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1.  Trimethoprim/sulfamethoxazole resistance in Burkholderia pseudomallei 
PMCID: PMC4195405  PMID: 25245211
Burkholderia; Pseudomallei; Melioidosis; Co-trimoxazole; Resistance; Susceptibility; Treatment; Cambodia; Laos
3.  CT stroke window settings: an unfortunate misleading misnomer? 
The British Journal of Radiology  2011;84(1008):1061-1066.
This commentary will discuss the use of the “stroke window” settings in the evaluation of CT head examinations and advocate their more widespread use in patients who present with neurological symptoms in addition to patients with suspected stroke. We present examples of the use of stroke windows, which revealed subtle abnormalities that were not readily apparent on default brain window settings and were subsequently confirmed on MRI or follow-up CT. As a result we suggest that stroke windows should be routine in the review of all CT head examinations.
PMCID: PMC3473839  PMID: 21976632
4.  Variation at the capsule locus, cps, of mistyped and non-typable Streptococcus pneumoniae isolates 
Microbiology  2012;158(Pt 6):1560-1569.
The capsule polysaccharide locus (cps) is the site of the capsule biosynthesis gene cluster in encapsulated Streptococcus pneumoniae. A set of pneumococcal samples and non-pneumococcal streptococci from Denmark, the Gambia, the Netherlands, Thailand, the UK and the USA were sequenced at the cps locus to elucidate serologically mistyped or non-typable isolates. We identified a novel serotype 33B/33C mosaic capsule cluster and previously unseen serotype 22F capsule genes, disrupted and deleted cps clusters, the presence of aliB and nspA genes that are unrelated to capsule production, and similar genes in the non-pneumococcal samples. These data provide greater understanding of diversity at a locus which is crucial to the antigenic diversity of the pathogen and current vaccine strategies.
PMCID: PMC3541774  PMID: 22403189
5.  Genetic changes that increase 5-hydroxymethyl furfural resistance in ethanol-producing Escherichia coli LY180 
Biotechnology Letters  2010;32(5):661-667.
The ability of a biocatalyst to tolerate furan inhibitors present in hemicellulose hydrolysates is important for the production of renewable chemicals. This study shows EMFR9, a furfural-tolerant mutant of ethanologenic E. coli LY180, has also acquired tolerance to 5-hydroxymethyl furfural (5-HMF). The mechanism of action of 5-HMF and furfural appear similar. Furan tolerance results primarily from lower expression of yqhD and dkgA, two furan reductases with a low Km for NADPH. Furan tolerance was also increased by adding plasmids encoding a NADPH/NADH transhydrogenase (pntAB). Together, these results support the hypothesis that the NADPH-dependent reduction of furans by YqhD and DkgA inhibits growth by competing with biosynthesis for this limiting cofactor.
PMCID: PMC2852031  PMID: 20131081
Furfural; Hexose; 5-Hydroxymethyl furfural; NADPH; Pentose; Transhydrogenase
Nature medicine  2009;15(7):746-749.
Memory T-cells promote allograft rejection particularly in costimulation blockade (CoB)-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (LFA3-Ig) selectively eliminates memory T-cells and when combined with a CoB-based regimen utilizing CTLA4-Ig, prevents renal allograft rejection and alloantibody formation in primates. These results support the development of an immediately translatable regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids, or pan-T-cell depletion.
PMCID: PMC2772128  PMID: 19584865
7.  Preparation for the next major incident: are we ready? 
Emergency Medicine Journal : EMJ  2006;23(9):709-712.
In 1996, Carley and Mackway‐Jones examined British hospital's readiness for a major incident. In the light of recent terrorist events in London, our group has re‐visited the issue and conducted a telephone survey of relevant parties to investigate whether the situation has changed almost 10 years on.
Materials and Methods
A proforma was devised, and registrars in anaesthesia, accident and emergency medicine, general surgery and trauma and orthopaedics were telephoned in trauma units across the UK and questioned about their readiness to respond to a major incident. Major incident co‐ordinators for each of the units were contacted, and their planning, readiness, training opportunities, and recent rehearsals were assessed.
