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1.  Competition as a source of constraint on life history evolution in natural populations 
Heredity  2013;112(1):70-78.
Competition among individuals is central to our understanding of ecology and population dynamics. However, it could also have major implications for the evolution of resource-dependent life history traits (for example, growth, fecundity) that are important determinants of fitness in natural populations. This is because when competition occurs, the phenotype of each individual will be causally influenced by the phenotypes, and so the genotypes, of competitors. Theory tells us that indirect genetic effects arising from competitive interactions will give rise to the phenomenon of ‘evolutionary environmental deterioration', and act as a source of evolutionary constraint on resource-dependent traits under natural selection. However, just how important this constraint is remains an unanswered question. This article seeks to stimulate empirical research in this area, first highlighting some patterns emerging from life history studies that are consistent with a competition-based model of evolutionary constraint, before describing several quantitative modelling strategies that could be usefully applied. A recurrent theme is that rigorous quantification of a competition's impact on life history evolution will require an understanding of the causal pathways and behavioural processes by which genetic (co)variance structures arise. Knowledge of the G-matrix among life history traits is not, in and of itself, sufficient to identify the constraints caused by competition.
PMCID: PMC3860166  PMID: 23443060
indirect genetic effects; evolutionary constraint; behaviour; personality; G-matrix
3.  The Minimal Preprocessing Pipelines for the Human Connectome Project 
NeuroImage  2013;80:105-124.
The Human Connectome Project (HCP) faces the challenging task of bringing multiple magnetic resonance imaging (MRI) modalities together in a common automated preprocessing framework across a large cohort of subjects. The MRI data acquired by the HCP differ in many ways from data acquired on conventional 3 Tesla scanners and often require newly developed preprocessing methods. We describe the minimal preprocessing pipelines for structural, functional, and diffusion MRI that were developed by the HCP to accomplish many low level tasks, including spatial artifact/distortion removal, surface generation, cross-modal registration, and alignment to standard space. These pipelines are specially designed to capitalize on the high quality data offered by the HCP. The final standard space makes use of a recently introduced CIFTI file format and the associated grayordinates spatial coordinate system. This allows for combined cortical surface and subcortical volume analyses while reducing the storage and processing requirements for high spatial and temporal resolution data. Here, we provide the minimum image acquisition requirements for the HCP minimal preprocessing pipelines and additional advice for investigators interested in replicating the HCP’s acquisition protocols or using these pipelines. Finally, we discuss some potential future improvements for the pipelines.
PMCID: PMC3720813  PMID: 23668970
Human Connectome Project; Image Analysis Pipeline; Surface-based Analysis; CIFTI; Grayordinates; Multi-modal Data Integration
4.  Human Connectome Project Informatics: quality control, database services, and data visualization 
NeuroImage  2013;80:10.1016/j.neuroimage.2013.05.077.
The Human Connectome Project (HCP) has developed protocols, standard operating and quality control procedures, and a suite of informatics tools to enable high throughput data collection, data sharing, automated data processing and analysis, and data mining and visualization. Quality control procedures include methods to maintain data collection consistency over time, to measure head motion, and to establish quantitative modality-specific overall quality assessments. Database services developed as customizations of the XNAT imaging informatics platform support both internal daily operations and open access data sharing. The Connectome Workbench visualization environment enables user interaction with HCP data and is increasingly integrated with the HCP's database services. Here we describe the current state of these procedures and tools and their application in the ongoing HCP study.
PMCID: PMC3845379  PMID: 23707591
5.  Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia 
Annals of Hematology  2014;94:361-373.
Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO’s licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto’s odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84–0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90–1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2218-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4317519  PMID: 25284166
Acute myeloid leukaemia; CD33 antigen; Systematic review; Meta-analysis; Randomised clinical trials; Gemtuzumab; Mylotarg; Humanised monoclonal antibodies
6.  The Application of Functional Imaging Techniques to Personalise Chemoradiotherapy in Upper Gastrointestinal Malignancies 
Functional imaging gives information about physiological heterogeneity in tumours. The utility of functional imaging tests in providing predictive and prognostic information after chemoradiotherapy for both oesophageal cancer and pancreatic cancer will be reviewed. The benefit of incorporating functional imaging into radiotherapy planning is also evaluated. In cancers of the upper gastrointestinal tract, the vast majority of functional imaging studies have used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Few studies in locally advanced pancreatic cancer have investigated the utility of functional imaging in risk-stratifying patients or aiding target volume definition. Certain themes from the oesophageal data emerge, including the need for a multiparametric assessment of functional images and the added value of response assessment rather than relying on single time point measures. The sensitivity and specificity of FDG-PET to predict treatment response and survival are not currently high enough to inform treatment decisions. This suggests that a multimodal, multiparametric approach may be required. FDG-PET improves target volume definition in oesophageal cancer by improving the accuracy of tumour length definition and by improving the nodal staging of patients. The ideal functional imaging test would accurately identify patients who are unlikely to achieve a pathological complete response after chemoradiotherapy and would aid the delineation of a biological target volume that could be used for treatment intensification. The current limitations of published studies prevent integrating imaging-derived parameters into decision making on an individual patient basis. These limitations should inform future trial design in oesophageal and pancreatic cancers.
PMCID: PMC4150923  PMID: 24998430
Functional imaging; oesophageal cancer; pancreatic cancer; radiotherapy treatment planning; response assessment; target volume delineation
7.  Robot-assisted intraocular surgery: development of the IRISS and feasibility studies in an animal model 
Eye  2013;27(8):972-978.
The aim of this study is to develop a novel robotic surgical platform, the IRISS (Intraocular Robotic Interventional and Surgical System), capable of performing both anterior and posterior segment intraocular surgery, and assess its performance in terms of range of motion, speed of motion, accuracy, and overall capacities.
Patients and methods
To test the feasibility of performing ‘bimanual' intraocular surgical tasks using the IRISS, we defined four steps out of typical anterior (phacoemulsification) and posterior (pars plana vitrectomy (PPV)) segment surgery. Selected phacoemulsification steps included construction of a continuous curvilinear capsulorhexis and cortex removal in infusion–aspiration (I/A) mode. Vitrectomy steps consisted of performing a core PPV, followed by aspiration of the posterior hyaloid with the vitreous cutter to induce a posterior vitreous detachment (PVD) assisted with triamcinolone, and simulation of the microcannulation of a temporal retinal vein. For each evaluation, the duration and the successful completion of the task with or without complications or involuntary events was assessed.
Intraocular procedures were successfully performed on 16 porcine eyes. Four eyes underwent creation of a round, curvilinear anterior capsulorhexis without radialization. Four eyes had I/A of lens cortical material completed without posterior capsular tear. Four eyes completed 23-gauge PPV followed by successful PVD induction without any complications. Finally, simulation of microcannulation of a temporal retinal vein was successfully achieved in four eyes without any retinal tears/perforations noted.
Robotic-assisted intraocular surgery with the IRISS may be technically feasible in humans. Further studies are pending to improve this particular surgical platform.
PMCID: PMC3740307  PMID: 23722720
intraocular surgery; robot; phacoemulsification; vitrectomy
8.  Brucellosis as an Emerging Threat in Developing Economies: Lessons from Nigeria 
Nigeria is the most populous country in Africa, has a large proportion of the world's poor livestock keepers, and is a hotspot for neglected zoonoses. A review of the 127 accessible publications on brucellosis in Nigeria reveals only scant and fragmented evidence on its spatial and temporal distribution in different epidemiological contexts. The few bacteriological studies conducted demonstrate the existence of Brucella abortus in cattle and sheep, but evidence for B. melitensis in small ruminants is dated and unclear. The bulk of the evidence consists of seroprevalence studies, but test standardization and validation are not always adequately described, and misinterpretations exist with regard to sensitivity and/or specificity and ability to identify the infecting Brucella species. Despite this, early studies suggest that although brucellosis was endemic in extensive nomadic systems, seroprevalence was low, and brucellosis was not perceived as a real burden; recent studies, however, may reflect a changing trend. Concerning human brucellosis, no studies have identified the Brucella species and most reports provide only serological evidence of contact with Brucella in the classical risk groups; some suggest brucellosis misdiagnoses as malaria or other febrile conditions. The investigation of a severe outbreak that occurred in the late 1970s describes the emergence of animal and human disease caused by the settling of previously nomadic populations during the Sahelian drought. There appears to be an increasing risk of re-emergence of brucellosis in sub-Saharan Africa, as a result of the co-existence of pastoralist movements and the increase of intensive management resulting from growing urbanization and food demand. Highly contagious zoonoses like brucellosis pose a threat with far-reaching social and political consequences.
