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1.  Evidence of a large, international network of international hepatitis C virus transmission in HIV-positive men who have sex with men 
Gastroenterology  2009;136(5):1609-1617.
Background
Since 2000, there has been a marked rise in acute hepatitis C virus (HCV) in HIV-positive men who have sex with men (MSM). We conducted an international phylogenetic study to investigate the existence of an HCV transmission network among MSM.
Methods
HIV-positive MSM diagnosed with recent HCV (n=226) in England (107), Netherlands (58), France (12), Germany (25) and Australia (24) between 2000 and 2006 were enrolled into a molecular phylogenetic study. Using real-time PCR, the NS5B region of the HCV genome (436 bp) was amplified, sequenced and compared with unrelated NS5B sequences.
Results
NS5B sequences were obtained from 200 (89%) cases. Circulating HCV genotypes were 1a (59%); 4d (23%), 3a (11%), 1b (5%), and 2b/c (3%). Phylogenetic analysis revealed 156 (78%) sequences that formed 11 clusters (bootstrap value >70%) containing between 4 and 37 individual sequences. Country mixing was associated with larger cluster size (17 vs 4.5 sequences; p=0.03). ‘Molecular clock’ analysis indicated that the majority (85%) of transmissions occurred since 1996.
Discussion
Phylogenetic analysis revealed a large international network of HCV transmission among HIV-positive MSM. The rapid spread of HCV among neighboring countries is supported by the large proportion (74%) of European MSM infected with an HCV strain co-circulating in multiple European countries; the low evolutionary distances among HCV isolates from different countries; and the trend toward increased country mixing with increasing cluster size. Temporally, this epidemic coincides with the introduction of highly active anti-retroviral therapy and associated increases in sexual risk behaviors. International collaborative public health efforts are needed to mitigate HCV transmission among this population.
PMCID: PMC4260925  PMID: 19422083
2.  Exploring the Innate Immunological Response of an Alternative Nonhuman Primate Model of Infectious Disease; the Common Marmoset 
Journal of Immunology Research  2014;2014:913632.
The common marmoset (Callithrix jacchus) is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease.
doi:10.1155/2014/913632
PMCID: PMC4129158  PMID: 25170519
3.  Computational models can predict response to HIV therapy without a genotype and may reduce treatment failure in different resource-limited settings 
Objectives
Genotypic HIV drug-resistance testing is typically 60%–65% predictive of response to combination antiretroviral therapy (ART) and is valuable for guiding treatment changes. Genotyping is unavailable in many resource-limited settings (RLSs). We aimed to develop models that can predict response to ART without a genotype and evaluated their potential as a treatment support tool in RLSs.
Methods
Random forest models were trained to predict the probability of response to ART (≤400 copies HIV RNA/mL) using the following data from 14 891 treatment change episodes (TCEs) after virological failure, from well-resourced countries: viral load and CD4 count prior to treatment change, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. Models were assessed by cross-validation during development, with an independent set of 800 cases from well-resourced countries, plus 231 cases from Southern Africa, 206 from India and 375 from Romania. The area under the receiver operating characteristic curve (AUC) was the main outcome measure.
Results
The models achieved an AUC of 0.74–0.81 during cross-validation and 0.76–0.77 with the 800 test TCEs. They achieved AUCs of 0.58–0.65 (Southern Africa), 0.63 (India) and 0.70 (Romania). Models were more accurate for data from the well-resourced countries than for cases from Southern Africa and India (P < 0.001), but not Romania. The models identified alternative, available drug regimens predicted to result in virological response for 94% of virological failures in Southern Africa, 99% of those in India and 93% of those in Romania.
Conclusions
We developed computational models that predict virological response to ART without a genotype with comparable accuracy to genotyping with rule-based interpretation. These models have the potential to help optimize antiretroviral therapy for patients in RLSs where genotyping is not generally available.
doi:10.1093/jac/dkt041
PMCID: PMC3654223  PMID: 23485767
antiretroviral therapy; computer models; HIV drug resistance; predictions; treatment outcomes; resource-limited settings.
