Albert E. Langley

Thyroid, bradycardic and hypothermic effects of perfluoro‐n‐decanoic acid in rats

A single ip injection of perfluoro-n-decanoic acid (PFDA) to male Wistar rats resulted in an initially rapid, then gradual decrease in food consumption and a parallel loss of body weight. Body temperatures and resting heart rates were significantly depressed by PFDA treatment. As early as 12 h following a single dose of PFDA, serum thyroxine (T4) levels were significantly reduced and remained depressed throughout the 8 day study. Serum triiodothyronine (T3) was reduced by 35% 12 h following PFDA treatment and remained at that level throughout the study. These preliminary data suggest that an action on the thyroid axis may be an early primary response to PFDA and that some of the observed subsequent effects may in part be secondary to the change in thyroid hormone levels.

Mechanism of the serum thyroid hormone lowering effect of perfluoro‐n‐decanoic acid (PFDA) in rats

The mechanism and consequences of the serum thyroid hormone lowering effect of perfluorodecanoic acid (PFDA) were examined. Thyroid and pituitary gland functions in PFDA-treated rats were assessed by measuring radioiodine uptake from the circulation and the ability of the thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3) in response to thyrotropin-releasing hormone (TRH) stimulation. Serum levels of reverse triiodothyronine (rT3) were measured to test for possible conversion of T4 to a biologically inactive product and the displacement of radiolabeled T4 from rat albumin in vitro by PFDA was examined. Finally, changes in activity of the thyroid hormone-sensitive liver enzymes glycerophosphate dehydrogenase (GPD) and malic enzyme (ME) in response to PFDA were analyzed. Functional activities of the thyroid and/or pituitary glands appear to be somewhat depressed by PFDA treatment. There was no increased conversion of T4 to rT3. PFDA displaced radiolabeled T4 from rat albumin with an affinity similar to thyroxine. The activities of both GPD and ME were significantly increased in livers from PFDA-treated rats. These results suggest that decreased serum levels of thyroid hormones may be due to (1) reduced responsiveness of the thyroid and/or pituitary glands to hormonal stimulation and (2) a displacement of circulating hormones from plasma protein binding sites by PFDA. Increased activity of the liver enzymes GPD and ME does not reflect the reduction in circulating thyroid hormones and indicates that PFDA-treated rats are apparently not functionally hypothyroid at the tissue level.

Effect of thyroxine supplementation on the response to perfluoro-n-decanoic acid (PFDA) in rats

The effects of thyroxine (T4) supplementation on perfluoro-n-decanoic acid- (PFDA) induced decreases in food consumption, body weight, and body temperature were examined. A dose-response study was carried out with 50-, 100-, 200-, or 250-micrograms/kg ip doses of T4 for 7 d prior to PFDA administration, and daily dosing with T4 was continued for an additional 30 d. From this study a T4 dose of 200 micrograms/kg was chosen, and subsequent experiments were conducted with this dose. Supplementation with T4 at 200 micrograms/kg daily alleviated the hypophagia but not the severe weight loss and hypothermia produced by PFDA treatment. Our results suggest that some component of the thyroid axis plays a role in feeding behavior. In addition, the PFDA-induced wasting syndrome and hypothermia appear to be unrelated to changes in serum thyroid hormones. The unexpected observation that severe weight loss occurred in the presence of essentially normal food intake suggests that PFDA alters basic cellular metabolic processes.

Teaching Medical Faculty How to Apply Continuous Quality Improvement to Medical Education

BACKGROUND An eight-hour workshop was conducted at a professional meeting in 1996 to introduce medical faculty to the principles of continuous quality improvement (CQI) as they relate to change in medical education and to provide participants with opportunities to use specific tools for applications to education. Four two-hour sessions focused on an introduction to CQI, understanding and mapping processes, identifying change ideas, and testing a change for improvement. TESTING A CHANGE FOR IMPROVEMENT The goals of the final session were to plan a pilot test of an improvement, identify the steps of the plan-do-study-act (PDSA) cycle, and consider change for improvement in the context of ones own organization. Working in small groups, participants chose a specific change one might try in the following example: improving student performance in a neuroscience course. POSTSESSION EVALUATION AND FOLLOW-UP: Immediately following the workshop sessions, participants represented by administrators in medical education and clinical and basic science teaching faculty completed evaluations on the usefulness and likelihood of their using CQI tools. One year later, of the 32 workshop registrants who were mailed surveys, 15 respondents rated their change in understanding of CQI and their use of CQI techniques. More than 60% of the respondents reported application of CQI principles at their organizations. CQI methods used most frequently included structured team meetings, prioritizing opportunities, and brainstorming. CONCLUSION The significant application of CQI principles and methods reported by participants one year after a brief intervention supports a need and utility for CQI principles and tools in medical education.

The effects of perfluoro-n-decanoic acid in the rat heart☆

Perfluoro-n-decanoic acid (PFDA) is a synthetic chemical resembling a 10-carbon fatty acid. Several studies have suggested that the toxic mechanism of PFDA may involve impaired lipid metabolism and/or altered cell membrane function. We examined the possibility that altered cell membrane structure in the heart might lead to changes in the functional activity of the organ. Functional characteristics were determined in the isolated perfused rat heart by measuring the ability of the heart to respond to either sympathetic nerve stimulation or infused norepinephrine. PFDA reduced the intrinsic resting heart rate and the inotropic response to a stimulus with maximal effects occurring 8 days after dosing. In addition, resting heart rate measured in vivo was found to be reduced in PFDA-treated rats 6 to 8 days after dosing. beta-Receptor binding studies conducted 8 days after a single dose of PFDA showed that the maximum binding capacity was reduced by PFDA treatment without significant changes in receptor affinity. It is concluded that the reduction in the inotropic response to catecholamines following PFDA treatment may be explained in part by lower beta-receptor density in the myocardial cell membrane. These effects may be related to the early fall in serum thyroid hormone levels as previously reported.

