Tropical sprue as a cause of traveler's diarrhea.
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Anti-Bacterial Agents↗
Biomedical subjects
G Ferguson
Publications and source records attributed to G Ferguson.
Subtype-specific kinetics of inhibitory adenosine receptor internalization are determined by sensitivity to phosphorylation by G protein-coupled receptor kinases.
Despite coupling to the same class of inhibitory G proteins and binding the same physiological ligand, the human A(1) and rat A(3) adenosine receptors (ARs) desensitize at different rates in response to sustained agonist exposure. This is due to the ability of the A(3)AR, but not the A(1)AR, to serve as a substrate for rapid phosphorylation and desensitization by members of the G protein-coupled receptor kinase (GRK) family. The aim of this study was to investigate whether these differences were also manifested in their abilities to undergo agonist-dependent receptor internalization. For the first time, we report that A(3)ARs internalize profoundly in response to short-term exposure to agonist but not activators of second messenger-regulated kinases. The A(3)AR-selective antagonist MRS1523 blocked both A(3)AR phosphorylation and internalization. Moreover, in contrast to the A(1)AR, which internalized quite slowly (t(1/2) = 90 min), A(3)ARs internalized rapidly (t(1/2) = 10 min) over a time frame that followed the onset of receptor phosphorylation. A nonphosphorylated A(3)AR mutant failed to internalize over a 60-min time course, suggesting that receptor phosphorylation was essential for rapid A(3)AR internalization to occur. In addition, fusion onto the A(1)AR of the A(3)AR C-terminal domain containing the sites for phosphorylation by GRKs conferred rapid agonist-induced internalization kinetics (t(1/2) = 10 min) on the resulting chimeric AR. In conclusion, these data suggest that GRK-stimulated phosphorylation of threonine residues within the C-terminal domain of the A(3)AR is obligatory to observe rapid agonist-mediated internalization of the receptor.
Animals↗
A study of junior doctors to investigate the factors that influence career decisions.
Both pre-registration house officers and general practitioner (GP) registrars agree on several desirable and undesirable factors that define their ideal career. These relate to fulfilling clinical work and preservation of a meaningful personal life. Many young doctors regret their choice of medicine as a career because of poor job conditions and stress and perceive career advice as inadequate. GP's influence over junior doctors at the time of their career decision making is very limited compared with that of consultants.
Career Choice↗
Crystal engineering using bisphenols: interwoven ladders, sheet and framework structures in the binary adducts of 4,4'-sulfonyldiphenol with pyrazine (2/1), 4,4'-bipyridyl (1/1), trans-1,2-bis(4-pyridyl)ethene (1/1), 1,2-bis(4-pyridyl)ethane (1/1) and 4,4'-trimethylenedipyridine (1/1), and in 4,4'-sulfonyldiphenol-4,4'-trimethylenedipiperidine-water (2/2/1).
