parole et de l'audition.

Ein neues PC‐System zum Testen der Sprachperzeption (‘speech pattern audiometer’ = ‘Sprachmuster Audiometer’) wird beschrieben, das als einfaches und effizientes Gerät zur Bewertung der Fähigkeit von Patienten, die für die Sprachperzeption grundlegende akustische Information zu verarbeiten, eingesetzt werden soll. Das Sprachmusteraudiometer wird hauptsächlich in audiologischen und logopädischen Zentren bei Patienten mit Gehörsstörungen und mit entwicklungsmä***ßigen oder erworbenen Sprachperzeptionstörungen Anwendung finden. Das System stellt ein Modell für eine ganze Arbeitsstation zur Bewertung und zur Therapie des Sprechens und Hörens sowie zum Einsatz in der Lehre dar.
Electrolaryngography in the assessment and treatment of incomplete mutation (puberphonia) in adults
Authors: Carlson Eva
Published: November 2007

ABSTRACTS

Puberphonia, or incomplete mutation of the adult voice, is a condition which causes the sufferer considerable distress and which carries a powerful social stigma. It can usually be treated successfully by a few sessions of speech therapy. This paper describes how these sessions may be made more effective by using laryngography to provide immediate visual feedback to the speaker in the form of the Lx waveform. Fundamental frequency distributions, measured from conversational and formally read passages, are also presented. These demonstrate the substantial lowering of pitch and reduction of pitch irregularity achieved after voice therapy. It is demonstrated that the perception of normal male voice quality is not only a matter of pitch but also involves a shift towards a longer closed quotient of the male chest register Lx waveform pattern.

La puberphonie, ou mue incomplète de la voix adulte, est un état qui cause une détresse considérable à celui qui en souffre, et qui est fortement montré du doigt du point de vue social. Quelques séances d'orthophonie réussissent le plus souvent à en venir à bout. Cet article décrit comment ces séances peuvent e̊tre rendues plus efficaces gråce à l'emploi de la laryngographie, qui fournit immé‐diatement au locuteur un renseignement visuel en retour sous la forme de la courbe de fréquence Lx. L'on présente aussi des distributions de fréquences fondamentales, mesurées àpartir de passages de conversations et de lecture formelle, qui montrent l'abaissement considérable de la hauteur et la réduction des irrégularités de hauteur obtenus aprés l'orthophonie. L'on démontre que la perception de la qualité normale de la voix masculine n'est pas seulement une question de hauteur, mais qu'elle implique une tendance à un quotient de fermeture plus long du type de courbe Lx du registre normal de la voix masculine.

Puberphonie, die unvollständige Mutation der Stimme bei Erwachsenen, ist ein Zustand, der beträchtliches Leiden für die betroffene Person verursacht und ein starkes soziales Stigma mit sich bringt. In der Regel kann sie mit Sprechtherapie in relativ kurzer Zeit erfolgreich behandelt werden. Hier wird beschrieben, wie die Behandlung durch den Einsatz der Laryngographie effektiver gestaltet werden kann, um mit dem Lx‐Signal dem Sprecher unmittelbare visuelle Rückkopplung zu geben. Grundfrequenzverteilungen von freier Unterhaltung und gelesenen Texten werden ebenfalls gezeigt. Diese illustrieren die beträchtliche Senkung des Stimmtons und die Reduktion der Stimmtonunregelmä***ßigkeit nach der Stimmtherapie. Es wird gezeigt, da***β die Perzeption einer normalen männlichen Stimmqualität nicht nur eine Frage der Tonhöhe ist, sondern auch mit einer Änderung zu einer längeren geschlossenen Phase hin zusammenhängt, wie sie beim Brustregister in der Lx Schwingungsform bei Männern üblich ist.
EPG bidimensional data reduction
Authors: Nguyen Noël
Published: November 2007

ABSTRACTS

A new method of electropalatographic (EPG) data reduction is proposed. It uses the so‐called discrete cosine transform for representing an EPG pattern as a weighted sum of elementary ‘pictures’. It is shown that several of these pictures can be considered as being articulatorily relevant. The respective contributions of these pictures to the spatial arrangement of the linguopalatal contacts are given by transform coefficients which are used here as a set of new EPG indices: the scaled sum of contacts index (SSU), the left–right asymmetry index (LRA), the alveolar–palatal index (APA) and the lateral–median index (LME). It is shown that the information extracted from an EPG pattern by means of these indices is maximised. Because of its robustness, this method could be usefully employed in studies on articulatory disorders.

