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Biomedical subjects

Andrew Davidson

Publications and source records attributed to Andrew Davidson.

13 recordsLinked to original sources
PubMed2006

Raman spectroscopic analysis of human remains from a seventh century cist burial on Anglesey, UK.

Specimens from human remains exhibiting unusual preservation excavated from a seventh century stone cist burial at Towyn y Capel in Anglesey, UK, have been analysed using Raman spectroscopy with near-infrared laser excitation at 1,064 and 785 nm. Specimens of hair and bone provided evidence for severe degradation and microbial colonisation. The deposits within the stone cist showed that some microbially mediated compounds had been formed. Analysis of crystals found at the interface between the hair and the skeletal neck vertebrae revealed a mixture of newberyite and haematite, associated with decomposition products of the hair and bone. An interesting differential degradation was noted in the specimens analysed which could be related to the air-void and the presence of plant root inclusions into the stone cist. This is the first time that Raman spectroscopy has been used in the forensic archaeological evaluation of burial remains in complex and dynamic environments.

Archaeology↗
PubMed2006

Virulence attenuation of Dengue virus due to augmented glycosaminoglycan-binding affinity and restriction in extraneural dissemination.

To gain insight into the role of cell surface glycosaminoglycans (GAG) in dengue virus (DEN) cell tropism and virulence, DEN-2 mouse brain-adapted vaccine candidate, neurovirulent prototype strain (NGC) and low-passage strain, PUO-218, were passaged in BHK-21 and SW13 cells to isolate variants with high affinity for GAG. Sequence comparisons of parent and passage variants revealed five GAG-binding determinants, which all cluster in a surface-exposed region in domain II of the three-dimensional structure of the DEN envelope protein. Using an infectious cDNA clone of NGC and an NGC/PUO-218 prM-E chimeric clone, it was demonstrated that the GAG-binding determinants augment the specific infectivity for BHK-21 and/or SW13 cells by 10- to 170-fold and in some cases marginally reduce that for Vero cells. This altered cell tropism was due to a greater dependence of the variants on cell surface GAG for attachment/entry, given their increased susceptibility to heparin inhibition. The effect of the GAG-binding determinants on virulence was examined in mice deficient in alpha/beta/gamma interferon responses. High GAG affinity strongly correlated with low neuroinvasiveness due to rapid virus clearance from the blood. It was speculated that this mechanism accounts for the attenuation in primates of some DEN vaccine candidates. Interestingly, the GAG-binding variants did not display marked attenuation of neurovirulence and the opposing effect of enhanced neurovirulence was associated with one determinant (Lys126) already present in mouse brain-adapted NGC. This discrepancy of attenuated neuroinvasiveness and augmented neurovirulence may be reconciled by the existence of different mechanisms of virus dissemination in the brain and in extraneural tissues.

Animals↗
PubMed2005

Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression.

Alpha/beta interferon (IFN-alpha/beta) is a key mediator of innate antiviral responses but has little effect on the established replication of dengue viruses, which are mosquito-borne flaviviruses of immense global health importance. Understanding how the IFN system is inhibited in dengue virus-infected cells would provide critical insights into disease pathogenesis. In a recent study analyzing the ability of individual dengue virus-encoded proteins to antagonize the IFN response, nonstructural (NS) protein 4B and possibly NS2A and NS4A were identified as candidate IFN antagonists. In monkey cells, NS4B appeared to inhibit both the IFN-alpha/beta and IFN-gamma signal transduction pathways, which are distinct but overlapping (J. L. Munoz-Jordan, G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre, Proc. Natl. Acad. Sci. USA 100:14333-14338, 2003). For this study, we examined the effects of dengue virus on the human IFN system, using cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and that expressed all of the dengue virus nonstructural proteins together. We show here that in replicon-containing cells dengue virus RNA replication and the replication of encephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviral effects of IFN-alpha. The presence of dengue virus replicons reduces global IFN-alpha-stimulated gene expression and specifically inhibits IFN-alpha but not IFN-gamma signal transduction. In cells containing replicons or infected with dengue virus, we found reduced levels of signal transducer and activator of transcription 2 (STAT2), which is a key component of IFN-alpha but not IFN-gamma signaling. Collectively, these data show that dengue virus is capable of subverting the human IFN response by down-regulating STAT2 expression.