4.  Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure 
Jose, Sophie | Hamzah, Lisa | Campbell, Lucy J. | Hill, Teresa | Fisher, Martin | Leen, Clifford | Gilson, Richard | Walsh, John | Nelson, Mark | Hay, Phillip | Johnson, Margaret | Chadwick, David | Nitsch, Dorothea | Jones, Rachael | Sabin, Caroline A. | Post, Frank A. | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Chadwick, David | Delpech, Valerie | Dunn, David | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hay, Phillip | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Orkin, Chloe | Palfreeman, Adrian | Phillips, Andrew | Pillay, Deenan | Post, Frank | Sabin, Caroline | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Hill, Teresa | Huntington, Susie | Josie, Sophie | Phillips, Andrew | Sabin, Caroline | Thornton, Alicia | Dunn, David | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Churchill, D. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Poulton, M. | Taylor, C. | Gleisner, Z. | Campbell, L. | Babiker, Abdel | Dunn, David | Glabay, Adam | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Gompels, M. | Allan, S. | Palfreeman, A. | Moore, A. | Chadwick, D. | Wakeman, K. | Kegg, Stephen | Main, Paul | Mitchell,  | Hunter,  | Sachikonye, Memory | Hay, Phillip | Dhillon, Mandip
The Journal of Infectious Diseases  2014;210(3):363-373.
Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy.
Methods. Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression.
Results. We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy.
Conclusions. This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.
doi:10.1093/infdis/jiu107
PMCID: PMC4091582  PMID: 24585896
tenofovir; highly active antiretroviral therapy; eGFR; eGFR slopes; renal function; kidney
5.  Antibacterial and Antibiofilm Activities of Tryptoquivalines and Meroditerpenes Isolated from the Marine-Derived Fungi Neosartorya paulistensis, N. laciniosa, N. tsunodae, and the Soil Fungi N. fischeri and N. siamensis 
Marine Drugs  2014;12(2):822-839.
A new meroditerpene, sartorypyrone C (5), was isolated, together with the known tryptoquivalines l (1a), H (1b), F (1c), 3′-(4-oxoquinazolin-3-yl) spiro[1H-indole-3,5′]-2,2′-dione (2) and 4(3H)-quinazolinone (3), from the culture of the marine sponge-associated fungus Neosartorya paulistensis (KUFC 7897), while reexamination of the fractions remaining from a previous study of the culture of the diseased coral-derived fungus N. laciniosa (KUFC 7896) led to isolation of a new tryptoquivaline derivative tryptoquivaline T (1d). Compounds 1a–d, 2, 3, and 5, together with aszonapyrones A (4a) and B (4b), chevalones B (6) and C (7a), sartorypyrones B (7b) and A (8), were tested for their antibacterial activity against four reference strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa), as well as the environmental multidrug-resistant isolates. Only aszonapyrone A (4a) and sartorypyrone A (8) exhibited significant antibacterial activity as well as synergism with antibiotics against the Gram-positive multidrug-resistant strains. Antibiofilm assays of aszonapyrone A (4a) and sartorypyrone A (8) showed that practically no biofilm was formed in the presence of their 2× MIC and MIC. However, the presence of a sub-inhibitory concentration of ½ MIC of 4a and 8 was found to increase the biofilm production in both reference strain and the multidrug-resistant isolates of S. aureus.
doi:10.3390/md12020822
PMCID: PMC3944517  PMID: 24477284
antibacterial; antibiofilm; multidrug-resistant; tryptoquivalines; meroditerpenes; Neosartorya; marine-derived fungi
6.  The ageing ovary and uterus: new biological insights 
Human Reproduction Update  2012;19(1):67-83.
BACKGROUND
Advanced maternal age is associated with reduced fertility and adverse pregnancy outcomes. This review details recent developments in our understanding of the biology and mechanisms underlying reproductive ageing in women and the implications for fertility and pregnancy.
METHODS
Sociological online libraries (IBSS, SocINDEX), PubMed and Google Scholar were searched for relevant demographic, epidemiological, clinical and biological studies, using key words and hierarchical MeSH terms. From this, we identified and focused on key topics where it was judged that there had been clinically relevant advances in the understanding of ovarian and uterine ageing with implications for improved diagnostics and novel interventions.