On propose ici une nouvelle méthode de réduction des données électropalatographiques (EPG). Elle utilise ce qu'on appelle la transformée cosinus en discrète pour représenter un patron EPG comme une somme d'‘images' élémentaires. Il est démontré que plusieurs de ces images peuvent e̊tre considérées comme pertinentes du point de vue articulatoire. Les contributions respectives de ces images à l'organisation spatiale des contacts linguo‐palataux sont données par les coefficients de la tranformée, que l'on utilise ici comme un ensemble de nouveaux indices EPG, à savoir: la somme de normalisée contacts (en anglais: SSU), l'indice d'asymétrie gauche–droite (en anglais: LRA), l'indice alvéolo‐palatal (en anglais: APA), et l'indice latéral–médian (en anglais: LME). On montre que l'information extraite d'un patron EPG au moyen de ces indices est maximisée. En raison de sa robustesse, cette méthode pourrait e̊tre employée de manière fructueuse dans des études sur les troubles articulatoires.

Eine neue Methode der Datenreduktion für die Elektropalatographie (EPG) wird vorgeschlagen. Sie verwendet die sogenannte diskrete Cosinus‐Transformation, um EPG‐Muster als gewichtete Summe einfacher ‘Bilder’ zu repräsentieren. Wir zeigen da***β mehrere dieser Bilder als artikulatorisch relevant betrachtet werden können. Den entsprechenden Beitrag der Bilder zum räumlichen Muster der linguopalaten Kontakte ergeben die Transferkoeffizienten, die hier als neue EPG‐Indizes verwendet werden: Das skalierte Kontaktsummenindex (SSV), das Links‐Rechts‐Assymetrieindex (ARA) das Alveolar‐Palatalindex (APA) und das Lateral‐Medianindex (LME). Es wird gezeigt, da***β die aus dem EPG‐Muster abgeleitete Information durch diese Indizes maximiert wird. Aufgrund ihrer Robustheit ist unsere Methode für die Untersuchung artikulatorischer Störungen nützlich.
New developments in EPG3 Software
Authors: Jones W. , Hardcastle W. J.
Published: November 2007

ABSTRACTS

New developments in EPG3 software are described including: a three‐dimensional display of the electrodes on the palate in the form of a wire frame representation; a facility for annotating EPG3 files; and a new data management system. Recent methods of EPG data reduction are also described, including numerical indices for representing tongue–palate contact profiles. A new clinical version of the Reading EPG system, EPG4, is introduced.

L'on décrit ici les progrès récents en matière de logiciels concernant l'électropalatographie tridimensionnelle; sont décrits tout d'abord une représentation à trois dimensions, au moyen d'un modèle en treillis, des électrodes posées sur le palais; puis une technique qui permet d'annoter les dossiers d'électropalatographie; et un nouveau système de gestion des données. L'on décrit également les méthodes récentes pour réduire les données électropalatographiques, y compris des indices numériques pour représenter les profils de contacts linguo‐palataux. Et l'on presente une nouvelle version clinique du système électropalatographique de Reading, à savoir l'EPG4.

Neue Entwicklungen der EPG3‐Software werden beschrieben: Eine dreidimensionale Darstellung der Elektroden am Gaumen in Form einer Drahtgestellrepräsentation; ein System zur Annotation von EPG3‐Dateien; ein neues Datenverwaltungssystem. Neuerer Methoden zur Reduktion von EPG‐Daten werden auch vorgestellt, u.a. numerische Idizierung zur Darstellung von Zungen‐Gaumen‐Kontaktprofilen. Eine neue Klinikversion des Reading'schen Systems, EPG4 wird präsentiert.