Biomedical subjects
Publications and source records attributed to J Fohlman.
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Rodioimmunoassayable somatostatin (SRIF) was found in acid ethanol extracts from various parts of the gastro-entero-pancreatic (GEP) endocrine system in reptiles, amphibians, teleost bony fish, cartilaginous fish, and jawless fish, as well as in a deuterostomian invertebrate, the tunicate, Ciona intestinalis. The cellular sites could, as a rule, be easily visualized light-microscopically by the peroxidase-anti-peroxidase (PAP) immunocytochemical procedure, using guinea-pig and rabbit antisera against synthetic SRIF. The standard Hellerström-Hellman technique, used to detect argyrophi SRIF-storing D cells, failed to visualize the SRIF cells in teh GEP endocrine system of the tumicate and of the jaw-less fish. Moreover, the results comfirmed the previous description that this technique only exceptionally (and sometimes only after further modifications) gave positive results when applied to the GEP endocrine system of bony fish, amphibians, and reptiles. In cartilaginous fish, however, it worked adequately and confirmed the radio-immunological and immunocytochemical observations. In the mucosa of the alimentary tract and in the parenchyma of its associated glands of one echinoderm and two pelecypod molluscs and one crustacean arthropod no sgns of the occurrence of SRIF-storing cells were observed using the three correlated procedures. In several of these tissues, signs of the occurrence of insulin-producing cells had perviously been observed. Thus, SRIF seems to appear at a later evolutionary stage than insulin. The principal islets (Brockmann corpusles) of the marine teleost fish, Cottus scorpius, had the highest concentrations of radioimmunoassayable SRIF of all the GEP organs and tissues investigated, viz. about 200 ng/mg wet weight. Nevertheless, it was only 1/5 of the actual insulin content.
Taipoxin (taipan toxin), purified from the venom of the Australian taipan (Oxyuranus s. scutellatus) by gel filtration on Sephadex G-75 followed by column zone electrophoresis, is the most lethal neurotoxin yet isolated from any snake venom. The LD50 is 2 mug/kg in the mouse. The main physiological effect is a gradual reduction to complete stop of evoked and spontaneous release of acetylcholine from motor nerve terminals. Intoxicated animals die of asphyxia caused by neuromuscular blockage of the respiratory muscles. Taipoxin is a moderately acidic sialo-glycoprotein (pI 5) with a molecular weight of 45 600 as calculated from composition data or 46 800 as determined by meniscus depletion sedimentation equilibrium. Taipoxin is a 1:1:1 ternary complex of subunits designated alpha, beta and gamma which dissociate completely at low pH and high ionic strength or in 6 M guanidine hydrochloride. The dissociation by guanidine at neutral pH is reversible, while the acid-induced dissociation is not . The alpha and beta components consist of 120 amino acid residues cross-linked by seven disulfide bridges, whereas the gamma component has 135 residues and eight disulfides. The very basic (pI Greater than 10) alpha component contains 13 residues of arginine and is the only subunit displaying lethal neurotoxicity (mouse LD50 approximately 300 mug/kg). The neutral beta fraction was separated by ion-exchange chromatography into two iso-component, beta 1 and beta2, which differ slightly in amino acid composition. The very acidic gamma component contains all of the carbohydrate, which includes 4-5 residues of sialic aid. The three subunits are homologous in sequence although the gamma component is eight residues longer on the N-terminus and must also contain extra amino acids elsewhere.
The isolated neurotoxins taipoxin and notexin from the venoms of the Elapidae, Oxyuranus scutellatus and Notechis scutatus scutatus respectively cause a neuromuscular block when administered to the mouse in vivo or to the phrenic nerve-hemidiaphragm preparation in vitro. The block is preceded by a latency period during which the toxins bind irreversibly to the nerve. The period is shortened by nerve activity. The frequency of the miniature end-plate potentials is gradually reduced, almost to zero, and their amplitude distribution is altered; small and very large miniature endplate potentials appearing. Ultrastructurally the endplates are altered in the presynaptic portion but not in the postsynaptic part. In an early stage of poisoning the axolemma has an increased number of omega-shaped indentations similar in size to synaptic vesicles. At a later stage, when the animals die of respiratory paralysis, the axolemmal indentations are more numerous and the synaptic vesicles greatly reduced in number, the remaining vesicles having a variable and frequently larger than normal size. When impulse activity in the phrenic nerve is stopped by cutting the nerve before the administration of toxin there is no reduction in the number of synaptic vesicles, only the appearance of an increased number of axolemmal indentations. It is suggested that taipoxin and notexin irreversibly interfere with the formation of synaptic vesicles by arresting vesicle membrane recycling at the level of the axolemma. When the pre-existing store of vesicles is depleted, by nerve activity, a neuromuscular block results.