Biomedical subjects
Publications and source records attributed to A D Wright.
We report a rare case of a non-insulin secreting malignant insulinoma of the pancreas and discuss its medical and surgical management. Surgical excision of malignant insulinoma produces good palliation and can increase survival.
A series of mainly marine derived natural products were tested for their activities against Mycobacterium tuberculosis and M. avium. Of the thirty-nine compounds tested fifteen demonstrated minimum inhibition concentrations (MICs) of 32 micrograms/ml or less, and eleven had MICs of 16 micrograms/ml or less. The most active compound found in this study was the sponge derived metabolite axisonitrile-3 (MIC 2 micrograms/ml).
Cerebral oxygenation is likely to be of critical importance in determining function at high altitude. The present study has used the technique of near-IR spectroscopy to monitor changes in cerebral regional oxygenation in response to inhaled carbon dioxide, hyperventilation and supplementary oxygen on ascent to 4680 m over 3 days. At sea level, inhaled CO(2) resulted in a significant rise in cerebral regional oxygenation [from mean 69.6% (S.D. 2.4% to 71. 1+/-2.3%; means+/-S.D.; P<0.001). At 4680 m, CO(2) increased regional cerebral oxygenation (63.8+/-2.5% to 65.9+/-2.2%; P<0.001) and also increased peripheral oxygen saturation (75.1+/-6.1% to 83. 6+/-4.0%; P<0.001). Voluntary hyperventilation resulted in improved peripheral oxygen saturation at 2770 m, 3650 m and 4680 m, whereas cerebral regional oxygenation was reduced at sea level and at 2770 m, unchanged at 3650 m and increased at 4680 m. Supplementary oxygen (6 1itres/min) at 4680 m resulted in greater improvements in peripheral oxygen saturation (76.7+/-7.9% to 98.1+/-1.5%; P<0.001) and cerebral regional oxygenation (64.6+/-3.3% to 70.6+/-2.9%; P<0. 001) than were found with CO(2) or hyperventilation. We conclude that attempts to increase CO(2) inhalation or ventilation at high altitude are likely to be beneficial for cerebral oxygenation in the short term.
The mechanism of how superantigens function to activate cells has been linked to their ability to bind and cross-link the major histocompatibility complex class II (MHCII) molecule. Cells that lack the MHCII molecule also respond to superantigens, however, with much less efficiency. Therefore, the purpose of this study was to confirm that staphylococcal enterotoxin A (SEA) could bind the MHCI molecule and to test the hypothesis that cross-linking SEA bound to MHCII-deficient macrophages would induce a more robust cytokine response than without cross-linking. We used a capture enzyme-linked immunosorbent assay and an immunprecipitation assay to directly demonstrate that MHCI molecules bind SEA. Directly cross-linking MHCI using monoclonal antibodies or cross-linking bound SEA with an anti-SEA antibody or biotinylated SEA with avidin increased TNF-alpha and IL-6 secretion by MHCII(-/-) macrophages. The induction of a vigorous macrophage cytokine response by SEA/anti-SEA cross-linking of MHCI offers a mechanism to explain how MHCI could play an important role in superantigen-mediated pathogenesis.
Phylogenetic relationships within the kinetoplastid flagellates were inferred from comparisons of small-subunit ribosomal RNA gene sequences. These included three new gene sequences from Cryptobia bullocki, (2091 bp), Cryptobia catostomi (2090 bp), and Cryptobia salmositica (2091 bp). Trees produced using maximum parsimony and distance-matrix methods (least squares and neighbor-joining) demonstrated with strong bootstrap support, that the kinetoplastids are a monophyletic group divided into two major lineages consistent with the two suborders, Trypanosomatina and Bodonina. Within the trypanosomatid clade, the genus Trypanosoma is a monophyletic group that divides into two groups, the salivarian trypanosomes and the stercorarian trypanosomes. Dimastigella and Rhynchobodo, currently classified in the Bodonina, are basal to the trypanosomatid-bodonid clade, suggesting that the suborder Bodonina is paraphyletic. Further, Trypanoplasma borreli grouped within the Cryptobia clade, and was more closely related to C. salmositica than to either C. bullocki or C. catostomi. This new molecular evidence, coupled with morphological similarities of the two genera, again calls into question the validity of the genus Trypanoplasma.
