Biomedical subjects
A Foster
Publications and source records attributed to A Foster.
Metabolism and excretion of exogenous [3H]-LTC4 in primates.
Four novel omega- and beta-oxidation (from the omega end) products of peptide leukotrienes, 20-hydroxy and 20-carboxy-LTE4, 18-carboxy-19, 20-dinor-LTE4 and 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-LTE4 were prepared by total synthesis and used as standards for identification of biliary and urinary metabolites in the cynomolgus monkey. After intravenous administration 14, 15-[3H] leukotriene C4 (10 microCi kg-1) was partially metabolized in and rapidly cleared from the vascular circulation. This resulted, within 24 hours, in significant urinary excretion (14.8 +/- 2.1%, n = 4), consisting largely of material more polar than LTE4 (61% of urinary excretion) as shown by reverse phase HPLC. The polar fraction demonstrated two predominant metabolites which coeluted in several HPLC solvent systems with synthetic 16-carboxytetranordihydro-LTE4 (major component) and 18-carboxydinor-LTE4 (minor component). Characterization of the major polar metabolite as 16-carboxytetranordihydro-LTE4 was substantiated by conversion to its N-acetylated derivative. The absence of the 14, 15 double bond was confirmed by product analysis of oxidative ozonolysis. In a single animal, the bile duct was cannulated, with significant biliary excretion of radioactivity demonstrated over 4 hours (58.6% recovery). The predominant polar biliary metabolites were also identified as the 18-carboxydinor and 16-carboxytetranordihydro derivatives of LTE4 mentioned above. These data suggest that beta-oxidation products generated from the omega-carboxyl end of the 20-carboxy-LTE4 are important products of [3H] LTC4 metabolism in the monkey. Quantitation of these urinary metabolites may be an important index of in vivo leukotriene production.
The "cage" splint: an added protection for flexor tendon repair.
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Metabolism of leukotriene C4 in the anesthetized guinea pig.
The distribution and metabolism of [3H] leukotriene (LT)C4 has been studied in the anesthetized guinea pig. The intravenous administration of [3H] LTC4 (1 muCi/kg) to seven guinea pigs showed a rapid vascular clearance of radioactivity with significant metabolism evident at the 15 sec and 1 min time points with material chromatographing like LTC4 (45.6 +/- 7.5%, 35.0 +/- 4.4%). LTD4 (18.4 +/- 5.1%, 33.2 +/- 4.4%) as well as polar material (25.5 +/- 6.0%, 29.7 +/- 4.7%) respectively. The biliary recovery of radioactivity was found to be 74.5 +/- 5.5% n = 4, over 120 min in the guinea pig with less than 1% of radioactivity present in the urine. Examination of the metabolic profile of the biliary radioactivity showed total conversion of LTC4 to LTD4 which was the major metabolite at early time points, and LTD4 as well as LTE4 at later time points. Significant radioactivity which increased with time was also present at the solvent front of the chromatogram indicating the presence of polar biliary metabolites. These results show that the major route of elimination of peptide leukotrienes is through the bile duct in the anesthetized guinea pig and that LTD4 is the major eliminated metabolite in this model.
Evaluation of ophthalmoscopy by nonophthalmologists in diagnosing chronic glaucoma in West Africa.
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Corn cures can damage your feet: an important lesson for diabetic patients.
Seven diabetic patients rapidly developed severe foot ulceration and sepsis after application of corn cures. Four patients needed forefoot surgery. Corn cures should not be used by diabetic patients.
Cutaneous anthrax leading to corneal scarring from cicatricial ectropion.
Eleven patients with cutaneous anthrax of the eyelids are presented. The complications were cicatricial ectropion (eight patients), resulting in corneal scarring (three patients). The ectropion was corrected by full thickness postauricular skin grafts, with good results. The predilection of this infection for the eyelids of young children and a seasonal variation suggest that a vector may be involved in transmission.