The effects of perfluoro-n-decanoic acid (PFDA) on rat heart β-receptors, adenylate cyclase, and fatty acid composition☆

Perfluoro-n-decanoic acid (PFDA) is a member of a family of surfactants with numerous industrial applications. The acute toxicity of PFDA is characterized by body wasting and delayed lethality. Recent reports have indicated that the effects of PFDA may involve an action on the structure of biological membranes which results in an alteration of function. In the present study we extend our work on the membrane actions of PFDA by examining its effects on myocardial beta-adrenoceptor binding characteristics and adenylate cyclase. Following a single injection of PFDA the apparent number of beta-receptor binding sites was reduced compared to pair-fed controls. This change in beta-receptor binding capacity was reflected in a reduced ability of norepinephrine to activate adenylate cyclase. No alterations were observed in basal adenylate cyclase activity or in the ability of NaF or guanylyl imidodiphosphate to stimulate the enzyme. The fatty acid composition of the heart was changed by PFDA treatment. Our results suggest that the toxic effects of PFDA may be due to an alteration of the membrane lipid bilayer leading to changes in the functional activity of myocardial membranes.

Developing a community-academic health center: strategies and lessons learned

The purpose of this paper is to describe the process that Wright State University School of Medicine used to establish and build partnerships with various stakeholders in the City of Dayton, Ohio, to develop a community—academic health center. To ensure the success of this effort, it was important to identify key stakeholders in an inner city health center, and to establish effective partnerships with the stakeholders. Common goals were developed for the health center that met the expectations of all the partners. Application of the principles of Continuous Quality Improvement (CQI) led the group to define the set of common goals. The needs of the community were identified, and mechanisms to address the needs were developed using the tools of the CQI process. The programs emphasized health promotion by focusing on patient education and behavioral modification. Accepting the various priorities for the center enabled the School of Medicine to establish a quality community-based educational site for students...

Dopaminergic and Cholinergic Muscarinic Receptor Effects of L-Alphacetylmethadol (LAAM) and Its Metabolites

Abstract In isolated rat hearts L-alphacetylmethadol (LAAM) produced a concentration-dependent decrease in the spontaneous beating rate. This effect was completely prevented by 1.0 μM atropine. Chronic treatment of rats with LAAM increased the number of striatal dopamine receptors measured by [3H]spiroperidol binding. The affinity of these binding sites for [3H]spiroperidol was unchanged by LAAM treatment. There were no significant changes in the number or affinity of binding sites for the labeled muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) with chronic LAAM treatment. The ability of LAAM, nor-LAAM, or dinor-LAAM to antagonize the binding of [3H]spiroperidol (40 pM) or [3H]QNB (125 pM) to striatal membrane fragments was tested. The measured affinity constants for LAAM and metabolites were 100-3000 times higher than the affinity constants of unlabeled spiroperidol at [3H]spiroperidol binding sites. The affinity constants of LAAM and metabolites at muscarinic binding sites were 10-20 times higher than pilocarpine and 5000-8000 times higher than atropine. These results suggest that LAAM can produce some of its effects by acting as a weak agonist at muscarinic receptor sites.

Stereotypy and striatal dopamine receptor changes with l-α-acetylmethadol (LAAM)

Abstract Narcotics like morphine and methadone produce effects on striatal dopaminergic mechanisms as evidenced by changes in a stereotyped behavior induced by apomorphine and binding of radioactive ligands to dopamine (DA) receptors. LAAM may replace methadone in the treatment of narcotic addiction. We investigated the effect of LAAM on apomorphine induced stereotypy and the binding of 3 H-spiroperidol to dopamine receptors isolated from mouse and guinea pig striata. Chronic LAAM treatment produced a behavioral supersensitivity to apomorphine. The biochemical expression of the behavioral effect was a significant increase in the number of dopamine receptor binding sites in mouse and guinea pig striata. These effects can be due to either a direct chronic blockade of postsynaptic dopamine receptors or stimulation of a presynaptic receptor which acts to reduce the amount of dopamine released during nerve activity. Work is in progress to determine the mechanism of this effect.

Milrinone Produces a Positive Inotropy but is not Inhibitory to Gastric ion Transport

Abstract The cardiac drugs ouabain and milrinone are positive inotropic agents. Since ouabain has inhibitory effects on ion transport in the gastrointestinal tract associated with vasoconstriction and hypoxia, milrinone needed to be tested also. This report indicates that therapeutic levels of milrinone on either side of the isolated stomach wall of the guinea pig has no significant effects on active chloride ion transport or the electrical parameters of the tissue. To verify that milrinone was active in the heart at these same levels, contractility of the isolated heart of the guinea pig was measured. Milrinone significantly increased ventricular pressure and pressure development. Thus milrinone may be expected to exert its inotropic stimulation of the heart during heart failure without compromising gastrointestinal functions.