The structures of six hydrogen-bonded adducts of 4,4'-sulfonyldiphenol with heteroaromatic amines have been determined. In 4,4'-sulfonyldiphenol-pyrazine (2/1) the pyrazine molecules lie across centres of inversion. The bisphenol molecules are linked into C(8) chains parallel to [100] by means of O-H.O=S hydrogen bonds, and antiparallel pairs of these chains are cross-linked by the pyrazine molecules, via O-H.N hydrogen bonds, to form molecular ladders containing R(6)(6)(50) rings between the rungs of the ladders. Each ladder is interwoven with two neighbouring ladders, thus producing a continuous two-dimensional sheet. The structure of 4,4'-sulfonyldiphenol-4,4'-bipyridyl (1/1) consists of spiral C(2)(2)(21) chains parallel to [010] containing alternating bisphenol and bipyridyl molecules linked by O-H.N hydrogen bonds: these chains are linked by two types of C-H.O hydrogen bonds which form C(5) chains along [001] and C(2)(2)(10) chains along [101], thus generating two interconnected nets characterized in the one case by a chequerboard pattern of R(6)(6)(44) and R(6)(6)(52) rings, and in the other by a single type of R(6)(6)(46) ring. 4,4'-Sulfonyldiphenol-trans-1,2-bis(4-pyridyl)ethene (1/1) [systematic name: 4,4'-sulfonyldiphenol-trans-4,4'-vinylenedipyridine (1/1)] and 4,4'-sulfonyldiphenol-1,2-bis(4-pyridyl)ethane (1/1) [systematic name: 4,4'-sulfonyldiphenol-trans-4,4'-ethylenedipyridine (1/1)] are isomorphous: the 1,2-bis(4-pyridyl)ethene component exhibits orientational disorder, corresponding approximately to a 180 degrees rotation of ca 23% of the molecules about the N.N vector; in each compound the structure is built from C(2)(2)(23) chains of alternating bisphenol and bis(pyridyl) molecules connected by O-H.N hydrogen bonds, running parallel to [112] and generated by translation. The [112] chains are linked by C-H.O hydrogen bonds which generate C(2)(2)(12) chains parallel to [101], so forming a two-dimensional net built from R(6)(6)(50) rings. The structure of 4,4'-sulfonyldiphenol-4,4'-trimethylenedipyridine (1/1) consists of C(2)(2)(24) chains parallel to [100] generated by translation and consisting of alternating bisphenol and bis(pyridyl) molecules linked by O-H.N hydrogen bonds. Pairs of such chains are coiled together to form double helices, and pairs of such double helices, of opposite hand, are linked together by paired C-H.O hydrogen bonds in R(2)(2)(10) rings to form pairs of interwoven ladders in which the C(2)(2)(24) chains form the uprights and the R(2)(2)(10) rings form the rungs, between which are R(6)(6)(50) rings: an R(2)(2)(10) ring belonging to one ladder lies at the centre of an R(6)(6)(50) ring belonging to the other. 4,4'-Sulfonyldiphenol-4,4'-trimethylenedipiperidine-water (2/2/1) is a salt, 2C(13)H(27)N(2)(+).2C(12)H(9)O(4)S(-).H(2)O, containing two independent singly protonated diamine cations, two independent bisphenolate anions, and neutral water molecules. The two independent diamine cations are linked by N-H.N hydrogen bonds into C(2)(2)(24) chains running parallel to [001] and generated by translation, and each type of bisphenolate anion forms an independent spiral C(12) chain, also parallel to [001]. The three types of chain are linked by the water molecules: the two types of bisphenolate chain are linked by water molecules acting as double donors in O-H.O(-) hydrogen bonds in a C(6)(4)(32) chain parallel to [100], thus generating a two-dimensional net built from R(8)(6)(56) rings; the diamine chains are linked to these nets by means of N-H.O hydrogen bonds in which the water molecules act as acceptors and further hydrogen bonds, of N-H.O(-) and N-H.O=S types, link these two-dimensional nets into a continuous three-dimensional framework.
Journal Article↗
Crystal engineering using bisphenols and trisphenols. Complexes with 1,10-phenanthroline: hydrogen-bonded chains in adducts with 4,4'-biphenol (1/1) and 4,4'-sulfonyldiphenol (2/3), pi-pi stacked chains in the (1/2) adduct with 4,4'-thiodiphenol, and pairwise-interwoven nets in 1,1,1-tris(4-hydroxyphenyl)ethane-1,10-phenanthroline-methanol (1/1/1).