Cell Line↗
PubMed2004

The nsp9 replicase protein of SARS-coronavirus, structure and functional insights.

As part of a high-throughput structural analysis of SARS-coronavirus (SARS-CoV) proteins, we have solved the structure of the non-structural protein 9 (nsp9). This protein, encoded by ORF1a, has no designated function but is most likely involved with viral RNA synthesis. The protein comprises a single beta-barrel with a fold previously unseen in single domain proteins. The fold superficially resembles an OB-fold with a C-terminal extension and is related to both of the two subdomains of the SARS-CoV 3C-like protease (which belongs to the serine protease superfamily). nsp9 has, presumably, evolved from a protease. The crystal structure suggests that the protein is dimeric. This is confirmed by analytical ultracentrifugation and dynamic light scattering. We show that nsp9 binds RNA and interacts with nsp8, activities that may be essential for its function(s).

Amino Acid Motifs↗
PubMed2004

The correlation between bispectral index and airway reflexes with sevoflurane and halothane anaesthesia.

BACKGROUND: Unwanted airway reflexes such as laryngospasm are a frequent cause for concern in paediatric anaesthesia. They are more active during light anaesthesia. Bispectral index (BIS) is a recognized measure of anaesthetic effect. Ensuring adequate depth with the BIS may prevent these reflexes. This study investigates the relationship between BIS and a defined measure of airway reactivity. METHODS: Sixty-two children scheduled for direct laryngoscopy and bronchoscopy were enrolled in this prospective nonrandomized blinded study. They were induced and maintained with either sevoflurane or halothane. When depth of anaesthesia was judged deep enough on clinical grounds, the cords were sprayed with 2% lidocaine. Using an A2000 monitor, the BIS was recorded at the moment of spraying the cords. The anaesthetist was blinded to the BIS and noted whether or not spraying resulted in complete closure of the cords. Breath holding, desaturation and coughing were also recorded as secondary endpoints. RESULTS: Using logistic regression there was a significant correlation between BIS and cord closure for halothane but not for sevoflurane (halothane Pseudo r2 = 0.5, P = 0.003; sevoflurane Pseudo r2 = 0.0004, P = 0.9). Although the study was not specifically designed to test for it, no difference was detected between agents in the incidence of cord closure (halothane 38%, sevoflurane 36%), or secondary endpoints (halothane 29%, sevoflurane 29%). CONCLUSIONS: The BIS may be useful to help prevent unwanted airway reflexes when using halothane but not with sevoflurane. The differing sites of anaesthetic action for sevoflurane and halothane may explain this result.

Adolescent↗
PubMed2004

Delayed rises in serum S100B levels and adverse neurological outcome in infants and children undergoing cardiopulmonary bypass.

BACKGROUND: The protein S100B is a marker of brain injury. Early after cardiopulmonary bypass (CPB), serum S100B levels are artefactually high. We investigated whether delayed (48 h) rise in S100B levels may have a role in detecting brain injury after CPB. METHODS: Data from 43 children were analysed in this study. Samples were collected at preincision and 30 min, 24 and 48 h postbypass and then analysed by using a commercially available radioimmunoassay (Sangtec100). Charts were reviewed at 3-5 months for evidence of neurological injury. RESULTS: S100B levels were high preoperatively in neonates and universally high immediately postbypass. In 36 children, samples were available for all time points. Compared with preoperative levels, rises occurred at both 24 and 48 h in three patients, only at 24 h in four patients and only at 48 h in three patients. Two patients had evidence of neurological injury. A rise at 48 h was associated with neurological injury (odds ratio 33.9, P < 0.03, 95% CI 1.39-827). There was no association between neurological injury and S100B levels at 24 h. Both the patients with neurological injury had rises at 48 h that were significantly higher than patients with rises at 48 h without injury. CONCLUSIONS: The results of this study suggest that monitoring S100B levels in the late postoperative period may still have a role in detecting neurological injury after cardiac surgery in children. Consistent with previous observations, S100B is high preoperatively in neonates and early postbypass in all patients.

Biomarkers↗
PubMed2004

Tetracycline-inducible packaging cell line for production of flavivirus replicon particles.