RESULTS
Mapping of the ovarian reserve, follicular dynamics and associated biomarkers, across the reproductive lifespan has recently been performed. This now allows an assessment of the effects of environmental, lifestyle and prenatal exposures on follicular dynamics and the identification of their impact during periods of germ cell vulnerability and may also facilitate early identification of individuals with shorter reproductive lifespans. If women choose to time their family based on their ovarian reserve this would redefine the meaning of family planning. Despite recent reports of the potential existence of stem cells which may be used to restore the primordial follicle and thereby the oocyte pool, therapeutic interventions in female reproductive ageing at present remain limited. Maternal ageing has detrimental effects on decidual and placental development, which may be related to repeated exposure to sex steroids and underlie the association of ageing with adverse perinatal outcomes.
CONCLUSIONS
Ageing has incontrovertible detrimental effects on the ovary and the uterus. Our enhanced understanding of ovarian ageing will facilitate early identification of individuals at greatest risk, and novel therapeutic interventions. Changes in both ovary and uterus are in addition to age-related co-morbidities, which together have synergistic effects on reducing the probability of a successful pregnancy outcome.
doi:10.1093/humupd/dms043
PMCID: PMC3508627  PMID: 23103636
ageing; fertility; infertility; ovarian reserve; anti-Müllerian hormone
7.  Buckling of a growing tissue and the emergence of two-dimensional patterns☆ 
Mathematical Biosciences  2013;246(2):229-241.
Highlights
•We model the growth of gut epithelial cells cultured upon a deformable substrate.•Growth generates buckling instabilities, contributing to crypt formation in vivo.•Variations in mechanical properties have little effect on resulting configurations.•Configurations are controlled by growth patterns & interactions with strata below.
The process of biological growth and the associated generation of residual stress has previously been considered as a driving mechanism for tissue buckling and pattern selection in numerous areas of biology. Here, we develop a two-dimensional thin plate theory to simulate the growth of cultured intestinal epithelial cells on a deformable substrate, with the goal of elucidating how a tissue engineer might best recreate the regular array of invaginations (crypts of Lieberkühn) found in the wall of the mammalian intestine. We extend the standard von Kármán equations to incorporate inhomogeneity in the plate’s mechanical properties and surface stresses applied to the substrate by cell proliferation. We determine numerically the configurations of a homogeneous plate under uniform cell growth, and show how tethering to an underlying elastic foundation can be used to promote higher-order buckled configurations. We then examine the independent effects of localised softening of the substrate and spatial patterning of cellular growth, demonstrating that (within a two-dimensional framework, and contrary to the predictions of one-dimensional models) growth patterning constitutes a more viable mechanism for control of crypt distribution than does material inhomogeneity.
doi:10.1016/j.mbs.2013.09.008
PMCID: PMC3863975  PMID: 24128749
Buckling; Tissue growth; Pattern formation; von Kármán plate
8.  Disruption of Gallbladder Smooth Muscle Function is an Early Feature in the Development of Cholesterol Gallstone Disease 
Neurogastroenterology and Motility  2012;24(7):e313-e324.
Background
Decreased gallbladder smooth muscle (GBSM) contractility is a hallmark of cholesterol gallstone disease, but the interrelationship between lithogenicity, biliary stasis and inflammation are poorly understood. We studied a mouse model of gallstone disease to evaluate the development of GBSM dysfunction relative to changes in bile composition and the onset of sterile cholecystitis.
Methods
BALB/cJ mice were fed a lithogenic diet for up to 8 weeks, and tension generated by gallbladder muscle strips was measured. Smooth muscle Ca2+ transients were imaged in intact gallbladder.
Key Results
Lipid composition of bile was altered lithogenically as early as one week, with increased hydrophobicity and cholesterol saturation indexes; however, inflammation was not detectable until the fourth week. Agonist-induced contractility was reduced from weeks 2 through 8. GBSM normally exhibits rhythmic synchronized Ca2+ flashes, and their frequency is increased by carbachol (3μM). After one week, lithogenic diet-fed mice exhibited disrupted Ca2+ flash activity, manifesting as clustered flashes, asynchronous flashes or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca2+ stores, which are required for agonist-induced contraction, and diminished basal tone of the organ. Responsiveness of Ca2+ transients to carbachol was reduced in mice on the lithogenic diet, particularly after 4-8 weeks, concomitant with appearance of mucosal inflammatory changes.
