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1.  Two Leucobacter Strains Exert Complementary Virulence on Caenorhabditis Including Death by Worm-Star Formation 
Current Biology  2013;23(21):2157-2161.
The nematode Caenorhabditis elegans has been much studied as a host for microbial infection. Some pathogens can infect its intestine [1, 2], while others attack via its external surface [1, 3–6]. Cultures of Caenorhabditis isolated from natural environments have yielded new nematode pathogens, such as microsporidia and viruses [7, 8]. We report here a novel mechanism for bacterial attack on worms, discovered during investigation of a diseased and coinfected natural isolate of Caenorhabditis from Cape Verde. Two related coryneform pathogens (genus Leucobacter) were obtained from this isolate, which had complementary effects on C. elegans and related nematodes. One pathogen, Verde1, was able to cause swimming worms to stick together irreversibly by their tails, leading to the rapid formation of aggregated “worm-stars.” Adult worms trapped in these aggregates were immobilized and subsequently died, with concomitant growth of bacteria. Trapped larval worms were sometimes able to escape from worm-stars by undergoing autotomy, separating their bodies into two parts. The other pathogen, Verde2, killed worms after rectal invasion, in a more virulent version of a previously studied infection [6]. Resistance to killing by Verde2, by means of alterations in host surface glycosylation, resulted in hypersensitivity to Verde1, revealing a trade-off in bacterial susceptibility. Conversely, a sublethal surface infection of worms with Verde1 conferred partial protection against Verde2. The formation of worm-stars by Verde1 occurred only when worms were swimming in liquid but provides a striking example of asymmetric warfare as well as a bacterial equivalent to the trapping strategies used by nematophagous fungi [4].
•Verde1 bacteria can trap swimming worms by tail adhesion and worm-star formation•Nematodes trapped in worm-stars are immobilized, killed, and used for nutrition•Trapped larval worms can escape from worm-stars by whole-body autotomy•Resistance to virulent Verde2 bacteria results in lethal hypersensitivity to Verde1
PMCID: PMC3898767  PMID: 24206844
2.  Maturation of the Human Fovea: Correlation of Spectral-Domain Optical Coherence Tomography Findings With Histology 
American journal of ophthalmology  2012;154(5):779-789.e2.
To correlate human foveal development visualized by spectral-domain optical coherence tomography (SDOCT) with histologic specimens.
Retrospective, observational case series.
Morphology and layer thickness of retinal SDOCT images from 1 eye each of 22 premature infants, 30 term infants, 16 children, and 1 adult without macular disease were compared to light microscopic histology from comparable ages.
SDOCT images correlate with major histologic findings at all time points. With both methods, preterm infants demonstrate a shallow foveal pit indenting inner retinal layers (IRL) and short, undeveloped foveal photoreceptors. At term, further IRL displacement forms the pit and peripheral photoreceptors lengthen; the elongation of inner and outer segments (IS and OS, histology) separates the IS band from retinal pigment epithelium. Foveal IS and OS are shorter than peripheral for weeks after birth (both methods). By 13 months, foveal cone cell bodies stack >6 deep, Henle fiber layer (HFL) thickens, and IS/OS length equals peripheral; on SDOCT, foveal outer nuclear layer (which includes HFL) and IS/OS thickens. At 13 to 16 years, the fovea is fully developed with a full complement of SDOCT bands; cone cell bodies >10 deep have thin, elongated, and tightly packed IS/OS.
We define anatomic correlates to SDOCT images from normal prenatal and postnatal human fovea. OCT bands typical of photoreceptors of the adult fovea are absent near birth because of the immaturity of foveal cones, develop by 24 months, and mature into childhood. This validates the source of SDOCT signal and provides a framework to assess foveal development and disease.
PMCID: PMC3612897  PMID: 22898189
3.  The health, social and educational needs of children who have survived meningitis and septicaemia: the parents’ perspective 
BMC Public Health  2013;13:954.
Survivors of bacterial meningitis and septicaemia can experience a range of after-effects. There is little published research on the needs and provision of aftercare for children surviving bacterial meningitis and septicaemia.