We have previously developed replicon vectors derived from the Australian flavivirus Kunjin that have a unique noncytopathic nature and have been shown to direct prolonged high-level expression of encoded heterologous genes in vitro and in vivo and to induce strong and long-lasting immune responses to encoded immunogens in mice. To facilitate further applications of these vectors in the form of virus-like particles (VLPs), we have now generated a stable BHK packaging cell line, tetKUNCprME, carrying a Kunjin structural gene cassette under the control of a tetracycline-inducible promoter. Withdrawal of tetracycline from the medium resulted in production of Kunjin structural proteins that were capable of packaging transfected and self-amplified Kunjin replicon RNA into the secreted VLPs at titers of up to 1.6 x 10(9) VLPs per ml. Furthermore, secreted KUN replicon VLPs from tetKUNCprME cells could be harvested continuously for as long as 10 days after RNA transfection, producing a total yield of more than 10(10) VLPs per 10(6) transfected cells. Passaging of VLPs on Vero cells or intracerebral injection into 2- to 4-day-old suckling mice illustrated the complete absence of any infectious Kunjin virus. tetKUNCprME cells were also capable of packaging replicon RNA from closely and distantly related flaviviruses, West Nile virus and dengue virus type 2, respectively. The utility of high-titer KUN replicon VLPs was demonstrated by showing increasing CD8(+)-T-cell responses to encoded foreign protein with increasing doses of KUN VLPs. A single dose of 2.5 x 10(7) VLPs carrying the human respiratory syncytial virus M2 gene induced 1,400 CD8 T cells per 10(6) splenocytes in an ex vivo gamma interferon enzyme-linked immunospot assay. The packaging cell line thus represents a significant advance in the development of the noncytopathic Kunjin virus replicon-based gene expression system and may be widely applicable to the basic studies of flavivirus RNA packaging and virus assembly as well as to the development of gene expression systems based on replicons from different flaviviruses.

Animals↗
PubMed2003

Ultrasonic locating devices for central venous cannulation: meta-analysis.

OBJECTIVES: To assess the evidence for the clinical effectiveness of ultrasound guided central venous cannulation. DATA SOURCES: 15 electronic bibliographic databases, covering biomedical, science, social science, health economics, and grey literature. DESIGN: Systematic review and meta-analysis of randomised controlled trials. Populations Patients scheduled for central venous access. INTERVENTION REVIEWED: Guidance using real time two dimensional ultrasonography or Doppler needles and probes compared with the anatomical landmark method of cannulation. DATA EXTRACTION: Risk of failed catheter placement (primary outcome), risk of complications from placement, risk of failure on first attempt at placement, number of attempts to successful catheterisation, and time (seconds) to successful catheterisation. DATA SYNTHESIS: 18 trials (1646 participants) were identified. Compared with the landmark method, real time two dimensional ultrasound guidance for cannulating the internal jugular vein in adults was associated with a significantly lower failure rate both overall (relative risk 0.14, 95% confidence interval 0.06 to 0.33) and on the first attempt (0.59, 0.39 to 0.88). Limited evidence favoured two dimensional ultrasound guidance for subclavian vein and femoral vein procedures in adults (0.14, 0.04 to 0.57 and 0.29, 0.07 to 1.21, respectively). Three studies in infants confirmed a higher success rate with two dimensional ultrasonography for internal jugular procedures (0.15, 0.03 to 0.64). Doppler guided cannulation of the internal jugular vein in adults was more successful than the landmark method (0.39, 0.17 to 0.92), but the landmark method was more successful for subclavian vein procedures (1.48, 1.03 to 2.14). No significant difference was found between these techniques for cannulation of the internal jugular vein in infants. An indirect comparison of relative risks suggested that two dimensional ultrasonography would be more successful than Doppler guidance for subclavian vein procedures in adults (0.09, 0.02 to 0.38). CONCLUSIONS: Evidence supports the use of two dimensional ultrasonography for central venous cannulation.

Adult↗
PubMed2003

Supernatants from dengue virus type-2 infected macrophages induce permeability changes in endothelial cell monolayers.