PMCID: PMC4109902  PMID: 25058178
9.  Evaluation of a modified Fitts law BCI target acquisition task in able and motor disabled individuals 
Journal of neural engineering  2009;6(5):056002.
A brain-computer interface (BCI) is a communication system that takes recorded brain signals and translates them into real-time actions, in this case movement of a cursor on a computer screen. This work applied Fitts’ law to the evaluation of performance on a target acquisition task during sensorimotor rhythm-based BCI training. Fitts’ law, which has been used as a predictor of movement time in studies of human movement, was used here to determine the information transfer rate, which was based on target acquisition time and target difficulty. The information transfer rate was used to make comparisons between control modalities and subject groups on the same task. Data were analyzed from eight able-bodied and five motor disabled participants who wore an electrode cap that recorded and translated their electroencephalogram (EEG) signals into computer cursor movements. Direct comparisons were made between able-bodied and disabled subjects and between EEG and joystick cursor control in able-bodied subjects. Fitts’ law aptly described the relationship between movement time and index of difficulty for each task movement direction when evaluated separately and averaged together. This study showed that Fitts’ law can be successfully applied to computer cursor movement controlled by neural signals.
PMCID: PMC4075430  PMID: 19700814
10.  Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer 
British Journal of Cancer  2013;108(5):1178-1181.
Evidence for non-steroidal anti-inflammatory drugs (NSAIDs) preventing head and neck cancer (HNC) is inconclusive; however, there is some suggestion that aspirin may exert a protective effect.
Using data from the United States National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined the association between aspirin and ibuprofen use and HNC.
Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use.
Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted.
PMCID: PMC3619083  PMID: 23449358
head and neck cancer; ibuprofen; aspirin; cohort study
11.  Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States over 10 Years: A Quality Research in Radiation Oncology Survey 
To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006–2007 versus in 1998–1999.
Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), comprising records from 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006–2007 versus patients treated in 1998–1999.
Use of all recommended procedures for staging and treatment was more common in 2006–2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006–2007 (vs. 42% in 1998–1999, p=0.0001) and in 84% of patients with LS-SCLC in 2006–2007 (vs. 58.3% in 1998–1999, p=0.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs. 45% in 1998–1999, p<0.0001) and for 90% of LS-SCLC patients (vs. 62.5% in 1998–1999, p<0.0001). Use of the recommended radiation dose (59–74 Gy for NSCLC and 60–70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006–2007) vs. 43% (1998–1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006–2007 vs. 8% in 1998–1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006–2007 (vs. 21% in 1998–1999).
Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also require improvement.
PMCID: PMC3897271  PMID: 23273996
lung cancer; QRRO; quality indicators; clinical performance measures; healthcare management; standard of care; patterns of care
This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female Balb/c mice were exposed to saline-control or OVA aerosols for 1hr per day for episodes of 3 days every week for up to 8 weeks. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 weeks and further enhanced to a sustained level after the 4th and 8th weeks. Although by the 8th week, diminished OVA-induced accumulations of eosinophils, neutrophils and monocyte-macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet cell hyperplasia and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the 1st, 2nd and 4th OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte-macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after the 4th week. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma.
PMCID: PMC3558838  PMID: 23356647
ovalbumin; airway reactivity; eosinophils; neutrophils; lymphocytes; macrophages
14.  Evaluation of Adherence to Quality Measures for Prostate Cancer Radiotherapy in the United States: Results from the Quality Research in Radiation Oncology (QRRO) Survey 
To test the feasibility of using proposed quality indicators to assess radiotherapy quality in prostate cancer management based on a 2007 stratified random survey of treating academic and non-academic US institutions.
Methods and Materials
414 patients with clinically localized prostate cancer treated with external beam radiotherapy (EBRT) or brachytherapy were selected from 45 institutions. Indicators used as specific measurable clinical performance measures to represent surrogates for quality of radiotherapy delivery included established measures, such as the use of prescription doses ≥75 Gy for intermediate- and high-risk EBRT patients and androgen-deprivation therapy (ADT) in conjunction with EBRT for patients with high-risk disease, and emerging measures, including daily target localization (image-guidance) to correct for organ motion for EBRT patients.
