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Biomedical subjects

L Harrington

Publications and source records attributed to L Harrington.

48 records · Page 3Linked to original sources
PubMed1991

Developmental analysis of ocular morphogenesis in alpha A-crystallin/diphtheria toxin transgenic mice undergoing ablation of the lens.

The role of the lens in early eye development was examined in transgenic mice carrying the cytotoxic diphtheria toxin A gene driven by hamster alpha A-crystallin promoter sequences. Mice hemizygous for this construct are microphthalmic and contain a vacuolated and highly disorganized lens, whereas adult homozygous mice are completely ablated of the lens and lack a pupil, aqueous and posterior chamber, vitreous humor, iris, and ciliary body and show extensive convolution of the sensory retina. Developmental analysis of animals homozygous for the transgene revealed that the optic cup and lens vesicle form normally and that ablation of the lens occurs as a gradual degenerative process beginning between Days 12 and 13 of gestation. Degeneration of the lens vesicle coincides with retarded growth and development of the neuroretina, sclera, and cornea. The anterior lip of the optic cup fails to differentiate into the normal epithelium of the iris and ciliary body and the vitreous body does not develop. Although the retinal layers apparently form normally, retinal folding becomes prominent following lens degeneration. These results suggest that development of a functional lens from Embryonic Day 12.5 onward is critical for formation of the ciliary epithelium, iris, and vitreous body, as well as for appropriate growth, development, and maintenance of morphology of the retina, cornea, sclera, and optic nerve. Our results also provide information on the time course of DT-A-mediated cell destruction in vivo and are discussed in context with previous lens ablation studies and the importance of developmental analysis for interpretation of the extent to which morphogenetic aberrations are concurrent with or secondary to genetic ablation of the target tissue.

Animals↗
PubMed1990

Heparin-induced thrombocytopenia and thrombosis syndrome: a case study.

Heparin is a commonly used drug in critical care. In this case study we describe a relatively unknown and unforeseen event whereby the administration of heparin to prevent thrombus formation paradoxically resulted in clot formation. Heparin-induced thrombocytopenia and thrombosis syndrome developed in a 36-year-old woman initially admitted to the coronary care unit with complaints of chest pain. We explore the theoretic basis of this syndrome as an immune-mediated response, along with the mechanisms leading to this syndrome as an immune-mediated response, along with the mechanisms leading to the clinical features and the difficulties associated with diagnosis treatment. In view of the frequent use of heparin and nurses' responsibility for recognizing the untoward effects of medications they administer, this case study is useful in gaining insight into a relatively unknown phenomenon.

Adult↗
PubMed1984

A review of the Food and Drug Administration risk analysis for polychlorinated biphenyls in fish.

This paper reviews the Food and Drug Administration (FDA) analysis of the risk to humans from consuming fish contaminated with polychlorinated biphenyls (PCBs). In brief, the FDA methodology employed "high" dose experiments on animals and extrapolated the observed rates of certain types of cancer at these elevated doses to the low doses found in human diets. These extrapolations were then used to define a recommended tolerance level of 5 ppm, and proposed reduction to 2 ppm, for fish sold in interstate commerce. Unfortunately, as is shown here, such a procedure is extremely sensitive to the basis for extrapolation. Important elements of the FDA analysis include the following: (i) FDA assumed a particular form of the dose-response model: the one-hit model. Many other models have been proposed and, on balance, appear equally plausible. These models estimate lower risks than does the one-hit model. (ii) FDA calculated 99% upper confidence bounds on these risks and, moreover, emphasized cases of fish eaters who consume greater amounts of PCB-contaminated fish than do 98.5% of the U.S. population. (iii) FDA based PCB ingestion computations on consumption of raw fish, whereas most fish are cooked before eating, and it is known that PCB levels in cooked fish are lower than PCB levels in raw fish. (iv) FDA based estimates of cancer risk on the assumption that PCB levels in fish would be constant over the nominal 70-year human life span used in the FDA "lifetime risk" computation. Recent data suggest that PCB levels have been declining in fish (particularly in sport fish) and humans as well. Such trends imply significantly lower cumulative lifetime PCB doses than were assumed in the FDA analysis. (v) FDA assumed that humans and test animals are equally sensitive to PCB ingestion when measured on a parts per million in diet basis. Extrapolations on an equivalent consumption per unit of body weight, thought appropriate by most researchers, result in much lower health risks. In short, when confronted with methodological choices, the FDA consistently selected "worst case" or conservative assumptions over other alternatives of at least equal plausibility. This philosophy of choice was explicitly acknowledged by the FDA. What was omitted from the FDA analysis, however, was the possible degree of overstatement of these risks. The results of replicate risk computations using alternative assumptions to examine the possible magnitude of overstatement of health risk are summarized in Table 12. As can be seen, this overstatement could easily account for a discrepancy of several orders of magnitude between actual and calculated risks.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1973

Voltage clamp of cardiac muscle in a double sucrose gap. A feasibility study.

A method of stabilizing the membrane potential of a small area of cardiac muscle membrane and the limitations of this method are described. Tiny bundles or strands, approximately 80 mum in diameter, of electrically interconnected fibers from the ventricles of rabbit hearts were used in a double sucrose gap. Current records associated with step changes in voltage were complicated by two capacitive surges of current of nodal and nonnodal origin and large "leakage" currents of nonnodal origin resulting mainly from the multifibered nature of the preparation and emphasized by the method. The transient, inward membrane currents in response to moderate depolarizing steps in command potential had the same duration as the upstroke of the action potential. In good runs, currents were smooth and free from notches. These initial currents behaved qualitatively like the initial sodium currents in squid axon and in other excitable membranes. A fraction of the initial sodium current persisted at least as long as 300 ms. The relationship between peak initial current and voltage was graded and linear in the positive direction. In the negative region the relationship was often very steep, indicating insufficient voltage control of all the membranes despite the squareness of the voltage record. Other indications of inadequacy of control could occur and thus even with this optimum preparation of cardiac muscle it was not feasible to analyze quantitatively either the initial or the prolonged sodium currents.

Action Potentials↗
PubMed1973

A linear dose-response curve at the motor endplate.

The motor endplate of frog sartorius muscle was voltage clamped and the peak current to different concentrations of acetylcholine and carbachol applied in the perfusing fluid was measured. Perfusing fluid was hypertonic in order to suppress contractions. Current responses were smooth and reached a peak value within 2-5 s. The dose-response curve was usually linear even with concentrations of 10(-2) M acetylcholine, indicating that the conductance change was probably proportional to the concentration of acetylcholine or carbachol. With high concentrations nonlinearity sometimes appeared but in these cases the fast onset of desensitization appeared to be preventing the current response from reaching its expected peak amplitude. When the depolarization produced by acetylcholine in a non-voltage-clamped endplate was measured the dose-response curve was hyperbolic. This relationship was imposed by the electrical properties of the endplate membrane and its surrounding sarcolemma, and could be predicted if the input resistance of the fiber was known. Experiments were also done on slow muscle fibers. Depolarizing analogues of acetylcholine had similar effects to acetylcholine. d-Tubocurarine reduced the proportionality constant between concentration of acetylcholine and conductance change, and this resulted in a parallel shift of the log-concentration depolarization curve. A linear dose-response curve was unexpected within the context of current theories of drug action.

Acetylcholine↗