A total of 179 registrars were contacted in 34 different units throughout Britain. One hundred and forty four responses were obtained. Sixty eight registrars (47%) had not read any of their hospitals major incident plan. Only 77 (54%) of the registrars questioned felt confident in the knowledge of their specific role during a major incident. Major incident co‐ordinators were contacted at 34 hospitals, and 17 responses obtained. It was remarkably difficult to achieve even that level of response. Rehearsal of major incident plans varied widely between hospitals with 82% of hospitals having practised within the past five years but only 35% were planning for a rehearsal in the next twelve months. 25% of hospitals that responded did not hold any teaching on major incident planning at their introduction sessions for junior and middle grade doctors. Limitations to improvement of major incident planning included: lack of funds, lack of a designated full‐time major incident co‐ordinator, and lack of technology. There was no significant difference between units within London and those in other regions.
Preparedness for major incidents in the UK remains poor 10 years after Carley and Mackway‐Jones examined the issue. Effective major incident plans require forethought, organisation, briefing of relevant staff and regular rehearsal. Increased resources should be provided for this at a local level and more regular rehearsals undertaken to ensure our preparedness for future major incidents.
PMCID: PMC2564219  PMID: 16921088
9.  Circadian photoreception: ageing and the eye’s important role in systemic health 
The British Journal of Ophthalmology  2008;92(11):1439-1444.
To analyse how age-related losses in crystalline lens transmittance and pupillary area affect circadian photoreception and compare the circadian performance of phakic and pseudophakic individuals of the same age.
The spectral sensitivity of circadian photoreception peaks in the blue part of the spectrum at approximately 460 nm. Photosensitive retinal ganglion cells send unconscious information about environmental illumination to non-visual brain centres including the human body’s master biological clock in the suprachiasmatic nuclei. This information permits human physiology to be optimised and aligned with geophysical day–night cycles using neural and hormonal messengers including melatonin. Age-related transmittance spectra of crystalline lenses and photopic pupil diameter are used with the spectral sensitivity of melatonin suppression and the transmittance spectra of intraocular lenses (IOLs) to analyse how ageing and IOL chromophores affect circadian photoreception.
Ageing increases crystalline lens light absorption and decreases pupil area resulting in progressive loss of circadian photoreception. A 10-year-old child has circadian photoreception 10-fold greater than a 95-year-old phakic adult. A 45-year-old adult retains only half the circadian photoreception of early youth. Pseudophakia improves circadian photoreception at all ages, particularly with UV-only blocking IOLs which transmit blue wavelengths optimal for non-visual photoreception.
Non-visual retinal ganglion photoreceptor responses to bright, properly timed light exposures help assure effective circadian photoentrainment and optimal diurnal physiological processes. Circadian photoreception can persist in visually blind individuals if retinal ganglion cell photoreceptors and their suprachiasmatic connections are intact. Retinal illumination decreases with ageing due to pupillary miosis and reduced crystalline lens light transmission especially of short wavelengths. Inadequate environmental light and/or ganglion photoreception can cause circadian disruption, increasing the risk of insomnia, depression, numerous systemic disorders and possibly early mortality. Artificial lighting is dimmer and less blue-weighted than natural daylight, contributing to age-related losses in unconscious circadian photoreception. Optimal intraocular lens design should consider the spectral requirements of both conscious and unconscious retinal photoreception.
PMCID: PMC2582340  PMID: 18757473
10.  Serological speciation of human schistosome infections by ELISA with a panel of three antigens 
Journal of Clinical Pathology  2004;57(11):1193-1196.
Aims: To find out whether serology can reliably speciate human schistosomiasis using a simple enzyme linked immunosorbent assay (ELISA) technique.
Methods: Stored sera from 66 patients with microscopically confirmed schistosomiasis were subjected to ELISA using a panel of three antigens, namely: unfractionated Schistosoma mansoni soluble egg antigen (SEA); CEF6, a cationic fraction of SEA; and crude S margrebowiei egg antigen, prepared from an animal schistosome closely related to S haematobium.
Results: The optical densities (ODs) obtained using CEF6 as antigen were significantly higher in sera from S mansoni infected patients than in sera from S haematobium infected patients (median OD, 0.810 v 0.595). Using S margrebowiei egg antigen, the optical densities were significantly higher in S haematobium sera than in S mansoni sera (median OD, 0.794 v 0.544). There was no significant difference in optical densities between S mansoni and S haematobium sera using SEA (median OD, 0.725 v 0.737). The ratio of ODs (CEF6 to S margrebowiei egg antigen) was calculated: a ratio of >1 indicated S mansoni infection (sensitivity, 88%) and a ratio of <1 indicated S haematobium infection (sensitivity, 84%). The odds ratio for S haematobium having an OD ratio of <1 was 36.8 (95% confidence interval, 7.0 to 194).
