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1.  Anti-Group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection☆ 
Vaccine  2015;33(5):621-627.
•HIV-infected women have lower anti-GBS surface binding antibody concentrations than uninfected controls with reduced antibody-mediated deposition of complement C3b/iC3b onto GBS bacteria.•HIV-exposed, uninfected infants have a lower concentration of antibody binding to the surface of GBS bacteria as well as a reduction in antibody-mediated deposition of complement C3b/iC3b onto the surface of GBS strains at birth compared to HIV-unexposed infants.•As a result, HIV-exposed uninfected infants may be at increased risk of early and late onset GBS disease compared to unexposed infants.
HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS.
We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay.
Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n = 46) compared to HIV-uninfected women (n = 58) for ST1a (surface-binding: 19.3 vs 29.3; p = 0.003; complement deposition: 2.9 vs 5.3 SU/mL; p = 0.003), STIb (24.9 vs 47.6; p = 0.003; 2.6 vs 4.9 SU/mL; p = 0.003), STII (19.8 vs 50.0; p = 0.001; 3.1 vs 6.2 SU/mL; p = 0.001), STIII (27.8 vs 60.1; p = 0.001; 2.8 vs 5.3 SU/mL; p = 0.001) and STV (121.9 vs 185.6 SU/mL; p < 0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p = 0.02), STIb (13.4 vs 24.5 SU/mL; p = 0.02), STII (14.6 vs 42.7 SU/mL; p = 0.03), STIII (26.6 vs 62.7 SU/mL; p = 0.03) and STV (90.4 vs 165.8 SU/mL; p = 0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22–0.59] vs 1.0 SU/mL [0.42–1.66]; p < 0.001), III (0.54 [0.31–1.03] vs 0.95 SU/mL [0.42–3.05], p = 0.05) and V (0.51 [0.28–0.79] vs 0.75 SU/mL [0.26–2.9], p = 0.04). The differences between infants remained significant at 16 weeks of age.
Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease.
PMCID: PMC4315133  PMID: 25543061
Antibody; Group B Streptococcus; HIV-exposed-uninfected infants; HIV; Immunity
2.  Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures 
This is an updated version of the original Cochrane review published in Issue 4, 2001.
Worldwide, phenytoin and phenobarbitone are commonly used antiepileptic drugs. They are more likely to be used in the developing world than the developed world, primarily because they are inexpensive. The aim of this review is to summarize data from existing trials comparing phenytoin and phenobarbitone.
To review the effects of phenobarbitone compared to phenytoin when used as monotherapy in patients with partial onset seizures or generalized tonic-clonic seizures with or without other generalized seizure types.
Search methods
We searched the Cochrane Epilepsy Group trials register (20 October 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2009) and MEDLINE (1950 to October week 2, 2009). In addition, we handsearched relevant journals, and contacted pharmaceutical companies and researchers in the field to seek any ongoing or unpublished studies.
Selection criteria
Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenobarbitone monotherapy with phenytoin monotherapy.
Data collection and analysis
This was an individual patient data review. Outcomes were time to (a) withdrawal of allocated treatment, (b) 12-month remission and (c) first seizure post randomization. Data were analyzed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR > 1 indicates an event is more likely to occur earlier on phenobarbitone than phenytoin.
Main results
To date, data have been obtained for four of ten studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 65% of the potential data. The main overall results (HR) were (a) time to treatment withdrawal 1.62 (95% confidence interval 1.22 to 2.14); (b) time to 12-month remission 0.93 (95% confidence interval 0.70 to 1.23) and (c) time to first seizure 0.84 (95% confidence interval 0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal and a non-significant advantage in terms of 12-month remission. Results for time to first seizure suggest a non-significant clinical advantage for phenobarbitone.
Authors’ conclusions
The results of this review favour phenytoin over phenobarbitone, as phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to adverse effects.
PMCID: PMC4176628  PMID: 11687150
Anticonvulsants [* therapeutic use]; Epilepsies, Partial [* drug therapy]; Epilepsy, Generalized [* drug therapy]; Phenobarbital [* therapeutic use]; Phenytoin [* therapeutic use]; Randomized Controlled Trials as Topic; Seizures [* drug therapy]; Humans
3.  Diagnostic accuracy of clinical examination features for identifying large rotator cuff tears in primary health care 
Rotator cuff tears are a common and disabling complaint. The early diagnosis of medium and large size rotator cuff tears can enhance the prognosis of the patient. The aim of this study was to identify clinical features with the strongest ability to accurately predict the presence of a medium, large or multitendon (MLM) rotator cuff tear in a primary care cohort.