In 4,4'-biphenol-1,10-phenanthroline (1/1) [systematic name: 4,4'-biphenyldiol-1,10-phenanthroline (1/1)] the diphenol molecules lie across centres of inversion and the phenanthroline molecules lie across twofold rotation axes; the phenanthroline molecules act as chain-building units and the molecular components are linked into steeply zigzag C(16) chains parallel to [101] by means of O-H.N hydrogen bonds. In the structure of 4,4'-thiodiphenol-1,10-phenanthroline (1/2) the phenanthroline molecules act as chain-terminating units; the supramolecular aggregation is finite, with the bisphenol linked to each phenanthroline molecule by means of a single O-H.N hydrogen bond. pi-pi stacking interactions between the phenanthroline molecules in neighbouring hydrogen-bonded aggregates serve to link these aggregates into a continuous two-dimensional array. The phenanthroline molecules in 4,4'-sulfonyldiphenol-1,10-phenanthroline (2/3) play two roles: molecules in general positions act as chain-terminating units and are linked to the sulfonyldiphenol molecules by means of three-centre O-H.(N)(2) hydrogen bonds, while those lying across twofold rotation axes act as chain builders and are linked to two different sulfonyldiphenol molecules by means of a two-centre O-H.N hydrogen bond in each case; the resulting U-shaped five-component aggregates are further linked by C-H.O=S hydrogen bonds into a C(3)(3)(17)[R(2)(2)(12)] 'chain of rings' along [001]. In 1,1,1-tris(4-hydroxyphenyl)ethane-1,10-phenanthroline-methanol (1/1/1) [systematic name: 4,4',4"-ethylidynetriphenol-1,10-phenanthroline-methanol (1/1/1)] the phenanthroline molecules again act as chain-terminating units: the trisphenol molecules and the methanol molecules are linked by O-H.O hydrogen bonds into two-dimensional nets built from R(6)(6)(42) rings, and pairs of these nets are interwoven. The formation of each net utilizes two hydroxyl groups per trisphenol molecule as hydrogen-bond donors and the remaining hydroxyl group acts as donor to the phenanthroline molecule in a three-centre O-H.(N)(2) hydrogenbond.
Journal Article↗
Dispensing--a service or a self-enriching exercise?
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Community Pharmacy Services↗
Synaptotagmin IV is an immediate early gene induced by depolarization in PC12 cells and in brain.
Subtractive library construction and differential screening were used to identify a cDNA for a cell type-specific immediate early gene induced in rat PC12 pheochromocytoma cells. Sequencing identified the protein product of this gene as rat synaptotagmin IV (SytIV). Synaptotagmins are synaptic vesicle proteins thought to play a role in depolarization-induced, calcium-mediated exocytosis and neurotransmitter release. SytIV mRNA accumulation is transiently induced in PC12 cells by potassium depolarization, calcium ionophore, ATP, and forskolin. In contrast, growth factors and phorbol 12-myristate 13-acetate induce little or no SytIV mRNA accumulation. Kainic acid-induced seizures in rats are followed by accumulation of SytIV message in the hippocampus and piriform cortex. The SytIV gene may provide a direct link between depolarization-induced neuronal gene expression and subsequent modulation of synaptic structure and function.
Adrenal Gland Neoplasms↗
Quantitative chest computed tomography as a means of predicting exercise performance in severe emphysema.
RATIONALE AND OBJECTIVES: We assessed the value of quantitative high-resolution computed tomography (CT) as a diagnostic and prognostic tool in smoking-related emphysema. METHODS: We performed an inception cohort study of 14 patients referred with emphysema. The diagnosis of emphysema was based on a compatible history, physical examination, chest radiograph, CT scan of the lung, and pulmonary physiologic evaluation. RESULTS: As a group, those who underwent exercise testing were hyperinflated (percentage predicted total lung capacity +/- standard error of the mean = 133 +/- 9%), and there was evidence of air trapping (percentage predicted respiratory volume = 318 +/- 31%) and airflow limitation (forced expiratory volume in 1 sec [FEV1] = 40 +/- 7%). The exercise performance of the group was severely limited (maximum achievable workload = 43 +/- 6%) and was characterized by prominent ventilatory, gas exchange, and pulmonary vascular abnormalities. The quantitative CT index was markedly elevated in all patients (76 +/- 9; n = 14; normal < 4). There were correlations between this quantitative CT index and measures of airflow limitation (FEV1 r2 = .34, p = 09; FEV1/forced vital capacity r2 = .46, p = .04) and between maximum workload achieved (r2 = .93, p = .0001) and maximum oxygen utilization (r2 = .83, p = .0007). CONCLUSION: Quantitative chest CT assessment of disease severity is correlated with the degree of airflow limitation and exercise impairment in pulmonary emphysema.
Aged↗
Role for poliovirus protease 2A in cap independent translation.