Conclusions & Inferences
These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.
doi:10.1111/j.1365-2982.2012.01935.x
PMCID: PMC3378777  PMID: 22621672
bile composition; cholecystitis; biliary motility; gallbladder emptying
9.  Divergence Times and the Evolutionary Radiation of New World Monkeys (Platyrrhini, Primates): An Analysis of Fossil and Molecular Data 
PLoS ONE  2013;8(6):e68029.
The estimation of phylogenetic relationships and divergence times among a group of organisms is a fundamental first step toward understanding its biological diversification. The time of the most recent or last common ancestor (LCA) of extant platyrrhines is one of the most controversial among scholars of primate evolution. Here we use two molecular based approaches to date the initial divergence of the platyrrhine clade, Bayesian estimations under a relaxed-clock model and substitution rate plus generation time and body size, employing the fossil record and genome datasets. We also explore the robustness of our estimations with respect to changes in topology, fossil constraints and substitution rate, and discuss the implications of our findings for understanding the platyrrhine radiation. Our results suggest that fossil constraints, topology and substitution rate have an important influence on our divergence time estimates. Bayesian estimates using conservative but realistic fossil constraints suggest that the LCA of extant platyrrhines existed at ca. 29 Ma, with the 95% confidence limit for the node ranging from 27–31 Ma. The LCA of extant platyrrhine monkeys based on substitution rate corrected by generation time and body size was established between 21–29 Ma. The estimates based on the two approaches used in this study recalibrate the ages of the major platyrrhine clades and corroborate the hypothesis that they constitute very old lineages. These results can help reconcile several controversial points concerning the affinities of key early Miocene fossils that have arisen among paleontologists and molecular systematists. However, they cannot resolve the controversy of whether these fossil species truly belong to the extant lineages or to a stem platyrrhine clade. That question can only be resolved by morphology. Finally, we show that the use of different approaches and well supported fossil information gives a more robust divergence time estimate of a clade.
doi:10.1371/journal.pone.0068029
PMCID: PMC3694915  PMID: 23826358
10.  A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease 
Neuroscience  2013;240(100):191-203.
Highlights
•We investigate the role of PPARδ in a model of Parkinson’s disease.•PPARδ is upregulated after the neurotoxin MPTP.•PPARδ antagonism enhances MPP+ toxicity which is reversible by PPARδ agonism.•PPARδ agonism protects against MPTP-toxicity.
Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson’s disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP+ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036 ± 195) when compared to vehicle-infused mice (3953 ± 460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.
doi:10.1016/j.neuroscience.2013.02.058
PMCID: PMC3661980  PMID: 23500098
DMEM, Dulbecco’s Modified Eagle Medium; DMSO, dimethyl sulfoxide; DPBS, Dulbecco’s phosphate-buffered saline; EDTA, ethylenediaminetetraacetic acid; FCS, foetal calf serum; GFAP, glial fibrillary acid protein; IL, interleukin; LDH, lactate dehydrogenase; MAC-1, macrophage antigen complex-1; MPP+, 1-methyl-4-phenylpyridinium iodide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PD, Parkinson’s disease; PFA, paraformaldehyde; PPAR, peroxisome proliferator-activated receptor; TH, tyrosine hydroxylase; TNFα, tumour necrosis factor-α; MPP+; neurodegeneration; neuroinflammation; SH-SY5Y; MPTP; PPAR delta
11.  Aging blunts hyperventilation-induced hypocapnia and reduction in cerebral blood flow velocity during maximal exercise 
Age  2011;34(3):725-735.
Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO2peak) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO2peak. In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO2peak. Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA Vmean; transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO2 (PETCO2) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO2peak, despite greater elevations in BP in OA, the change in MCA Vmean was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO2peak, the hyperventilation-induced declines in both PETCO2 (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA Vmean (−21% (YA) vs. −7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO2peak), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.