Participants were consecutively recruited from primary health care practices (n = 203). All participants underwent a standardized history and physical examination, followed by a standardized X-ray series and diagnostic ultrasound scan. Clinical features associated with the presence of a MLM rotator cuff tear were identified (P<0.200), a logistic multiple regression model was derived for identifying a MLM rotator cuff tear and thereafter diagnostic accuracy was calculated.
A MLM rotator cuff tear was identified in 24 participants (11.8%). Constant pain and a painful arc in abduction were the strongest predictors of a MLM tear (adjusted odds ratio 3.04 and 13.97 respectively). Combinations of ten history and physical examination variables demonstrated highest levels of sensitivity when five or fewer were positive [100%, 95% confidence interval (CI): 0.86–1.00; negative likelihood ratio: 0.00, 95% CI: 0.00–0.28], and highest specificity when eight or more were positive (0.91, 95% CI: 0.86–0.95; positive likelihood ratio 4.66, 95% CI: 2.34–8.74).
Combinations of patient history and physical examination findings were able to accurately detect the presence of a MLM rotator cuff tear. These findings may aid the primary care clinician in more efficient and accurate identification of rotator cuff tears that may require further investigation or orthopedic consultation.
PMCID: PMC3744848  PMID: 24421626
Sensitivity; Specificity; Physical examination; Primary health care; Rotator cuff
4.  Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease1 
Alzheimer’s disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2–3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49 – 62%) and activated glia (42– 68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.
PMCID: PMC4067320  PMID: 19561098
5.  High-resolution analysis of cis-acting regulatory networks at the α-globin locus 
We have combined the circular chromosome conformation capture protocol with high-throughput, genome-wide sequence analysis to characterize the cis-acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10–1000 kb), the 4C approach provides a comprehensive, high-resolution analysis of a specific locus with the aim of defining, in detail, the cis-regulatory elements controlling a single gene or gene cluster. Using the human α-globin locus as a model, we detected all known local and long-range interactions with this gene cluster. In addition, we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the α-globin cluster.
PMCID: PMC3682726  PMID: 23650635
α-globin locus; cis-regulatory elements; chromatin conformation capture
6.  Neural Tube Defects, Folate, and Immune Modulation 
Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.
PMCID: PMC4053177  PMID: 24078477
complement; C5a; neural tube defects; folate; neurulation
7.  HTML5 PivotViewer: high-throughput visualization and querying of image data on the web 
Bioinformatics  2014;30(18):2691-2692.
Motivation: Visualization and analysis of large numbers of biological images has generated a bottle neck in research. We present HTML5 PivotViewer, a novel, open source, platform-independent viewer making use of the latest web technologies that allows seamless access to images and associated metadata for each image. This provides a powerful method to allow end users to mine their data.
Availability and implementation: Documentation, examples and links to the software are available from The software is licensed under GPLv2.
Contact: and
PMCID: PMC4155252  PMID: 24849578
8.  ATRX Dysfunction Induces Replication Defects in Primary Mouse Cells 
PLoS ONE  2014;9(3):e92915.
The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, for proliferation of a variety of cellular progenitors, for chromosome congression and for the maintenance of telomeres. Mutations in ATRX have recently been identified in tumours which maintain their telomeres by a telomerase independent pathway involving homologous recombination thought to be triggered by DNA damage. It is as yet unknown whether there is a central underlying mechanism associated with ATRX dysfunction which can explain the numerous cellular phenomena observed. There is, however, growing evidence for its role in the replication of various repetitive DNA templates which are thought to have a propensity to form secondary structures. Using a mouse knockout model we demonstrate that ATRX plays a direct role in facilitating DNA replication. Ablation of ATRX alone, although leading to a DNA damage response at telomeres, is not sufficient to trigger the alternative lengthening of telomere pathway in mouse embryonic stem cells.
PMCID: PMC3961441  PMID: 24651726
9.  Precautionary labelling of foods for allergen content: are we ready for a global framework? 
Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.
PMCID: PMC4005619  PMID: 24791183
Allergen labelling; Food allergy; Legislation; Precationary allergen labelling; Anaphylaxis; Allergen avoidance; Mandatory labelling
10.  Dynamic Analysis of Gene Expression and Genome-wide Transcription Factor Binding during Lineage Specification of Multipotent Progenitors 
Cell Stem Cell  2013;13(6):754-768.