The polyhalogenated monoterpene content of six samples of the tropical marine red alga Plocamium hamatum, collected from the southern, central and northern regions of The Great Barrier Reef, Australia, was assessed. In all but two of the samples, the polyhalogenated monoterpene content was shown to differ markedly. In total, eleven previously reported compounds were isolated and characterised (1-11). Compound 2 was obtained for the first time as a pure natural product. For compound 4 a single crystal X-ray crystallographic analysis was undertaken which established its absolute configuration as (1S,2S,4R,5R,1'E)-2-bromo-1- bromomethyl-1,4-dichloro-5-(2'-chloroethenyl)-5-methylcyclohexa ne. Complete and unambiguous 1H and 13C NMR data are reported for 2 and 4. For 6-8, some prior 13C NMR assignments are revised. The biological activities of compounds 2-8 and 11 were assessed and indicated 4 to have potent antialgal activity towards Chlorella fusca in an agar diffusion bioassay, as well as being moderately antitubercular and cytotoxic. Compound 6 demonstrated moderate cytotoxicity.
From the lipophilic extract of the marine brown alga Stypopodium zonale (Dictyotaceae) the new terpenoid compound stypoquinonic acid (1) together with the known compounds taondiol (2) and atomaric acid (3) were isolated. The structures of all isolates were determined from their spectroscopic data, including 1- and 2-dimensional NMR methods. The new compound, 1, and atomaric acid (3), showed inhibition of tyrosine kinase (p56lck).
Inhibitors of HIV reverse transcriptase (RT) are important drugs for the treatment of acquired immuno-deficiency syndrome (AIDS). One approach to identify novel inhibitors of HIV-1-RT is the screening of natural compounds. Many natural products have been shown to be active as RT inhibitors. These compounds belong to a wide range of different structural classes, e.g., coumarins, flavonoids, tannins, alkaloids, lignans, terpenes, naphtho- and anthraquinones, and polysaccharides. The life forms from which the bioactive compounds were isolated are as equally diverse and comprise terrestrial and marine plants, micro-organisms, and marine animals. From the most extensive screening effort, carried out by the NCl, calanolide A, isolated from the terrestrial plant Calophyllum lanigerum (Guttiferae), has been discovered as the most interesting natural RT inhibitor. The promise of this natural product probably relates to a novel mechanism of action. The current review describes natural products from various sources that are able to inhibit HIV-RT.
Bioassay guided fractionation of the lipophilic extract of the marine cyanobacterium Phormidium ectocarpi yielded a new natural product hierridin B and the previously described compound 2,4-dimethoxy-6-heptadecyl-phenol. Both structures were secured by extensive spectroscopic analysis (1D and 2D NMR, MS, GC-MS, IR). The isolate (mixture) showed antiplasmodial activity towards Plasmodium falciparum.
Three new terpenoid metabolites (1-3) were isolated from the CH2Cl2 extract of the soft coral Lobophytum crassum together with the eudesmane derivative 4 and the known cembrane (2S,7S,8S)-sarcophytoxide (5). Compound 1 is a new cembrane-based diterpene with an C7-C8-epoxide and a methyl ester functionality at C-16. (3E,5Z)- (2) and (3Z,5E)-2-methyl-6-(4a'-methyl-8'-methylene-trans-perhydr onaphthalen-2'-yl)hepta-3,5-dien-2-ol (3) represent two new carbon-carbon double bond isomers of 4, which has the 3E,5E-configuration. The structures of 1-5 were established by interpretation of their spectroscopic data, mainly 1D and 2D NMR and MS. Biological activity evaluation of compounds 1 and 5 and the crude extracts was carried out using agar diffusion assays toward microbial targets and ELISA assays for investigating the inhibition of HIV-1 reverse transcriptase and p56lck tyrosine kinase.
From a Maltese sample of the marine sponge Agelas oroides, five compounds: oroidin (1), 2-cyano-4,5-dibromopyrrole (2), 4,5-dibromopyrrole-2-carboxylic acid (3), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (4), and 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol (5) have been isolated. For compounds 1-5, completely assigned 1H- and 13C-NMR data are reported for the first time. For 2 a single crystal X-ray crystallographic analysis proved its structure unambiguously. The X-ray analysis of 2 indicated it to crystallise in an unexpected polar space group. Biological activity assessment of all isolates indicate 5 to have moderate antiplasmodial activity, as well as being cytotoxic, and 2 to be moderately cytotoxic towards several cancer cell lines.