doi:10.1007/s11357-011-9258-9
PMCID: PMC3337932  PMID: 21559869
Cerebral blood flow; Humans; Aging; Ventilation; Exercise intensity; Cycling; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
12.  Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study 
Dolling, David I. | Dunn, David T. | Sutherland, Katherine A. | Pillay, Deenan | Mbisa, Jean L. | Parry, Chris M. | Post, Frank A. | Sabin, Caroline A. | Cane, Patricia A. | Aitken, Celia | Asboe, David | Webster, Daniel | Cane, Patricia | Castro, Hannah | Dunn, David | Dolling, David | Chadwick, David | Churchill, Duncan | Clark, Duncan | Collins, Simon | Delpech, Valerie | Geretti, Anna Maria | Goldberg, David | Hale, Antony | Hué, Stéphane | Kaye, Steve | Kellam, Paul | Lazarus, Linda | Leigh-Brown, Andrew | Mackie, Nicola | Orkin, Chloe | Rice, Philip | Pillay, Deenan | Phillips, Andrew | Sabin, Caroline | Smit, Erasmus | Templeton, Kate | Tilston, Peter | Tong, William | Williams, Ian | Zhang, Hongyi | Zuckerman, Mark | Greatorex, Jane | Wildfire, Adrian | O'Shea, Siobhan | Mullen, Jane | Mbisa, Tamyo | Cox, Alison | Tandy, Richard | Hale, Tony | Fawcett, Tracy | Hopkins, Mark | Ashton, Lynn | Booth, Claire | Garcia-Diaz, Ana | Shepherd, Jill | Schmid, Matthias L. | Payne, Brendan | Hay, Phillip | Rice, Phillip | Paynter, Mary | Bibby, David | Kirk, Stuart | MacLean, Alasdair | Gunson, Rory | Coughlin, Kate | Fearnhill, Esther | Fradette, Lorraine | Porter, Kholoud | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Palfreeman, Adrian | Post, Frank | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Huntington, Susie | Jose, Sophie | Thornton, Alicia | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Welch, J. | Poulton, M. | MacDonald, C. | Gleisner, Z. | Campbell, L. | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Allan, S. | Palfreeman, A. | Moore, A. | Wakeman, K.
Journal of Antimicrobial Chemotherapy  2013;68(10):2339-2343.
Objectives
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Methods
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Results
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Conclusions
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
doi:10.1093/jac/dkt199
PMCID: PMC3772741  PMID: 23711895
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure
13.  Incidental sinonasal findings identified during preoperative evaluation for endoscopic transsphenoidal approaches 
Background:
The endoscopic transsphenoidal approach (eTSA) to lesions of the sellar region is typically performed jointly by neurosurgeons and otolaryngologists. Occasionally, the approach is significantly altered by sinonasal disease, anatomic variants, or previous surgery. However, there are no current guidelines that describe which physical or radiological findings should prompt a change in the plan of care. The purpose of this study was to determine the incidence of sinonasal pathology or anatomic variants noted endoscopically or by imaging that altered preoperative or intraoperative management.
Methods:
A retrospective review was performed of 355 consecutive patients who underwent combined neurosurgery–otolaryngology endoscopic sella approach from August 1, 2007 to April 1, 2011. Our practice in these patients involves preoperative otolaryngology clinical evaluation and MRI review. Intraoperative image guidance is not routinely used in uncomplicated eTSA.
Results:
The most common management alteration was the addition of image guidance based on anatomic variants on MRI, which occurred in 81 patients (35.0%). Eight patients (2.9%) were preoperatively treated with antibiotics and surgery was postponed secondary to acute or chronic purulent rhinosinusitis; two (0.7%) required functional endoscopic sinus surgery for medically refractory disease before eTSA. Five patients (1.8%) required anterior septoplasty intraoperatively for severe nasal septal deviation. Two patients (0.7%) had inverted papilloma and one patient had esthesioneuroblastoma identified preoperatively during rigid nasal endoscopy.
Conclusion:
This is one of the larger reviews of patients undergoing eTSA for sellar lesions and the only study that describes how intraoperative management may be altered by preoperative sinonasal evaluation. We found a significant incidence of sinonasal pathology and anatomic variants that altered routine operative planning; therefore, a thorough sinonasal evaluation is warranted in these cases.
doi:10.2500/ajra.2013.27.3871
PMCID: PMC3649855  PMID: 23710956
Endoscopic; image-guided surgery; incidental; preoperative; sella; sinonasal; transsphenoidal
14.  Staging recurrent ovarian cancer with 18FDG PET/CT 
Oncology Letters  2012;5(2):593-597.