Viral protein synthesis in poliovirus infected cells was found to be influenced by mutations in part of the viral 5'-non-coding region (NCR) in a temperature dependent manner. At elevated temperatures these mutations resulted in virus titre reductions that allowed selection of revertant viruses. Some revertants were found to have retained the 5'-NCR mutations but had compensating mutations in the 2A protease gene that were responsible for the suppression of the temperature sensitive phenotypes. The mutations in 2A enhanced viral protein synthesis at a stage when cap dependent translation was already abolished, suggesting that the virally encoded protein 2A is directly involved in the process of cap independent translation in addition to its role in abolishing cap dependent translation.
Amino Acid Sequence↗
GRAVITY AND LIGHT INFLUENCE THE COUNTERSHADING REFLEXES OF THE CUTTLEFISH SEPIA OFFICINALIS
Rotation (roll or pitch) of a cuttlefish away from its normal orientation produces countershading reflexes (CSRs) that consist of chromatophore expansion on the ventral body surface. When rotation is in the roll plane, the CSR has two components on each side of the body. The first (component A) consists of a unilateral expansion of chromatophores on the uppermost latero-ventral edge of the mantle, the underside of the upper fin and the uppermost side of the head; it occurs when the angle of rotation is less than 90°. Further rotation (from approximately 90° to approximately 180°) adds the second component (component B): a unilateral expansion of the chromatophores on the upper half of the ventral surface of the mantle, funnel, head and arms. When rotation is in the pitch plane, chromatophores expand on the posterior part of the ventral mantle and fins when the head is down; when the head is up, chromatophores expand on the ventral surface of the arms, head and funnel and on the anterior part of the ventral mantle and fins. The pitch CSR is always bilateral. Destruction of the gravity or the angular acceleration receptor systems of the statocysts demonstrates that it is the gravity receptor systems that drive the CSRs. Unilateral destruction of the gravity receptor systems shows that the pitch CSR is driven bilaterally, whereas the roll CSR is driven unilaterally. Components A and B of the roll CSR are driven by input from the ipsilateral statocyst, but component A is additionally driven by light. Brain lesions provide evidence that the pathways for the CSRs run through the lateral basal lobes in the supraoesophageal part of the brain.
Journal Article↗
Intralesional steroid injection following keloid surgery.
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Anesthesia, Dental↗
Prediction of the three-dimensional structures of the nerve growth factor and epidermal growth factor binding proteins (kallikreins) and an hypothetical structure of the high molecular weight complex of epidermal growth factor with its binding protein.
We have predicted the three-dimensional structures of the serine protease subunits (gamma-NGF, alpha-NGF, and EGF-BP) of the high molecular weight complexes of nerve growth factor (7S NGF) and epidermal growth factor (HMW-EGF) from the mouse submandibular gland (from the X-ray crystal structures of two related glandular kallikreins). The conformations of three of the six loops surrounding the active site are relatively well defined in the models of gamma-NGF and EGF-BP, but three other loops are likely to have flexible conformations. Although the amino acid sequence of alpha-NGF is closely related to those of gamma-NGF and EGF-BP, it is catalytically inactive. Model-building studies on alpha-NGF suggested that mutations (in alpha-NGF) just prior to the active site serine (195) and an unusual N-terminal sequence are consistent with alpha-NGF having a zymogen-like conformation (similar to that in chymotrypsinogen). An hypothetical model of the quaternary structure of HMW-EGF has been constructed using this model of EGF-BP and the NMR structure of murine EGF. The C-terminal arm of EGF was modeled into the active site of EGF-BP based on data indicating that the C-terminal arginine of EGF occupies the S1 subsite of EGF-BP. Data suggesting one of the surface loops of EGF-BP is buried in the HMW-EGF complex and symmetry constraints were important in deriving a schematic model. A molecular docking program was used to fit EGF to EGF-BP.
Amino Acid Sequence↗
Genetic basis of attenuation of the Sabin type 2 vaccine strain of poliovirus in primates.