The 3-hydroxy-3-methylglutaric acid (HMG) containing flavonoid glucoside chamaemeloside, has been determined to have in vivo hypoglycaemic activity comparable to that of free HMG. An improved isolation scheme for obtaining chamaemeloside from Chamaemelum nobile is presented.
Hypoxia plays a key role in the pathogenesis of acute mountain sickness (AMS), but individual susceptibility is variable and cerebral symptoms do not always correlate with PaO2 measurements. Cerebral hypoxia may be more relevant than PaO2. We studied trends in cerebral regional oxygen saturation by the technique of near-infrared spectroscopy in 20 subjects ascending rapidly to 4680 m. Subjects were enrolled in a placebo-controlled, double-blind trial of medroxyprogesterone for the prevention of AMS. The fall in cerebral oxygen saturation was less than in the periphery. At 4680 m, cerebral oxygenation correlated with peripheral saturation but not with PaCO2 or with cerebral symptoms scores. At 4680 m, subjects on medroxyprogesterone had higher cerebral and peripheral saturation compared with those on a placebo. We conclude that cerebral oxygenation monitored with the Critikon 2020 system provided important information on the complex relationship of hypoxia to AMS and that other factors, such as changes in blood flow or capillary permeability, may be equally important.
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From the CH2Cl2 extract of the temperate marine red alga, Laurencia rigida, which has antifouling properties, eight sesquiterpenes (1-8) were isolated. Of these, four (3-acetoxy-E-gamma-bisabolene (1), (-)-10 alpha-bromo-9 beta-hydroxy-alpha-chamigrene (2), rigidol (3), and (+)-(10S)-10-bromo-beta-chamigrene (4)), were shown to be new natural products. For the known compound deschloroelatol (5), reassignment of the 1H- and 13C-NMR data was found to be necessary on the basis of extensive NMR measurements. For elatol (6), complete 1H- and 13C-NMR data are also reported. The antimicrobial and antialgal activities of all isolates were assessed.
A novel C18 lipid, containing a 10-membered lactone, mueggelone (1), was isolated from a field-collected sample of Aphanizomenon flos-aquae, together with the known compound lupenyl acetate (3). Both structures were secured using extensive spectroscopic analysis (1D and 2D NMR, MS, IR). Biological activity assessment of both compounds indicated them to have significant inhibitory effects on fish embryo larval development.
From the tubers of Cyclamen coum (Primulaceae) three new saponins, cyclaminorin (1), cyclacoumin (3) and mirabilin lactone (4) were isolated together with a known saponin, deglucocyclamin (2). The structures of the new compounds were established as 13 beta,28-epoxy-3 beta-(([beta-D-glucopyranosyl-(1-->2)]- [beta-D-glucopyranosyl-(1-->4)]-alpha-L-arabinopyranosyl) oxy) 16 alpha-hydroxy-olean-30-al (1), 13 beta,28-epoxy-3 beta-((([beta-D-xylopyranosyl-(1-->2) -beta-D-glucopyranosyl-(1-->4)]-[beta-D-glucopyranosyl-(1-->2)]- alpha-L-arabinopyranosyl)oxy)-16 alpha,23-dihydroxy-olean-30-al (3) and 16 alpha-hydroxy-3 beta-((([beta-D-xylopyranosyl-(1-->2)]- [beta-D-glucopyranosyl-1-->6)]-beta D-glucopyranosyl-(1-->4))- [beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl)-oxy) olean-12-eno-30,28-lactone (4). Structure elucidattions were accomplished using both spectral (NMR, MS, IR) and chemical methods.
From the roots of Astragalus melanophrurius eight known saponins (1-8) were isolated. Based on spectral data (IR, 1H- and 13C-NMR, and FABMS), the structures were established as astrasieversianins II (1) and X (4), astragalosides I (2), II (3), IV (5) and VI (7), and cyclocanthosides E (6) and G (8). The isolates were evaluated in a broad range of bioassay systems and found to be inactive. Modest antibacterial activity was observed, however, as was immunomodulatory activity, as indicated by stimulation of isolated human lymphocytes.