National survey of blindness and low vision in The Gambia: results.
A population based survey of blindness and eye disease has been conducted throughout the whole country of The Gambia, and 8174 people were examined. The prevalence of blindness (best acuity less than 3/60) was 0.7% and low vision (6/24-3/60) 1.4%. The causes of blindness were cataract (55%), non-trachomatous corneal opacity/phthisis (20%), and trachoma (17%). An estimated 5500 people in The Gambia require cataract surgery, 4600 eyelid surgery for entropion, and 4600 people spectacles to correct a refractive error which causes a visual acuity of less than 6/18. More than half the current burden of blindness in The Gambia is potentially remediable through the provision of cataract surgery and aphakic spectacles.
L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor.
L-663,536 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2, 2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMN) (IC50, 2.5 nM). Similarly, L-663,536 inhibited A23187-induced LTB4 formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1 microM), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 micrograms topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.
Immediate hypersensitivity reactions in the guinea-pig conjunctiva: studies with a second-generation leukotriene D4 receptor antagonist, MK-571.
The role of leukotriene D4 (LTD4) as a mediator of immediate hypersensitivity reactions in the guinea-pig conjunctiva was examined using a potent, second-generation LTD4 receptor antagonist, MK-571 (also known as L-660,711). The microvascular permeability changes in the guinea-pig conjunctiva following challenge with either LTD4 or antigen were measured through accumulation of intravenously administered 99mtechnetium-labeled albumin. Topical application of MK-571 (up to 2 h pretreatment) significantly inhibited the conjunctival responses to LTD4 (ED50 of 18-60 ng/eye) but not to histamine. The responses to a single topical antigen challenge in ovalbumin-sensitized guinea pigs were significantly inhibited (44%) by topical treatment with MK-571, in contrast to the lack of effect previously observed with prototypic antagonists. The inhibitory effects of MK-571 did not involve an action on conversion of [3H]LTC4 to LTD4 and LTE4. Following a second antigen challenge (24 h after the first), MK-571 inhibited the resultant permeability changes by 78%. Specific histamine H1 and H2 antagonists similarly inhibited the responses to the first and second challenges (63 and 74%, respectively). The present study suggests that LTD4 is involved in conjunctival hypersensitivity reactions and that potent LTD4 receptor antagonists may be of therapeutic value in the treatment of allergic conjunctivitis.
Ocular trauma.
Well over half a million people in the world are blind as a result of eye injuries. It is not known how much of the final visual damage is the result of delayed or inappropriate management at the primary care level. However, it is certain that the outcome of ocular trauma by prompt action that will prevent serious loss of sight. He or she requires neither specialist knowledge, nor expensive instruments, but only the common sense application of a few basic clinical skills.
Metabolism of peptide leukotrienes in the rat.
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The in vivo production of peptide leukotrienes after pulmonary anaphylaxis in the rat.