We used the paradigmatic GATA-PU.1 axis to explore, at the systems level, dynamic relationships between transcription factor (TF) binding and global gene expression programs as multipotent cells differentiate. We combined global ChIP-seq of GATA1, GATA2, and PU.1 with expression profiling during differentiation to erythroid and neutrophil lineages. Our analysis reveals (1) differential complexity of sequence motifs bound by GATA1, GATA2, and PU.1; (2) the scope and interplay of GATA1 and GATA2 programs within, and during transitions between, different cell compartments, and the extent of their hard-wiring by DNA motifs; (3) the potential to predict gene expression trajectories based on global associations between TF-binding data and target gene expression; and (4) how dynamic modeling of DNA-binding and gene expression data can be used to infer regulatory logic of TF circuitry. This rubric exemplifies the utility of this cross-platform resource for deconvoluting the complexity of transcriptional programs controlling stem/progenitor cell fate in hematopoiesis.
•Cross-platform resource for TF-network regulation of multipotent blood cell fate•DNA motif dependence and changing specificity of GATA factors in lineage choice•Modeling-based inference identifies GATA2 repression of PU.1 in multipotent cells•Priming, recruitment, and switching modes of GATA interplay during differentiation
A systems-level resource of the GATA-PU.1 axis provides insight into the dynamics of transcriptional programs during hematopoietic lineage commitment and differentiation.
PMCID: PMC3878573  PMID: 24120743
11.  C5a Receptor Signaling Prevents Folate Deficiency-Induced Neural Tube Defects in Mice 
The complement system is involved in a range of diverse developmental processes including cell survival, growth, differentiation, and regeneration. However, little is known about the role of complement in embryogenesis. Herein we demonstrate a novel role for the canonical complement 5a receptor (C5aR) in the development of the mammalian neural tube under conditions of maternal dietary folic acid deficiency. Specifically, we found C5aR and C5 to be expressed throughout the period of neurulation in wildtype mice and localized the expression to the cephalic regions of the developing neural tube. C5aR was also found to be expressed in the neuroepithelium of early human embryos. Ablation of the C5ar1 gene or the administration of a specific C5aR peptide antagonist to folic acid-deficient pregnant mice resulted in a high prevalence of severe anterior neural tube defect-associated congenital malformations. These findings provide a new and compelling insight into the role of the complement system during mammalian embryonic development.
PMCID: PMC3608813  PMID: 23420882
12.  Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis 
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1G93A mice during defined disease stages.
hSOD1G93A and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1G93A and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression.
We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1G93A mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death.
These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1G93A mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS.
PMCID: PMC3850877  PMID: 24067070
C1q; C4; Factor B; C3; C5; CD55; CD88; Motor neuron disease; Neuroinflammation
13.  Reduced dosage of ERF causes complex craniosynostosis in humans and mice, and links ERK1/2 signaling to regulation of osteogenesis 
Nature genetics  2013;45(3):308-313.
The extracellular signal-related kinases (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets1. Here we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs 2-7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf reduced to ~30% of normal exhibit postnatal multisuture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to distal regulatory elements containing RUNX or AP1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes.
PMCID: PMC3683605  PMID: 23354439
14.  Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes 
Human Molecular Genetics  2013;22(8):1654-1662.
Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries—a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5′ untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5′ UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
PMCID: PMC3605834  PMID: 23335590
15.  Cohesion Fatigue Explains Why Pharmacological Inhibition of the APC/C Induces a Spindle Checkpoint-Dependent Mitotic Arrest 
PLoS ONE  2012;7(11):e49041.
The Spindle Assembly Checkpoint (SAC) delays the onset of anaphase in response to unattached kinetochores by inhibiting the activity of the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. Once all the chromosomes have bioriented, SAC signalling is somehow silenced, which allows progression through mitosis. Recent studies suggest that the APC/C itself participates in SAC silencing by targeting an unknown factor for proteolytic degradation. Key evidence in favour of this model comes from the use of proTAME, a small molecule inhibitor of the APC/C. In cells, proTAME causes a mitotic arrest that is SAC-dependent. Even though this observation comes at odds with the current view that the APC/C acts downstream of the SAC, it was nonetheless argued that these results revealed a role for APC/C activity in SAC silencing. However, we show here that the mitotic arrest induced by proTAME is due to the induction of cohesion fatigue, a phenotype that is caused by the loss of sister chromatid cohesion following a prolonged metaphase. Under these conditions, the SAC is re-activated and APC/C inhibition is maintained independently of proTAME. Therefore, these results provide a simpler explanation for why the proTAME-induced mitotic arrest is also dependent on the SAC. While these observations question the notion that the APC/C is required for SAC silencing, we nevertheless show that APC/C activity does partially contribute to its own release from inhibitory complexes, and importantly, this does not depend on proteasome-mediated degradation.