The aim of the present study was to evaluate the use of 2-deoxy-2-(18F)-fluoro-D-glucose (18FDG) positron emission tomography (PET)/computed tomography (CT) in patients with suspected ovarian cancer recurrence and describe the distribution of metastasis. A total of 45 female patients who underwent PET/CT scan due to raised CA-125 levels, clinical suspicion of ovarian cancer recurrence or alterations detected on ultrasound (US), CT or magnetic resonance imaging (MRI) were included in this retrospective study. PET/CT results were compared with histological findings (n=15) or clinical, laboratory and repeated imaging techniques during subsequent follow-up for at least six months (n=30). CA-125 was elevated in 34 patients, 14 patients had clinical symptoms of disease and 23 presented with alterations on US, CT and MRI. A total of 42 patients were confirmed to have ovarian cancer recurrence, all with abnormal findings on PET/CT. Three patients remained free of disease during clinical follow-up, all with normal PET/CT findings. There were 11 patients with raised CA-125 levels and normal conventional imaging, all with positive PET/CT. Among the 11 patients with normal CA-125 levels, eight presented with positive PET/CT scan. Lymph nodes were the most frequent site of relapse of disease, followed by peritoneal implants. Distant sites of metastasis included the liver, spleen, pleura, lung and bone. PET/CT detected unsuspected lesions in 20/45 patients (44.4%). 18FDG PET/CT was a useful tool for evaluating the extent of ovarian cancer recurrence. In the current series, lymph nodes were the most frequent site of relapse of disease, with supradiaphragmatic lymph node metastasis in a large number of cases.
doi:10.3892/ol.2012.1075
PMCID: PMC3573129  PMID: 23420711
18FDG; PET scan; ovarian neoplasms
15.  High Plasma Level of Fibroblast Growth Factor 21 Is an Independent Predictor of Type 2 Diabetes 
Diabetes Care  2011;34(9):2113-2115.
OBJECTIVE
To investigate whether circulating levels of fibroblast growth factor 21 (FGF21), which previously has been shown to be elevated in obesity, could predict the development of type 2 diabetes in a 5.4-year, population-based, prospective study.
RESEARCH DESIGN AND METHODS
Baseline plasma FGF21 levels were measured using an enzyme-linked immunosorbent assay in 1,900 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). The prospective association of FGF21 with diabetes development over 5.4 years was analyzed using multiple logistic regression.
RESULTS
At baseline, plasma levels of FGF21 increased progressively with worsening dysglycemia from normal glucose tolerance, through prediabetes, to diabetes (global trend, P < 0.001). Of 1,292 subjects without diabetes at baseline, a high baseline FGF21 level was a strong independent predictor for diabetes development (odds ratio 1.792; P < 0.01), together with waist circumference and fasting plasma glucose levels.
CONCLUSIONS
Plasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans.
doi:10.2337/dc11-0294
PMCID: PMC3161267  PMID: 21750278
16.  TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells 
The British journal of dermatology  2011;165(3):526-533.
Background
Isotretinoin’s (13-cis RA) full mechanism of action in treating acne is unknown. 13-cis RA induces key genes in sebocytes that are involved in apoptosis. In this study, we report that 13-cis RA up-regulates expression of Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL) within SEB-1 sebocytes.
Methods/Results
Treatment with recombinant human TRAIL (rhTRAIL) protein increases TUNEL positive staining in SEB-1 sebocytes. TRAIL siRNA significantly decreases the percentage of TUNEL positive SEB-1 sebocytes in response to 13-cis RA treatment. Furthermore, TRAIL expression increases in the skin of acne patients after one week of isotretinoin therapy compared to baseline. TRAIL expression localized within sebaceous glands. Unlike sebocytes, TRAIL protein expression is not increased in normal human epidermal keratinocytes in response to 13-cis RA, nor does rhTRAIL induce apoptosis in keratinocytes, suggesting that TRAIL is key in the sebocyte-specific apoptotic effects of 13-cis RA.
Conclusions
Taken together, our data suggests that TRAIL, like the neutrophil gelatinase-associated lipocalin is involved in mediating 13-cis RA apoptosis of sebocytes.
doi:10.1111/j.1365-2133.2011.10392.x
PMCID: PMC3166444  PMID: 21564055
isotretinoin; sebaceous gland; acne; TRAIL; apoptosis
17.  Isotretinoin Increases Skin Surface Levels of Neutrophil Gelatinase-Associated Lipocalin in Patients Treated for Severe Acne 
The British journal of dermatology  2011;165(2):302-310.