Inbred hyper-reactive rats, actively sensitized to OVA, were anesthetized, cannulated, and ventilated with room air. Tracheal instillation of Ag (OVA) resulted in an elevation of airways pressure (14.4 +/- 0.6 cm H2O). Measurement of biliary peptide leukotriene levels before and after Ag challenge using reverse phase HPLC and RIA techniques showed significant elevations in leukotriene (LT) levels, the amounts released being LTC4 (3.65 +/- 0.78), LTD4 (2.8 +/- 1.11), and N-Ac LTE4 (3.87 +/- 1.15) expressed as ng/100 g of body weight, n = 13. Identification of these metabolites were confirmed by HPLC/RIA techniques and LTC4 was further characterized by UV spectroscopy and its enzymatic conversion by gamma-glutamyl transpeptidase to LTD4. [3H]LTC4 (16 ng) administration by tracheal instillation resulted in a 31.4 +/- 4.3% recovery of radioactivity through the bile over 4 h (n = 3) with the major identified metabolite being N-Ac LTE4. [3H]LTC4 (16 ng) plus synthetic LTC4 (5 micrograms) showed a 30.8 +/- 3.1% recovery through the bile after tracheal instillation (3-h collection, n = 4) with significant amounts of LTC4 as well as N-Ac LTE4 present. [3H]LTC4 administration by the portal vein resulted in a 37.4 +/- 8.8% biliary recovery over 60 min (n = 6), the metabolites present in the bile being LTC4, LTD4, LTE4, and N-Ac LTE4. Pretreatment with the 5-lipoxygenase inhibitor L-656,224 (15 mg/kg, 3.5 h pre-p.o.) before Ag challenge resulted in a significant inhibition (greater than 90%, p less than 0.05) of biliary leukotriene levels in this model. Our study demonstrates that peptide leukotrienes are produced in the anesthetized rat after pulmonary anaphylaxis and that biliary leukotriene measurement is suitable for showing the biochemical efficacy of leukotriene inhibitors in vivo. In vivo tracer experiments suggest that the biliary metabolic profile of the peptide leukotrienes is dependent on the site and levels of release as well as the efficiency of the vascular clearance of the various metabolites.
Synthesis of beta-oxidation products as potential leukotriene metabolites and their detection in bile of anesthetized rat.
Two novel beta-oxidation products of peptido leukotrienes, 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetyl LTE4 and 18-carboxy-19,20-dinor-N-acetyl LTE4, were prepared by total synthesis and used to identify previously unknown polar rat biliary metabolites. When [3H] LTC4 and synthetic N-acetyl-LTE4 were administered intravenously to anesthetized inbred male rats, extraction of the bile and subsequent reverse-phase HPLC fractionation allowed the isolation of two novel metabolites of N-acetyl-LTE4. Comparison of U.V. spectra and coelution experiments revealed that these metabolites correspond to the above-mentioned synthetic beta-oxidation products. This was further confirmed by the coelution of the corresponding methyl esters. Oxidative ozonolysis of the metabolically produced 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetyl LTE4 (major metabolite) confirmed the absence of the 14,15-unsaturation. The presence of these metabolites indicates that peptide leukotrienes undergo N-acetylation followed by omega and subsequent beta-oxidation in the anesthetized rat.
Some aspects of lumbrical function.
An electromyographic investigation was performed on the hands of six volunteers. The functioning of the lumbrical and flexor digitorum profundus muscles during resisted and unresisted extension was studied. No subject showed much simultaneous contraction of the two muscles in unresisted extension of the interphalangeal joints, but some showed marked simultaneous contraction during resisted extension. We suggest that, in these individuals, the profundus is acting to steady the origin of the lumbrical so that it can act more efficiently.
Anaphylatoxin C3a peptide contracts human pulmonary vasculature.
Complement anaphylatoxin C3a C-terminus octapeptide Ala-Ala-Ala-Leu-Gly-Leu-Ala-Arg (C3apep) contracted both pulmonary artery (PA) and pulmonary vein (PV) in a dose-dependent manner over the concentration range of 0.1 micrograms/ml to 100 micrograms/ml with the latter having maximal contractile activity. Removal of the terminal arginine caused complete loss of activity of C3apep. Contractions consisted of an early and a sustained component with the latter component being much greater in PV than PA. The early component was inhibited by pretreatment of tissues with the cyclooxygenase inhibitor indomethacin, or the thromboxane synthase inhibitors dazoxiben or U63,557A. The sustained contractile component was inhibited by the leukotriene antagonist FPL55712 or the 5-lipoxygenase inhibitors U60,257 (Piriprost) or nordihydroguaiiararetic (NDGA). C3apep challenge of both PA and PV resulted in the generation of leukotriene C4. These results suggest that C3apep causes contraction of human pulmonary arteries and veins by the production of thromboxane A2 and leukotrienes.
Measles, corneal ulceration and childhood blindness: prevention and treatment.
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