PMCID: PMC3492190  PMID: 23145059
16.  High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism 
Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C antigen. This polymorphism was recently shown to be a marker for a protective variant in the 3′UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with ‘high’ HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesised that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles which also correlated with IFN-γ production by HLA-C-restricted CD8+ T-cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlights the potential role of HLA-C-restricted responses in HIV control. This is the first in vivo evidence supporting the protective role of HLA-C-restricted responses in non-Caucasians during HIV infection.
PMCID: PMC3378658  PMID: 22474021
17.  Lower Healthcare Costs Associated with the Use of a Single-Pill ARV Regimen in the UK, 2004–2008 
PLoS ONE  2012;7(10):e47376.
Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months.
Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996–2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively.
All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens.
The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.
PMCID: PMC3484120  PMID: 23118869
18.  Selfish Spermatogonial Selection: Evidence from an Immunohistochemical Screen in Testes of Elderly Men 
PLoS ONE  2012;7(8):e42382.
The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia–caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively–represent classical examples of paternal age-effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply that normal testes are mosaic for clusters of mutant cells: these clusters are predicted to have altered growth and signalling properties leading to their clonal expansion (selfish spermatogonial selection), but DNA extraction eliminates the possibility to study such processes at a tissue level. Using a panel of antibodies optimised for the detection of spermatocytic seminoma, a rare tumour of spermatogonial origin, we demonstrate that putative clonal events are frequent within normal testes of elderly men (mean age: 73.3 yrs) and can be classed into two broad categories. We found numerous small (less than 200 cells) cellular aggregations with distinct immunohistochemical characteristics, localised to a portion of the seminiferous tubule, which are of uncertain significance. However more infrequently we identified additional regions where entire seminiferous tubules had a circumferentially altered immunohistochemical appearance that extended through multiple serial sections that were physically contiguous (up to 1 mm in length), and exhibited enhanced staining for antibodies both to FGFR3 and a marker of downstream signal activation, pAKT. These findings support the concept that populations of spermatogonia in individual seminiferous tubules in the testes of older men are clonal mosaics with regard to their signalling properties and activation, thus fulfilling one of the specific predictions of selfish spermatogonial selection.
PMCID: PMC3412839  PMID: 22879958
20.  Complement activation in the injured central nervous system: another dual-edged sword? 
The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.
PMCID: PMC3464784  PMID: 22721265
21.  RYBP-PRC1 Complexes Mediate H2A Ubiquitylation at Polycomb Target Sites Independently of PRC2 and H3K27me3 
Cell  2012;148(4):664-678.
Polycomb-repressive complex 1 (PRC1) has a central role in the regulation of heritable gene silencing during differentiation and development. PRC1 recruitment is generally attributed to interaction of the chromodomain of the core protein Polycomb with trimethyl histone H3K27 (H3K27me3), catalyzed by a second complex, PRC2. Unexpectedly we find that RING1B, the catalytic subunit of PRC1, and associated monoubiquitylation of histone H2A are targeted to closely overlapping sites in wild-type and PRC2-deficient mouse embryonic stem cells (mESCs), demonstrating an H3K27me3-independent pathway for recruitment of PRC1 activity. We show that this pathway is mediated by RYBP-PRC1, a complex comprising catalytic subunits of PRC1 and the protein RYBP. RYBP-PRC1 is recruited to target loci in mESCs and is also involved in Xist RNA-mediated silencing, the latter suggesting a wider role in Polycomb silencing. We discuss the implications of these findings for understanding recruitment and function of Polycomb repressors.
Graphical Abstract
► H2A ubiquitylation is retained at Polycomb target loci in the absence of H3K27me3 ► Mutually exclusive complexes, CBX-PRC1 and RYBP-PRC1, mediate H2A ubiquitylation ► RYBP-PRC1 localizes to Polycomb target sites independent of H3K27me3 ► RYBP-PRC1 is required for maintenance of global H2AK119u1 in mESCs
A newly identified variant of the PRC1 complex containing the RYBP subunit allows PRC1 to act independently of PRC2. This alternative complex is important for maintaining the proper chromatin state in ESCs and on the inactive X chromosome.