Conclusions: The identity of the infecting species of schistosome can be determined using the panel of antigens described. SEA should be used to screen serum samples, and the CEF6 : S margrebowiei egg antigen ELISA optical density ratio can be used where serological speciation is required.
PMCID: PMC1770487  PMID: 15509682
schistosomiasis; serodiagnosis; enzyme linked immunosorbent assay
11.  Lactobacillus rhamnosus Strain GG Reduces Aflatoxin B1 Transport, Metabolism, and Toxicity in Caco-2 Cells▿  
Applied and Environmental Microbiology  2007;73(12):3958-3964.
The probiotic Lactobacillus rhamnosus GG is able to bind the potent hepatocarcinogen aflatoxin B1 (AFB1) and thus potentially restrict its rapid absorption from the intestine. In this study we investigated the potential of GG to reduce AFB1 availability in vitro in Caco-2 cells adapted to express cytochrome P-450 (CYP) 3A4, such that both transport and toxicity could be assessed. Caco-2 cells were grown as confluent monolayers on transmembrane filters for 21 days prior to all studies. AFB1 levels in culture medium were measured by high-performance liquid chromatography. In CYP 3A4-induced monolayers, AFB1 transport from the apical to the basolateral chamber was reduced from 11.1% ± 1.9% to 6.4% ± 2.5% (P = 0.019) and to 3.3% ± 1.8% (P = 0.002) within the first hour in monolayers coincubated with GG (1 × 1010 and 5 × 1010 CFU/ml, respectively). GG (1 × 1010 and 5 × 1010 CFU/ml) bound 40.1% ± 8.3% and 61.0% ± 6.0% of added AFB1 after 1 h, respectively. AFB1 caused significant reductions of 30.1% (P = 0.01), 49.4% (P = 0.004), and 64.4% (P < 0.001) in transepithelial resistance after 24, 48, and 72 h, respectively. Coincubation with 1 × 1010 CFU/ml GG after 24 h protected against AFB1-induced reductions in transepithelial resistance at both 24 h (P = 0.002) and 48 h (P = 0.04). DNA fragmentation was apparent in cells treated only with AFB1 cells but not in cells coincubated with either 1 × 1010 or 5 × 1010 CFU/ml GG. GG reduced AFB1 uptake and protected against both membrane and DNA damage in the Caco-2 model. These data are suggestive of a beneficial role of GG against dietary exposure to aflatoxin.
PMCID: PMC1932713  PMID: 17449679
13.  Lactobacillus rhamnosus Strain GG Modulates Intestinal Absorption, Fecal Excretion, and Toxicity of Aflatoxin B1 in Rats▿  
Applied and Environmental Microbiology  2006;72(11):7398-7400.
In this study, the modulation of aflatoxin B1 (AFB1) uptake in rats by administration of the probiotic Lactobacillus rhamnosus GG was demonstrated. Fecal AFB1 excretion in GG-treated rats was increased via bacterial AFB1 binding. Furthermore, AFB1-associated growth faltering and liver injury were alleviated with GG treatment.
PMCID: PMC1636196  PMID: 16980432
14.  Laboratory-Dependent Bacterial Ecology: a Cautionary Tale 
Although laboratory dependence is an acknowledged problem in microbiology, it is seldom intensively studied or discussed. We demonstrate that laboratory dependence is real and quantifiable even in the popular model Escherichia coli. Here laboratory effects alter the equilibrium composition of a simple community composed of two strains of E. coli. Our data rule out changes in the bacterial strains, chemical batches, and human handling but implicate differences in growth medium, especially the water component.
PMCID: PMC1449003  PMID: 16598013
15.  BMD and airways disease 
Thorax  2002;57(2):186.
PMCID: PMC1746243  PMID: 11828055
17.  Clinical evaluation of keratometry and computerised videokeratography: intraobserver and interobserver variability on normal and astigmatic corneas 
AIMS—To evaluate intra- and interobserver variability in measurements on normal and astigmatic corneas with keratometry and computerised videokeratography.