167 patients (47%) were treated with 6 MV photons, 31 (9%) were treated with 10 MV, 65 (18%) received 15 MV, and the remaining 90 (26%) 16–23 MV. For intermediate- plus high-risk patients (n=181), 78% were treated to ≥75 Gy. Among favorable-risk patients, 72% were treated to ≥75 Gy. Among high-risk EBRT patients, 60 (87%) were treated with ADT in conjunction with EBRT and 13% (n=9) with radiotherapy alone. Among low- and intermediate-risk patients, 10% and 42%, respectively, were treated with ADT plus EBRT. For 24% of EBRT patients (85/354), weekly electronic portal imaging was obtained as verification films without daily target localization and the remaining 76% were treated with daily localization of the target using various methods.
Adherence to defined quality indicators was observed in a majority of patients. ≈90% of high-risk patients are treated with ADT plus EBRT and ≈80% of intermediate- and high-risk patients receive prescription doses >=75 Gy, consistent with the published results of randomized trials.
PMCID: PMC3587045  PMID: 23471563
external beam radiotherapy; quality indicators; androgen deprivation therapy; dose escalation; prostate cancer
15.  Prone Whole-Breast Irradiation Using Three-Dimensional Conformal Radiotherapy in Women Undergoing Breast Conservation for Early Disease Yields High Rates of Excellent to Good Cosmetic Outcomes in Patients With Large and/or Pendulous Breasts 
International journal of radiation oncology, biology, physics  2011;83(3):10.1016/j.ijrobp.2011.08.020.
To report our institution’s experience using prone positioning for three-dimensional conformal radiotherapy (3D-CRT) to deliver post-lumpectomy whole breast irradiation (WBI) in a cohort of women with large and/or pendulous breasts, to determine the rate of acute and late toxicities and, more specifically, cosmetic outcomes. We hypothesized that using 3D-CRT for WBI in the prone position would reduce or eliminate patient and breast size as negative prognostic indicators for toxicities associated with WBI.
Methods and Materials
From 1998 to 2006, 110 cases were treated with prone WBI using 3D-CRT. The lumpectomy, breast target volumes, heart, and lung were contoured on all computed tomography scans. A dose of 45–50 Gy was prescribed to the breast volume using standard fractionation schemes. The planning goals were ≥95% of prescription to 95% of the breast volume, and 100% of boost dose to 95% of lumpectomy planning target volume. Toxicities and cosmesis were prospectively scored using the Common Terminology Criteria for Adverse Effects Version 3.0 and the Harvard Scale. The median follow-up was 40 months.
The median body mass index (BMI) was 33.6 kg/m2, and median breast volume was 1396 cm3. The worst toxicity encountered during radiation was Grade 3 dermatitis in 5% of our patient population. Moist desquamation occurred in 16% of patients, with only 2% of patients with moist desquamation outside the inframammary/axillary folds. Eleven percent of patients had Grade ≥2 late toxicities, including Grade 3 induration/fibrosis in 2%. Excellent to good cosmesis was achieved in 89%. Higher BMI was associated with moist desquamation and breast pain, but BMI and breast volume did not impact fibrosis or excellent to good cosmesis.
In patients with higher BMI and/or large–pendulous breasts, delivering prone WBI using 3D-CRT results in favorable toxicity profiles and high excellent to good cosmesis rates. Higher BMI was associated with moist desquamation, but prone positioning removed BMI and breast size as factors for poorer cosmetic outcomes. This series adds to the growing literature demonstrating that prone WBI may be advantageous in select patients.
PMCID: PMC3845369  PMID: 22208973
Prone; Breast; Radiation; Body mass index; Cosmesis
16.  Multiplex Cytological Profiling Assay to Measure Diverse Cellular States 
PLoS ONE  2013;8(12):e80999.
Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological profiling assay that “paints the cell” with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar  annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.
PMCID: PMC3847047  PMID: 24312513
17.  Nitric Oxide-Mediated Regulation of β-Amyloid Clearance via Alterations of MMP-9/TIMP-1 
Journal of neurochemistry  2012;123(5):736-749.