The type 2 live-attenuated vaccine strain of poliovirus (P2/Sabin) is associated with rare cases of poliomyelitis in vaccinees or their contacts. Recombinants were generated between infectious clones of a neurovirulent isolate from one such case (P2/117) and P2/Sabin and neurovirulence assays suggested that a maximum of six nucleotide differences between the two strains were responsible for their phenotypic difference. Site-directed mutagenesis of P2/Sabin showed that mutations at just two positions, at 481 in the 5' non-coding region and at VP1-143 in the capsid proteins, resulted in a highly neurovirulent virus. Other nucleotide changes may have weaker phenotypic effects. These results are consistent with those reported in the mouse model by Ren et al. [J. Virol. 65, 1377, (1991)] indicating that, for P2/Sabin at least, the same determinants of attenuation are important in both primates and transgenic mice expressing the poliovirus receptor. Sequence analysis of isolates from other vaccine-associated cases of poliomyelitis and from healthy vaccinees showed that both major determinants of attenuation are unstable on human passage, although selection pressures against an A at 481 are stronger than those against an Ile at 1143.
Capsid↗
Designed to serve: the New Brunswick Extra-Mural Hospital.
I see the scope for the Extra-Mural Hospital as a component of community care and of ambulatory care that is not yet nearly realized. Many opportunities lie ahead if we continue to approach them in a sensitive manner and if we remain cost conscious but patient centered. We must continue to work harmoniously with all other contributors to the health care system and strive to achieve our self-appointed role of being a catalyst to bring about the ideal continuum of care that will be cost and care effective.
Continuity of Patient Care↗
Correlation of RNA secondary structure and attenuation of Sabin vaccine strains of poliovirus in tissue culture.
Part of the 5' noncoding regions of all three Sabin vaccine strains of poliovirus contains determinants of attenuation that are shown here to influence the ability of these strains to grow at elevated temperatures in BGM cells. The predicted RNA secondary structure of this region (nt 464-542 in P3/Sabin) suggests that both phenotypes are due to perturbation of base-paired stems. Ts phenotypes of site-directed mutants with defined changes in this region correlated well with predicted secondary structure stabilities. Reversal of base-pair orientation had little effect whereas stem disruption led to marked increases in temperature sensitivity. Phenotypic revertants of such viruses displayed mutations on either side of the stem. Mutations destabilizing stems led to intermediate phenotypes. These results provided evidence for the biological significance of the predicted RNA secondary structure.
Base Sequence↗
Addressing sexual orientation in a public high school.
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Adolescent↗
Correlation of contralateral stenosis and intraoperative electroencephalogram change with risk of stroke during carotid endarterectomy.
Two hundred ninety-three carotid endarterectomies were performed with electroencephalogram (EEG) monitoring and without the use of a shunt. Two hundred sixteen patients had contralateral carotid stenosis of less than 70%; 45 had contralateral stenosis of 70 to 99%; and 32 had contralateral occlusion. There were six perioperative strokes (2.0%) and two deaths (0.7%). Major EEG changes were seen in 11 of the 77 patients (14.3%) with significant contralateral stenosis or occlusion versus 11 of the 216 patients (5.1%) in those without (P less than 0.025). The risk of immediate postoperative deficit was significantly higher in the subgroup with major EEG changes (4 of 22, 18.2%) than in those without such changes (5 of 271, 1.8%) (P less than 0.005). The risk in patients with less than 70% contralateral stenosis (7 of 216, 3.2%) was not significantly different from those with greater contralateral stenosis or occlusion (2 of 77, 2.6%). Carotid endarterectomy can be safely performed without a temporary shunt. Contralateral stenosis or occlusion alone does not confer increased risk. Major EEG changes are infrequent, but they identify a subgroup with significantly higher risk of intraoperative stroke.
Adult↗
The 5' noncoding region of the type 2 poliovirus vaccine strain contains determinants of attenuation and temperature sensitivity.
Intratypic recombinants of P2/Sabin and P2/117, a neurovirulent vaccine revertant, have been generated in vitro using infectious cDNA clones and used to demonstrate that strong determinants of the attenuation and temperature-sensitive phenotypes of P2/Sabin reside in the 5' 492 nucleotides. In this region of the genome the viruses differ only at nucleotides 437 and 481. The ts phenotype associated with the 5' noncoding region is expressed at different temperatures in different cell lines, suggesting an involvement of cellular factors which may be species specific. Suppression of both the ts and attenuation phenotypes correlates with an A-G mutation at nucleotide 481, although other changes are also involved.
Animals↗