METHODS—Keratometric readings with the 10 SL/O Zeiss keratometer and topographic maps with the TMS-1 were obtained by two independent examiners on 32 normal and 33 postkeratoplasty corneas. Inter- and intraobserver coefficients of variability (COR) for measurements of steep and flat meridian power and location, in addition to the magnitude of astigmatism, were assessed.
RESULTS—Compared with TMS-1, the 10 SL/O keratometer showed a superior repeatability in measuring normal corneas (intraobserver COR for keratometry and TMS-1 respectively: 0.22 and 0.30 D for steep meridian power; 0.18 and 0.44 D for flat meridian power; 0.26 and 0.40 D for astigmatism; 5° and 26° for steep meridian location; 5° and 13° for flat meridian location). Astigmatism intraobserver COR (0.20 D and 0.26 D for the two observers) and interobserver COR (0.28 D) of the keratometer for normal corneas was very good and not affected by observers' experience. Repeatability of the TMS-1 on normal corneas was found to be: (a) observer related, and (b) astigmatism related. A novice observer showed a much greater COR (1.62 D for astigmatism, 30° for flat meridian location) compared with the experienced examiner (0.40 D for astigmatism, 13° for flat meridian location). Higher deviation scores were observed for corneas with higher astigmatism. For the postkeratoplasty corneas, again the keratometer achieved superior reproducibility (astigmatism interobserver COR 1.12 D for keratometry, 4.06 D for TMS-1; steep meridian location interobserver COR 10° for keratometry, 34° for TMS-1).
CONCLUSION—Keratometric readings are more reproducible than topographic data both for normal and postkeratoplasty corneas. The two instruments should not be used interchangeably especially on highly astigmatic corneas. For the TMS-1, users with the same level of experience should be employed in clinical or experimental studies.

 Keywords: keratometry; computerised videokeratography; astigmatic corneas
PMCID: PMC1722645  PMID: 9797664
18.  A novel neuropeptide-endocrine interaction controlling ecdysteroid production in ixodid ticks. 
Ixodid (hard) ticks are blood-feeding arthropods that require a blood meal to complete each stage of development. However, the hormonal events coordinating aspects of feeding and development are only poorly understood. We have delineated a new neuropeptide-endocrine interaction in the adult tick, Amblyomma hebraeum, that stimulates the synthesis of the moulting hormones, the ecdysteroids. In adult female ticks, ecdysteroid synthesis could be demonstrated in integumental tissue incubated in vitro with a synganglial (central nervous system) extract, but not in its absence. Stimulation by the synganglial extract is both time- and dose-dependent, but is completely abolished by trypsin treatment, suggesting that the activity is due to a peptide/protein. Integumental tissue ecdysteroidogenesis is also stimulated by elevation of the cAMP concentration using forskolin and 3-isobutyl-l-methyl-xanthine, or by 8-bromo-cAMP. This suggests the involvement of at least a cAMP second messenger system in the neuropeptide-ecdysteroidogenesis axis, without precluding a role for other second messengers as well. Despite involving a quite different steroidogenic tissue, the foregoing system has some parallels with the known prothoracicotropic hormone (neuropeptide)-prothoracic gland endocrine axis of insects.
PMCID: PMC1688385  PMID: 9149427
19.  Hyperresponsiveness in the human nasal airway: new targets for the treatment of allergic airway disease. 
Mediators of Inflammation  1999;8(3):133-146.
Allergic rhinitis is a condition which affects over 15% of the population in the United Kingdom. The pathological process involves two stages: nasal inflammation, and the development of nasal airway hyperresponsiveness (AHR) to allergen and a number of other stimuli. This results in the amplification of any subsequent allergic reaction, contributing to the chronic allergic state. A number of different hypotheses have been proposed to explain the underlying mechanism of AHR, including a role for eosinophil-derived proteins, free radicals and neuropeptides. While there may be a number of independent pathways which can result in AHR, evidence obtained from both animal models and in vivo experiments in humans indicate that some mediators may interact with one another, resulting in AHR. Further research into these interactions may open new avenues for the pharmacological treatment of chronic allergic rhinitis, and possibly other allergic airway diseases.
PMCID: PMC1781794  PMID: 10704051
20.  Activation of Caspases in Pig Kidney Cells Infected with Wild-Type and CrmA/SPI-2 Mutants of Cowpox and Rabbitpox Viruses 
Journal of Virology  1998;72(5):3524-3533.