Mixed methods study employing a survey and follow-up interviews with a sample of survey participants recruited from Meningitis Research Foundation’s member database and social media.
Of 194 eligible survey respondents, 77% reported at least moderate short-term after-effects, and 57% a need for aftercare or support. Most parents reported that their child received a hearing test (98%) and follow-up appointment with a paediatrician (66%). Psychosocial after-effects were most common and the greatest need was for educational support. About half of participants felt their children’s needs for aftercare were met. We conducted interviews with 18 parents. Findings suggest access could be limited by: parents’ inability to navigate systems in place, child’s age, and delayed identification of sequelae. Parents felt a comprehensive explanation of possible after-effects on discharge from hospital was required, and found uncertain prognoses difficult. Good communication between professionals enabled a service tailored to the child’s needs.
Our study supports the NICE and SIGN guidelines and highlights areas for improvement in the aftercare of these children.
PMCID: PMC3852620  PMID: 24112360
Meningitis; Septicaemia; Sequelae; Aftercare; Survey; Qualitative
4.  Mammalian cell entry genes in Streptomyces may provide clues to the evolution of bacterial virulence 
Scientific Reports  2013;3:1109.
Understanding the evolution of virulence is key to appreciating the role specific loci play in pathogenicity. Streptomyces species are generally non-pathogenic soil saprophytes, yet within their genome we can find homologues of virulence loci. One example of this is the mammalian cell entry (mce) locus, which has been characterised in Mycobacterium tuberculosis. To investigate the role in Streptomyces we deleted the mce locus and studied its impact on cell survival, morphology and interaction with other soil organisms. Disruption of the mce cluster resulted in virulence towards amoebae (Acanthamoeba polyphaga) and reduced colonization of plant (Arabidopsis) models, indicating these genes may play an important role in Streptomyces survival in the environment. Our data suggest that loss of mce in Streptomyces spp. may have profound effects on survival in a competitive soil environment, and provides insight in to the evolution and selection of these genes as virulence factors in related pathogenic organisms.
PMCID: PMC3552289  PMID: 23346366
5.  Distribution, Population Biology, and Trophic Ecology of the Deepwater Demersal Fish Halosauropsis macrochir (Pisces: Halosauridae) on the Mid-Atlantic Ridge 
PLoS ONE  2012;7(2):e31493.
Halosauropsis macrochir ranked amongst the most abundant and widespread demersal fishes on the mid-Atlantic Ridge of the North Atlantic (Iceland-Azores) with greatest abundance at 1700–3500 m. All sizes, ranging from 10–76 cm total length, occurred in the area without any apparent spatial pattern or depth trend. Using otolith sections displaying growth increments assumed to represent annuli, the age range recorded was 2–36 years, but most individuals were <20 years. Length and weight at age data were used to fit growth models. No differences between sexes in length and weight at age were observed. The majority of samples had a surplus of males. Diet analysis showed that H. macrochir feeds on Crustacea, Teleostei, Polychaeta, and Cephalopoda, but few prey could be identified to lower taxonomical levels. The mid-Atlantic Ridge constitutes a major portion of the North Atlantic living space of the abyssal halosaur where it completes its full life cycle, primarily as an actively foraging euryophagous micronekton/epibenthos and infauna feeder, becoming a partial piscivore with increasing size.
PMCID: PMC3285165  PMID: 22384030
6.  Duplication and Evolution of devA-Like Genes in Streptomyces Has Resulted in Distinct Developmental Roles 
PLoS ONE  2011;6(10):e25049.