Fibrillar amyloid plaques are largely composed of amyloid-beta (Aβ) peptides that are metabolized into products, including Aβ1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Aβ proteins is critical to amyloid accumulation and resulting disease. Regulation of MMP-9 and its endogenous inhibitor TIMP-1 by nitric oxide (NO) has been shown. We hypothesize that NOS2 protects against AD pathology by increasing amyloid clearance through NO regulation of MMP-9/TIMP-1 balance. We show NO-mediated increased MMP-9/TIMP-1 ratios enhanced the degradation of fibrillar Aβ in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Aβ degradation was examined by comparing an AD mouse model that expresses NOS2 with a model lacking NOS2. To quantitate MMP-9 mediated changes, we generated an antibody recognizing the Aβ1-16 fragment, and used mass spectrometry multi-reaction monitoring (MRM) assay for detection of immunoprecipitated Aβ1-16 peptides. Aβ1-16 levels decreased in brain lysates lacking NOS2 when compared to strains that express human APP on the NOS2 background. TIMP-1 increased in the APPSwDI/NOS2−/− mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP/TIMP balance and plaque clearance.
PMCID: PMC3614913  PMID: 23016931
matrix metalloproteinase-9; tissue inhibitor of metalloproteinase-1; NOS2; nitric oxide; amyloid; mass spectrophotometry; microglia; mouse models; immunity
18.  Plio-Pleistocene history and phylogeography of Acacia senegal in dry woodlands and savannahs of sub-Saharan tropical Africa: evidence of early colonisation and recent range expansion 
Heredity  2012;109(6):372-382.
Drylands are extensive across sub-Saharan Africa, socio-economically and ecologically important yet highly sensitive to environmental changes. Evolutionary history, as revealed by contemporary intraspecific genetic variation, can provide valuable insight into how species have responded to past environmental and population changes and guide strategies to promote resilience to future changes. The gum arabic tree (Acacia senegal) is an arid-adapted, morphologically diverse species native to the sub-Saharan drylands. We used variation in nuclear sequences (internal transcribed spacer (ITS)) and two types of chloroplast DNA (cpDNA) markers (PCR-RFLP, cpSSR) to study the phylogeography of the species with 293 individuals from 66 populations sampled across its natural range. cpDNA data showed high regional and rangewide haplotypic diversity (hT(cpSSR)=0.903–0.948) and population differentiation (GST(RFLP)=0.700–0.782) with a phylogeographic pattern that indicated extensive historical gene flow via seed dispersal. Haplotypes were not restricted to any of the four varieties, but showed significant geographic structure (GST(cpSSR)=0.392; RST=0.673; RST>RST (permuted)), with the major division separating East and Southern Africa populations from those in West and Central Africa. Phylogenetic analysis of ITS data indicated a more recent origin for the clade including West and Central African haplotypes, suggesting range expansion in this region, possibly during the Holocene humid period. In conjunction with paleobotanical evidence, our data suggest dispersal to West Africa, and across to the Arabian Peninsula and Indian subcontinent, from source populations located in the East African region during climate oscillations of the Plio-Pleistocene.
PMCID: PMC3499837  PMID: 22929152
aridity; gum arabic; hybridisation; long-distance dispersal; phylogeny; refugia
19.  Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource 
Diabetologia  2012;55(11):2970-2984.
Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.
We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (Fsts) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ±250 kb around each EuA SNP in AfAs.
Allele frequency differences ranged from 0.6% to 54%. Fst exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p=5.8 × 10-8; MTNR1B, p=8.5 × 10-9; and FADS1, p=2.2 × 10-4) or FI (GCKR, p=5.9 × 10-4). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r2<0.2), suggesting allelic heterogeneity for association with FG at these loci.
Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.
PMCID: PMC3804308  PMID: 22893027
African ancestry; Genetics; Genome-wide association; LD mapping; Minorities; Type 2 diabetes
20.  Characterization of Restricted Diffusion in Uni- and Multi-lamellar Vesicles Using Short Distance iMQCs 
Improved understanding of the entrapment, transport, and release of drugs and small molecules within vesicles is important for drug delivery. Most methods rely on contrast agents or probe molecules; here, we propose a new MRI method to detect signal from water spins with restricted diffusion. This method is based on intermolecular double quantum coherences (iDQCs), which can probe the restricted diffusion characteristics at well-defined and tunable microscopic distance scales. By using an exceedingly short (and previously inaccessible) distance, the iDQC signal arises only from restricted diffusion spins and thereby provides a mechanism to directly image vesicle entrapment, transport, and release. Using uni- and multi-lamellar liposomes and polymersomes, we show how the composition, lamellar structure, vesicle size, and concentration affects the iDQC signal between coupled water spins at very short separation distances. The iDQC signal correlates well with conventional diffusion MRI and a proposed biexponential (multicompartmental) diffusion model. Finally, the iDQC signal was used to monitor dynamic changes in the lamellar structure as temperature-sensitive liposomes released their contents. These short distance iDQCs can probe the amount and diffusion of water entrapped in vesicles, which may be useful to further understand vesicle properties in materials science and drug delivery applications.