Background
A clear-cut need exists for safe and effective alternatives to the use of isotretinoin in severe acne. Lack of data regarding the specifics of isotretinoin’s mechanism of action has hampered progress in this area. Recently the protein neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a mediator of the apoptotic effect of isotretinoin on sebocytes. The goal of this paper is to further establish the clinical relevance of NGAL and to elucidate the factors that induce NGAL expression in sebocytes.
Methods/Results
Methods were developed to isolate and quantify skin surface levels of NGAL from normal subjects and acne patients undergoing treatment with isotretinoin. Acne patients were found to have higher skin levels of NGAL compared to normal subjects. Studies in SEB-1 sebocytes indicate that NGAL expression is increased in response to P. acnes and IL-1β. In patients, isotretinoin increases NGAL levels by 2.4-fold on the skin surface and this increase precedes decreases in sebum and P. acnes counts.
Conclusions
These data support the hypothesis that NGAL is an important mediator of the early effects of isotretinoin on the sebaceous glands and provide insights into the mechanisms that regulate NGAL expression in the skin.
doi:10.1111/j.1365-2133.2011.10362.x
PMCID: PMC3142306  PMID: 21466536
Acne; Isotretinoin; NGAL; P. acnes
18.  Combined Use of Serum Adiponectin and Tumor Necrosis Factor-Alpha Receptor 2 Levels Was Comparable to 2-Hour Post-Load Glucose in Diabetes Prediction 
PLoS ONE  2012;7(5):e36868.
Background
Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction.
Methods
We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte–fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples.
Results
Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, “adiponectin + TNF-α R2” improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the “CDP + 2-hour post-OGTT glucose” model (AUC  = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC  = 0.829 [95% CI: 0.808–0.849]).
Conclusions
The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.
doi:10.1371/journal.pone.0036868
PMCID: PMC3353952  PMID: 22615828
19.  Abnormal Microstructure of the Atrophic Thalamus in Preterm Survivors with Periventricular Leukomalacia 
BACKGROUND AND PURPOSE
The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions.
MATERIALS AND METHODS
We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years).
RESULTS
The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ⊥ (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network.
CONCLUSIONS
There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.
doi:10.3174/ajnr.A2243
PMCID: PMC3281310  PMID: 20930003
20.  The KCNJ11 E23K Polymorphism and Progression of Glycaemia in Southern Chinese: A Long-Term Prospective Study 
PLoS ONE  2011;6(12):e28598.
Context
The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies.
Objective
This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population.
Methods/Principal Findings
We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, Page, sex, BMI and fasting plasma glucose [FPG] adjusted  = 0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, Page, sex, BMI and FPG adjusted  = 0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P = 0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P = 4×10−3; random effect: OR 1.11, P = 0.035).
Conclusions
Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes.
doi:10.1371/journal.pone.0028598
PMCID: PMC3230634  PMID: 22163043
21.  Comprehensive Analysis of Tissue Preservation and Recording Quality from Chronic Multielectrode Implants 
PLoS ONE  2011;6(11):e27554.
Multielectrodes have been used with great success to simultaneously record the activity of neuronal populations in awake, behaving animals. In particular, there is great promise in the use of this technique to allow the control of neuroprosthetic devices by human patients. However, it is crucial to fully characterize the tissue response to the chronic implants in animal models ahead of the initiation of human clinical trials. Here we evaluated the effects of unilateral multielectrode implants on the motor cortex of rats weekly recorded for 1–6 months using several histological methods to assess metabolic markers, inflammatory response, immediate-early gene (IEG) expression, cytoskeletal integrity and apoptotic profiles. We also investigated the correlations between each of these features and firing rates, to estimate the impact of post-implant time on neuronal recordings. Overall, limited neuronal loss and glial activation were observed on the implanted sites. Reactivity to enzymatic metabolic markers and IEG expression were not significantly different between implanted and non-implanted hemispheres. Multielectrode recordings remained viable for up to 6 months after implantation, and firing rates correlated well to the histochemical and immunohistochemical markers. Altogether, our results indicate that chronic tungsten multielectrode implants do not substantially alter the histological and functional integrity of target sites in the cerebral cortex.