The cowpox virus (CPV) CrmA and the equivalent rabbitpox virus (RPV) SPI-2 proteins have anti-inflammatory and antiapoptosis activity by virtue of their ability to inhibit caspases, including the interleukin-1β-converting enzyme (ICE; caspase-1). Infection of LLC-PK1 pig kidney cells with a CPV CrmA mutant, but not with wild-type (wt) CPV, results in the induction of many of the morphological features of apoptosis (C. A. Ray and D. J. Pickup, Virology 217:384–391, 1996). In our study, LLC-PK1 cells infected with CPVΔcrmA, but not those infected with wt CPV, showed induction of poly(ADP-ribose) polymerase (PARP)- and lamin A-cleaving activities and processing of the CPP32 (caspase-3) precursor to a mature 18-kDa form. Surprisingly, infection of LLC-PK1 cells with either wt RPV (despite the presence of the SPI-2 protein) or RPVΔSPI-2 resulted in cleavage activity against PARP and lamin A and the appearance of the mature subunit of CPP32/caspase-3. The biotinylated specific peptide inhibitor Ac-Tyr-Val-Lys(biotinyl)-Asp-2,6-dimethylbenzoyloxymethylketone [AcYV(bio)KD-aomk] labeled active caspase subunits of 18, 19, and 21 kDa in extracts from LLC-PK1 cells infected with CPVΔcrmA, wt RPV, or RPVΔSPI-2 but not wt CPV. Mixed infection of LLC-PK1 cells with wt RPV and wt CPV gave no PARP-cleaving activity, and all PARP cleavage mediated by SPI-2 and CrmA mutants of RPV and CPV, respectively, could be eliminated by coinfection with wt CPV. These results suggest that the RPV SPI-2 and CPV CrmA proteins are not functionally equivalent and that CrmA, but not SPI-2 protein, can completely prevent apoptosis in LLC-PK1 cells under these conditions.
PMCID: PMC109571  PMID: 9557631
21.  Pharmacokinetics of naftopidil, a novel anti-hypertensive drug, in patients with hepatic dysfunction. 
Postgraduate Medical Journal  1994;70(823):363-366.
The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, were investigated in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic parameters obtained for the i.v. administration were comparable in both groups (half life 3.6 +/- 3.4 hours in liver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopidil were significantly increased in liver impairment (t1/2 16.6 +/- 19.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean values for the absolute bioavailability in patients with hepatic dysfunction were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surgery, is the probable cause of the observed alteration in naftopidil kinetics. This phenomenon occurred only following the oral 50 mg dose whereas the intravenous 5 mg dose obviously still could be normally handled. Naftopidil demethylation and hydroxylation were both less and non-uniformly affected. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.
PMCID: PMC2397621  PMID: 8016009
22.  Views of hospital staff on the management of hypertension. 
Postgraduate Medical Journal  1994;70(823):355-358.
A questionnaire concerning the detection and management of hypertension was presented to 265 hospital doctors, 114 medical students and 59 student nurses. Of these 75% were completed. Although only 76% thought that routine measurement was necessary in outpatients, 92% of respondents thought that blood pressure (BP) should be measured routinely in all in-patients. A total of 17% of all doctors and 11% of physicians indicated that they would not use drug treatment until the diastolic BP exceeded 105 mmHg. Thirty-four per cent of respondents still use diastolic phase IV and 84% felt that BP should be measured 2-4 times before deciding on treatment but the posture of the patient (lying, sitting or standing) during recording was inconsistent. Seventy-seven per cent of respondents indicated that they recorded BP to the nearest 5 mmHg and 4% to the nearest 10 mmHg. Despite the literature on the subject, there are still widely differing opinions amongst medical staff on how to record BP and at what level it should be treated.
PMCID: PMC2397620  PMID: 8016007
25.  A pharmacokinetic interaction between cimetidine or ranitidine and lornoxicam. 
Postgraduate Medical Journal  1993;69(817):865-866.
Cimetidine 400 mg twice daily significantly increased serum concentrations and reduced apparent oral clearance of lornoxicam 8 mg twice daily in 12 healthy volunteers. Ranitidine 150 mg twice daily produced no significant changes in lornoxicam pharmacokinetics.
PMCID: PMC2399905  PMID: 8290432

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