PMCID: PMC3594806  PMID: 22975234
Intermolecular multiple quantum coherences; liposomes; restricted diffusion
21.  Opportunistic pathology-based screening for diabetes 
BMJ Open  2013;3(9):e003411.
To determine the potential of opportunistic glycated haemoglobin (HbA1c) testing of pathology samples to detect previously unknown diabetes.
Pathology samples from participants collected for other reasons and suitable for HbA1c testing were utilised for opportunistic diabetes screening. HbA1c was measured with a Biorad Variant II turbo analyser and HbA1c levels of ≥6.5% (48 mmol/mol) were considered diagnostic for diabetes. Confirmation of previously unknown diabetes status was obtained by a review of hospital medical records and phone calls to general practitioners.
Hospital pathology laboratory receiving samples from hospital-based and community-based (CB) settings.
Participants were identified based on the blood sample collection location in the CB, emergency department (ED) and inpatient (IP) groups. Exclusions pretesting were made based on the electronic patient history of: age <18 years, previous diabetes diagnosis, query for diabetes status in the past 12 months, evidence of pregnancy and sample collected postsurgery or transfusion. Only one sample per individual participant was tested.
Of the 22 396 blood samples collected, 4505 (1142 CB, 1113 ED, 2250 IP) were tested of which 327 (7.3%) had HbA1c levels ≥6.5% (48 mmol/mol). Of these 120 (2.7%) were determined to have previously unknown diabetes (11 (1%) CB, 21 (1.9%) ED, 88 (3.9%) IP). The prevalence of previously unknown diabetes was substantially higher (5.4%) in hospital-based (ED and IP) participants aged over 54 years.
Opportunistic testing of referred pathology samples can be an effective method of screening for diabetes, especially in hospital-based and older persons.
PMCID: PMC3787471  PMID: 24065696
Diabetes and Endocrinology; Diabetes Screening; HbA1c
22.  Ciliated hepatic cyst leading to squamous cell carcinoma of the liver – A case report and review of the literature☆ 
Ciliated hepatic foregut cysts (CHFC) are rare, typically benign liver lesions. Primary squamous cell carcinoma (SCC) of the liver is also a rare entity with only approximately 25 reported cases in the literature. Recently, there have been four reports of malignant transformation of CHFC into primary squamous cell carcinoma of the liver. Here we report a fifth with unique presentation and review the literature.
A 34 year-old man, with a history of ulcerative colitis, was incidentally found to have a 10 cm lesion in the right anterior sector plus left medial section of the liver on computerized tomography (CT) scan. The patient was asymptomatic at presentation and neoplastic markers were not elevated. Sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE) allowed for left lateral section plus segment 1 hypertrophy and subsequent resection. Histology later revealed the cyst to be a CHFC and showed its malignant transformation. At 6 month follow-up, the patient has lung and abdominal recurrence.
With now the fifth case of malignant transformation of CHFC being reported, approximately 5% of all reported CHFC have undergone malignant transformation. This frequency, taken together with the aggressive disease course and poor prognosis, suggests that CHFC must not be presumed benign and should be regarded with clinical suspicion.
Accurate diagnosis of CHFC is mandatory given its potential malignant transformation. Even in asymptomatic CHFC, surgical excision is recommended. In addition, in cases of otherwise unresectable lesions, sequential TACE and PVE may provide optimal hypertrophy of future liver remnant.
PMCID: PMC3825928  PMID: 24055921
Ciliated hepatic foregut cyst; Squamous cell carcinoma; Transcatheter arterial chemoembolization (TACE); Portal vein embolization (PVE); Liver
23.  Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK 
Diabetologia  2013;56(10):2238-2249.
This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}]) and physical activity.
One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40–70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMAIR), plus other risk factors, and underwent assessment of physical activity (using accelerometry), \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}, body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA1c levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMAIR and fasting glucose between South Asian and European men.
HOMAIR and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}, lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMAIR. Lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document} and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose.
Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2969-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3764328  PMID: 23811809
Adiposity; Ethnicity; Fitness; Glycaemia; Insulin resistance; Maximal oxygen uptake; Obesity; Physical activity; Sedentary; South Asian

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