PMCID: PMC3281992  PMID: 22325148
22.  Genome Sequence of Rhodobacter sphaeroides Strain WS8N▿  
Journal of Bacteriology  2011;193(15):4027-4028.
Rhodobacter sphaeroides is a metabolically diverse photosynthetic alphaproteobacterium found ubiquitously in soil and freshwater habitats. Here we present the annotated genome sequence of R. sphaeroides WS8N.
PMCID: PMC3147498  PMID: 21622735
23.  The impact of HIV-1 infection and exposure on natural killer (NK) cell phenotype in Kenyan infants during the first year of life 
Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV–, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV– infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38brightCD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56dim (p = 0.005) and CD56bright compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56dim compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants.
PMCID: PMC3533178  PMID: 23293640
NK cell; HIV-1; infancy; mother-to-child transmission; age; exposure; immune activation; cord blood
24.  The Cost-Effectiveness of Early Access to HIV Services and Starting cART in the UK 1996–2008 
PLoS ONE  2011;6(12):e27830.
To calculate use, cost and cost-effectiveness of people living with HIV (PLHIV) starting routine treatment and care before starting combination antiretroviral therapy (cART) and PLHIV starting first-line 2NRTIs+NNRTI or 2NRTIs+PIboosted, comparing PLHIV with CD4≤200 cells/mm3 and CD4>200 cells/mm3. Few studies have calculated the use, cost and cost-effectiveness of routine treatment and care before starting cART and starting cART above and below CD4 200 cells/mm3.
Use, costs and cost-effectiveness were calculated for PLHIV in routine pre-cART and starting first-line cART, comparing CD4≤200 cells/mm3 with CD4>200 cells/mm3 (2008 UK prices).
cART naïve patients CD4≤200 cells/mm3 had an annual cost of £6,407 (95%CI £6,382 to £6,425) PPY compared with £2,758 (95%CI £2,752 to £2,761) PPY for those with CD4>200 cells/mm3; cost per life year gained of pre-cART treatment and care for those with CD4>200 cells/mm3 was £1,776 (cost-saving to £2,752). Annual cost for starting 2NRTIs+NNRTI or 2NRTIs+PIboosted with CD4≤200 cells/mm3 was £12,812 (95%CI £12,685–£12,937) compared with £10,478 (95%CI £10,376–£10,581) for PLHIV with CD4>200 cells/mm3. Cost per additional life-year gained on first-line therapy for those with CD4>200 cells/mm3 was £4639 (£3,967 to £2,960).
PLHIV starting to use HIV services before CD4≤200 cells/mm3 is cost-effective and enables them to be monitored so they start cART with a CD4>200 cells/mm3, which results in better outcomes and is cost-effective. However, 25% of PLHIV accessing services continue to present with CD4≤200 cells/mm3. This highlights the need to investigate the cost-effectiveness of testing and early treatment programs for key populations in the UK.
PMCID: PMC3237423  PMID: 22194795
25.  Defining the Role of APC in the Mitotic Spindle Checkpoint In Vivo: APC Deficient Cells Are Resistant to Taxol 
Oncogene  2010;29(49):6418-6427.
Mutations in the adenomatous polyposis coli (APC) tumour suppressor are the key initiating event of colorectal cancer. Although the control of WNT signaling is well established as a central tumour suppressive function, the significance of APC in regulating chromosome instability is less well established. In this study, we test whether APC-deficient cells have a functional spindle assembly checkpoint in vivo by examining the response of these cells to Taxol and Vinorelbine.
Here we show for the first time that APC deficiency compromises the arrest response to Taxol in vivo. This effect is independent of the role APC plays in WNT signaling. At higher levels of Taxol, APC-deficient cells arrest as efficiently as wild-type cells. Importantly, this dose of Taxol strongly suppresses intestinal tumourigenesis in models of benign (APCMin/+ mouse) and invasive (AhCreER+ APCfl/+ PTENfl/fl) cancer.
In contrast to intestinal enterocytes with a general spindle assembly checkpoint defect due to Bub1 deletion, APC-deficient enterocytes arrest equivalently to wild-type when treated with Vinorelbine. This suggests that the failed arrest in response to Taxol is due to a specific defect in microtubule stabilisation following Taxol treatment rather than a general role of the APC protein in the mitotic spindle checkpoint.
In summary, this study clarifies the role of APC as a mitotic spindle checkpoint protein in vivo and shows that APC-deficient cells have a compromised response to Taxol.
PMCID: PMC3016607  PMID: 20729907
APC; WNT signaling; Taxol; Mitotic spindle assembly checkpoint

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