doi:10.1371/journal.pone.0027554
PMCID: PMC3212580  PMID: 22096594
22.  Intensive Care Usage by HIV-Positive Patients in the HAART Era 
In the 1980s the outlook for patients with the acquired immunodeficiency syndrome (AIDS) and critical illness was poor. Since then several studies of outcome of HIV+ patients on ICU have shown improving prognosis, with anti-retroviral therapy playing a large part. We retrospectively examined intensive care (ICU) admissions in a large HIV unit in London. Between April 2001 and April 2006 43 patients were admitted to the ICU. The mean age of patients was 44 years and 74% were male. Fifty-six percent of admissions were receiving anti-retroviral therapy and 44% had an AIDS defining diagnosis. The median CD4 count was 128 cells/mL and the median APACHE II score was 21. The commonest diagnostic ICU admission category was respiratory disease. This group experienced higher mortality despite slightly lower APACHE II scores, though this did not achieve statistical significance. The follow up period was one year or until April 2007, when data were censored. ICU mortality was 33%, in hospital mortality was 51% and overall mortality at the end of the study period was 67%. Median survival was 1008 days. The CD4 count did not predict long-term survival, although the sample size was too small for this to be conclusive.
doi:10.1155/2011/847835
PMCID: PMC3205706  PMID: 22121360
23.  DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma 
British Journal of Cancer  2010;103(2):265-274.
Background:
The mitogen-activated protein kinase (MAPK) phosphatases or dual specificity phosphatases (DUSPs) are a family of proteins that catalyse the inactivation of MAPK in eukaryotic cells. Little is known of the expression, regulation or function of the DUSPs in human neoplasia.
Methods:
We used RT–PCR and quantitative PCR (qPCR) to examine the expression of DUSP16 mRNA. The methylation in the DUSP16 CpG island was analysed using bisulphite sequencing and methylation-specific PCR. The activation of MAPK was determined using western blotting with phospho-specific antibodies for extra-cellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK). The proliferation of cell lines was assessed using the CellTiter 96 Aqueous One assay.
Results:
The expression of DUSP16, which inactivates MAPK, is subject to methylation-dependent transcriptional silencing in Burkitt's Lymphoma (BL) cell lines and in primary BL. The silencing is associated with aberrant methylation in the CpG island in the 5′ regulatory sequences of the gene blocking its constitutive expression. In contrast to BL, the CpG island of DUSP16 is unmethylated in other non-Hodgkin's lymphomas (NHLs) and epithelial malignancies. In BL cell lines, neither constitutive nor inducible ERK or p38 activity varied significantly with DUSP16 status. However, activation of JNK was increased in lines with DUSP16 methylation. Furthermore, methylation in the DUSP16 CpG island blocked transcriptional induction of DUSP16, thereby abrogating a normal physiological negative feedback loop that limits JNK activity, and conferred increased cellular sensitivity to agents, such as sorbitol and anthracycline chemotherapeutic agents that activate JNK.
Conclusion:
DUSP16 is a new epigenetically regulated determinant of JNK activation in BL.
doi:10.1038/sj.bjc.6605711
PMCID: PMC2906728  PMID: 20551953
DUSP; Epigenetics; HIV; Burkitt's lymphoma
24.  Modelling response to HIV therapy without a genotype: an argument for viral load monitoring in resource-limited settings 
In the absence of widespread access to individualized laboratory monitoring, which forms an integral part of HIV patient management in resource-rich settings, the roll-out of highly active antiretroviral therapy (HAART) in resource-limited settings has adopted a public health approach based on standard HAART protocols and clinical/immunological definitions of therapy failure. The cost-effectiveness of HIV-1 viral load monitoring at the individual level in such settings has been debated, and questions remain over the long-term and population-level impact of managing HAART without it. Computational models that accurately predict virological response to HAART using baseline data including CD4 count, viral load and genotypic resistance profile, as developed by the Resistance Database Initiative, have significant potential as an aid to treatment selection and optimization. Recently developed models have shown good predictive performance without the need for genotypic data, with viral load emerging as by far the most important variable. This finding provides further, indirect support for the use of viral load monitoring for the long-term optimization of HAART in resource-limited settings.
doi:10.1093/jac/dkq032
PMCID: PMC2837552  PMID: 20154024
computational modelling; antiretroviral therapy; HIV/AIDS; access

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