The ability of dengue virus-infected human monocyte-derived macrophages to induce permeability changes in primary human umbilical vein endothelial cells was investigated. Supernatants from dengue virus type 2-infected monocyte-derived macrophages increased permeability in human umbilical vein endothelial cell monolayers without inducing endothelial cell infection. Production of permeabilising activity from monocyte-derived macrophages occurred after the peak of progeny virus release. TNF-alpha, a known inducer of endothelial cell permeability, was released from dengue virus infected monocyte-derived macrophages but its release did not coincide with release of endothelial cell permeabilising activity. Permeability induction was enhanced by pre-incubation with supernatants from infected monocyte-derived macrophages harvested at the time of peak release of TNF-alpha and infectious virus. Thus, supernatants from dengue virus-infected monocyte-derived macrophages contain factors that increase human umbilical vein endothelial cell permeability, but this is not accompanied by endothelial cell infection or directly correlated with release of dengue virus or TNF-alpha from monocyte-derived macrophages. This model system can be used for further in vitro analysis of mechanisms that may relate to capillary leakage and the development of dengue haemorrhagic fever/dengue shock syndrome.

Cell Membrane Permeability↗
PubMed2003

Potential for antiviral treatment of severe acute respiratory syndrome.

PURPOSE OF REVIEW: Severe acute respiratory syndrome is a new, sometimes lethal disease of humans that is caused by a novel coronavirus. To date there have been over 750 related deaths and there is clearly an urgent need to develop specific antiviral drugs to combat this disease. In this review, the authors shall focus on the molecular biology of the coronavirus and suggest how this information can be used to identify possible targets for antiviral drugs. RECENT FINDINGS: Within a remarkably short period of time, the severe acute respiratory syndrome coronavirus has been isolated, its genome has been sequenced and the structure of at least one key viral enzyme has been deduced. In addition, bioinformatic analysis has predicted a number of enzymatic activities associated with proteins of the viral replicase-transcriptase complex. In some cases, these functions have been confirmed by biochemical analysis. Thus, there has been significant progress in the rational approach to anti-severe acute respiratory syndrome coronavirus drug design. This approach, combined with the random screening of licensed compounds or existing compound libraries, should result in the identification of novel lead compounds and the expeditious development of antiviral drugs. SUMMARY: Although the initial severe acute respiratory syndrome epidemic has been controlled by conventional measures, the animal reservoir for the coronavirus progenitor has not been identified. It is therefore likely that the virus will be reintroduced into the human population in the future. When this happens, the most economical and effective way to contain the virus will be the therapeutic use of antiviral drugs.

Antiviral Agents↗
PubMed2002

The correlation of bispectral index with endtidal sevoflurane concentration and haemodynamic parameters in preschoolers.

BACKGROUND: Bispectral index (BIS) is a signal processing device that potentially is a pharmacodynamic measure of the effects of anaesthesia on the central nervous system. METHODS: In this prospective blinded study, we investigated the pharmacodynamic relationship between BIS, haemodynamic changes during anaesthesia and endtidal nonsteady state concentrations of sevoflurane in 30 children, mean age 3.3 +/- 1.1 years, who were undergoing tonsillectomy and adenoidectomy. A standardized anaesthetic technique was used and included induction and maintenance with sevoflurane, nitrous oxide and oxygen. BIS, heart rate, mean arterial pressure (MAP) and endtidal sevoflurane (ETsevo) concentrations were continuously recorded and specifically noted at the time of intubation, placement of Dingman gag, incision of adenoid, adenoid out, incision of tonsil, tonsil one out, tonsil two out, last agent off, first spontaneous movement, first eye opening and extubation. The anaesthetist was blinded to BIS throughout the procedure. RESULTS: Using a Spearman correlation analysis, there was significant negative correlation between BIS and ETsevo concentrations (r=- 0.888, P < 0.01) and a pharmacodynamic relationship with EC50 (ETsevo at which BIS=50) of 1.48% (95% confidence interval 0.84-2.11). There was a weak negative correlation between sevoflurane and MAP (r=- 0.391, P < 0.01) but no significant correlation between sevoflurane and heart rate. CONCLUSIONS: In preschool children undergoing sevoflurane anaesthesia for tonsillectomy and adenoidectomy, endtidal sevoflurane concentrations are more closely correlated with BIS than with MAP or heart rate.

Adenoidectomy↗