Understanding morphological transformations is essential to elucidating the evolution and developmental biology of many organisms. The Gram-positive soil bacterium, Streptomyces coelicolor has a complex lifecycle which lends itself well to such studies. We recently identified a transcriptional regulator, devA, which is required for correct sporulation in this organism, with mutants forming short, mis-septate aerial hyphae. devA is highly conserved within the Streptomyces genus along with a duplicate copy, devE. Disruption of devE indicates this gene also plays a role in sporulation; however the phenotype of a devE mutant differs from a devA mutant, forming long un-septate aerial hyphae. Transcriptional analysis of devA and devE indicates that they are expressed at different stages of the lifecycle. This suggests that following duplication they have diverged in regulation and function. Analysis of fully sequenced actinomycete genomes shows that devA is found in a single copy in morphologically simpler actinobacteria, suggesting that duplication has lead to increased morphological complexity. Complementation studies with devA from Salinispora, which sporulates but does not form aerial hyphae, indicates the ancestral gene cannot complement devA or devE, suggesting neo-functionalisation has occurred. Analysis of the synonymous and non-synonymous nucleotide changes within the devA paralogues suggest subfunctionalisation has occurred as both copies have diverged from the ancestral sequences. Divergence is also asymmetric with a higher level of functional constraint observed in the DNA binding domain compared with the effector binding/oligomerisation domain, suggesting diversification in the substrate specificity of these paralogues has contributed to their evolution.
PMCID: PMC3187754  PMID: 21998634
7.  Assessing the adequacy of procedure-specific consent forms in orthopaedic surgery against current methods of operative consent 
This is an audit of patient understanding following their consent for orthopaedic procedures and uses information on new Orthoconsent forms endorsed by the British Orthopaedic Association as the set standard. The objectives were to: (i) assess whether patients& understanding of knee arthroscopy (KA) and total knee replacement (TKR) at the point of confirming their consent reaches the set standard; and (ii) to ascertain whether issuing procedure-specific Orthoconsent forms to patients can improve this understanding.
This was a prospective audit using questionnaires consisting of 26 (for KA) or 35 (for TKR) questions based on the appropriate Orthoconsent form in a department of orthopaedic surgery within a UK hospital. Participants were 100 patients undergoing KA and 60 patients undergoing TKR between February and July 2008. Participants were identified from sequential operating lists and all had capacity to give consent. During the first audit cycle, consent was discussed with the patient and documented on standard yellow NHS Trust approved generic consent forms. During the second audit cycle, patients were additionally supplied with the appropriate procedure-specific consent form downloaded from which they were required to read at home and sign on the morning of surgery.
Knee arthroscopy patients consented with only the standard yellow forms scored an average of 56.7%, rising to 80.5% with use of Orthoconsent forms. Similarly, total knee replacement patients& averages rose from 57.6% to 81.6%.
Providing patients with an Orthoconsent form significantly improves knowledge of their planned procedure as well as constituting a more robust means of information provision and consent documentation.
PMCID: PMC3080073  PMID: 20412675
Informed consent; Consent documentation; Orthopaedic surgery; Audit; 
8.  Improving the quality of procedure-specific operation reports in orthopaedic surgery 
The objectives of this study were to: (i) assess whether handwritten operation reports for hip hemi-arthroplasties adhere to The Royal College of Surgeons of England (RCSE) guidelines on surgical documentation; (ii) improve adherence to these guidelines with procedure-specific computerised operation reports; and (iii) improve the quality of documentation in surgery.
Thirty-three parameters based on RCSE guidelines were used to score hip hemi-arthroplasty operation reports. The first audit cycle was performed retrospectively to assess 50 handwritten operation reports, and the second cycle prospectively to assess 30 new computerised procedure-specific operation reports produced for hip hemi-arthroplasties. Eighty patients undergoing hip hemi-arthroplasty in a department of orthopaedic surgery within a UK hospital between September 2007 and August 2008 formed the study cohort.
The main outcome measure was the average scores attained by handwritten versus computerised operation reports. Handwritten reports scored an average of 58.7%, rising significantly (P < 0.01) to 92.8% following the introduction of detailed, computerised proformas for the operation note. Adherence to each RCSE parameter was improved.
Computerised proformas reduce variability between different operation reports for the same procedure and increase their content in line with RCSE recommendations. The proformas also constitute a more robust means of operative documentation.
PMCID: PMC3025226  PMID: 19995491
Operation report; Orthopaedic surgery; Computerised proforma; Audit; Documentation
9.  Foreskin management 
Canadian Family Physician  2010;56(10):986.
PMCID: PMC2954071  PMID: 20944035
10.  A randomized, controlled trial of the safety of candidate microbicide SPL7013 Gel when applied to the penis 
To determine the safety of the candidate vaginal microbicide SPL7013 Gel (VivaGel®) when applied to the penis.
A randomized, double blind, placebo controlled study. Thirty-six healthy men (18 circumcised, 18 uncircumcised), were randomized in a 2:1 ratio and treated with 3% SPL7013 Gel (N=24) or placebo gel (N=12), applied once daily for 7 days. Genital toxicity was determined by interview, diary, and examination.
There were 10 genital adverse events (AEs) in 6 men (25%) receiving SPL7013 Gel, and 5 genital AEs in 4 men (33%) receiving the placebo that were possibly or probably related to the study product (difference of −8%, 95% CI: −40% to 23%, p=0.70). The most common genital AEs were genital pruritus and application site erythema. All genital AEs were mild (grade 1), and all but one, in the placebo group, were transient. Analysis of vital signs, non-genital AEs, and laboratory results indicated no safety or tolerability issues with SPL7013 Gel, irrespective of circumcision status. There was no detectable absorption of SPL7013 into the plasma.
3% SPL7013 Gel was safe and well tolerated, and comparable with placebo, when administered to the penis of both circumcised and uncircumcised men once daily for 7 days, with no evidence of systemic absorption or toxicity.
PMCID: PMC2680448  PMID: 19214122
Microbicide; HIV prevention; Phase 1 Clinical Trial; SPL7013; VivaGel™
11.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes 
Cancer cell  2006;10(6):515-527.
Recent studies suggest that thousands of genes may contribute to breast cancer pathophysiologies when deregulated by genomic or epigenomic events. Here, we describe a model “system” to appraise the functional contributions of these genes to breast cancer subsets. In general, the recurrent genomic and transcriptional characteristics of 51 breast cancer cell lines mirror those of 145 primary breast tumors, although some significant differences are documented. The cell lines that comprise the system also exhibit the substantial genomic, transcriptional, and biological heterogeneity found in primary tumors. We show, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.
The description of the in vitro breast cancer cell line system described here allows assessment of similarities and differences between the cell lines and primary human breast tumors. In general, the system seems well suited to assess the functional contributions of genome copy number abnormalities to breast cancer pathophysiologies, since most of the recurrent genomic deregulation of transcription present in primary tumors is retained in the cell lines. The genomically and biologically heterogeneous cell line system also may be used to identify molecular features that predict or indicate response (or lack thereof) to pathway-targeted therapeutic agents. These features may be assessed as candidate response predictors/indicators to guide early-phase clinical trials.
PMCID: PMC2730521  PMID: 17157791
12.  Siblings of Children With Severe Emotional Disturbances 
This study examines risks, resources, and adjustment among siblings of children with severe emotional disturbances (SED) involved in an initiative to develop family centered Systems of Care in North Carolina. These siblings experience many of the same risks as the children who have been diagnosed with SED (i.e., “targets”), but have received relatively little attention from the system or researchers. This first systematic study of these siblings describes an early sample (n = 56), compares them to their system-identified brothers and sisters, and explores contextual factors related to sibling resources and adjustment. Findings suggest the siblings, much like the targets: (a) have been exposed to extremely high levels of adversity, and (b) evidence substantial variability in behavioral and emotional strengths and social-emotional adjustment. Although many siblings exhibit significant strengths and positive adjustment, a substantial proportion displays levels of competencies or problem behaviors on par with those targeted to receive services. Factors associated with positive sibling adjustment are consistent with those identified in prior risk and resilience work. Additional systematic study of these children could have implications for service delivery and preventive interventions.
PMCID: PMC2692691  PMID: 18444721
siblings; children with severe emotional disturbance; systems of care

Results 1-12 (12)