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1.  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.
doi:10.1088/1741-2560/6/5/056002
PMCID: PMC4075430  PMID: 19700814
2.  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.
Background:
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.
Methods:
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.
Results:
Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use.
Conclusion:
Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted.
doi:10.1038/bjc.2013.73
PMCID: PMC3619083  PMID: 23449358
head and neck cancer; ibuprofen; aspirin; cohort study
3.  Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States over 10 Years: A Quality Research in Radiation Oncology Survey 
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ijrobp.2012.10.016
PMCID: PMC3897271  PMID: 23273996
lung cancer; QRRO; quality indicators; clinical performance measures; healthcare management; standard of care; patterns of care
4.  RECURRING BALB/C MOUSE LUNG INFLAMMATORY RESPONSES TO EPISODIC ALLERGEN EXPOSURE 
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.
doi:10.1080/15287394.2013.752323
PMCID: PMC3558838  PMID: 23356647
ovalbumin; airway reactivity; eosinophils; neutrophils; lymphocytes; macrophages
6.  Evaluation of Adherence to Quality Measures for Prostate Cancer Radiotherapy in the United States: Results from the Quality Research in Radiation Oncology (QRRO) Survey 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.prro.2012.01.006
PMCID: PMC3587045  PMID: 23471563
external beam radiotherapy; quality indicators; androgen deprivation therapy; dose escalation; prostate cancer
7.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1016/j.ijrobp.2011.08.020
PMCID: PMC3845369  PMID: 22208973
Prone; Breast; Radiation; Body mass index; Cosmesis
8.  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.
doi:10.1371/journal.pone.0080999
PMCID: PMC3847047  PMID: 24312513
9.  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.
doi:10.1111/jnc.12028
PMCID: PMC3614913  PMID: 23016931
matrix metalloproteinase-9; tissue inhibitor of metalloproteinase-1; NOS2; nitric oxide; amyloid; mass spectrophotometry; microglia; mouse models; immunity
10.  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.
doi:10.1038/hdy.2012.52
PMCID: PMC3499837  PMID: 22929152
aridity; gum arabic; hybridisation; long-distance dispersal; phylogeny; refugia
11.  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.
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
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.
doi:10.1007/s00125-012-2656-4
PMCID: PMC3804308  PMID: 22893027
African ancestry; Genetics; Genome-wide association; LD mapping; Minorities; Type 2 diabetes
12.  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.
doi:10.1016/j.jmr.2012.07.021
PMCID: PMC3594806  PMID: 22975234
Intermolecular multiple quantum coherences; liposomes; restricted diffusion
13.  Opportunistic pathology-based screening for diabetes 
BMJ Open  2013;3(9):e003411.
Objective
To determine the potential of opportunistic glycated haemoglobin (HbA1c) testing of pathology samples to detect previously unknown diabetes.
Design
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.
Setting
Hospital pathology laboratory receiving samples from hospital-based and community-based (CB) settings.
Participants
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.
Results
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.
Conclusions
Opportunistic testing of referred pathology samples can be an effective method of screening for diabetes, especially in hospital-based and older persons.
doi:10.1136/bmjopen-2013-003411
PMCID: PMC3787471  PMID: 24065696
Diabetes and Endocrinology; Diabetes Screening; HbA1c
14.  Ciliated hepatic cyst leading to squamous cell carcinoma of the liver – A case report and review of the literature☆ 
INTRODUCTION
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.
PRESENTATION OF CASE
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.
DISCUSSION
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.
CONCLUSION
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.
doi:10.1016/j.ijscr.2013.07.030
PMCID: PMC3825928  PMID: 24055921
Ciliated hepatic foregut cyst; Squamous cell carcinoma; Transcatheter arterial chemoembolization (TACE); Portal vein embolization (PVE); Liver
15.  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;56:2238-2249.
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
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.
doi:10.1007/s00125-013-2969-y
PMCID: PMC3764328  PMID: 23811809
Adiposity; Ethnicity; Fitness; Glycaemia; Insulin resistance; Maximal oxygen uptake; Obesity; Physical activity; Sedentary; South Asian
18.  A Micro-Electrocorticography Platform and Deployment Strategies for Chronic BCI Applications 
Over the past decade, electrocorticography (ECoG) has been used for a wide set of clinical and experimental applications. Recently, there have been efforts in the clinic to adapt traditional ECoG arrays to include smaller recording contacts and spacing. These devices, which may be collectively called “micro-ECoG” arrays, are loosely defined as intercranial devices that record brain electrical activity on the submillimeter scale. An extensible 3D-platform of thin film flexible micro-scale ECoG arrays appropriate for Brain-Computer Interface (BCI) application, as well as monitoring epileptic activity, is presented. The designs utilize flexible film electrodes to keep the array in place without applying significant pressure to the brain and to enable radial subcranial deployment of multiple electrodes from a single craniotomy. Deployment techniques were tested in non-human primates, and stimulus-evoked activity and spontaneous epileptic activity were recorded. Further tests in BCI and epilepsy applications will make the electrode platform ready for initial human testing.
PMCID: PMC3653975  PMID: 22208124
Brain-Computer Interface; Electrocorticography; Electroencephalography; Epilepsy Monitoring; 3D-Platform
19.  Quantitative genetics of immunity and life history under different photoperiods 
Heredity  2011;108(5):569-576.
Insects with complex life-cycles should optimize age and size at maturity during larval development. When inhabiting seasonal environments, organisms have limited reproductive periods and face fundamental decisions: individuals that reach maturity late in season have to either reproduce at a small size or increase their growth rates. Increasing growth rates is costly in insects because of higher juvenile mortality, decreased adult survival or increased susceptibility to parasitism by bacteria and viruses via compromised immune function. Environmental changes such as seasonality can also alter the quantitative genetic architecture. Here, we explore the quantitative genetics of life history and immunity traits under two experimentally induced seasonal environments in the cricket Gryllus bimaculatus. Seasonality affected the life history but not the immune phenotypes. Individuals under decreasing day length developed slower and grew to a bigger size. We found ample additive genetic variance and heritability for components of immunity (haemocyte densities, proPhenoloxidase activity, resistance against Serratia marcescens), and for the life history traits, age and size at maturity. Despite genetic covariance among traits, the structure of G was inconsistent with genetically based trade-off between life history and immune traits (for example, a strong positive genetic correlation between growth rate and haemocyte density was estimated). However, conditional evolvabilities support the idea that genetic covariance structure limits the capacity of individual traits to evolve independently. We found no evidence for G × E interactions arising from the experimentally induced seasonality.
doi:10.1038/hdy.2011.125
PMCID: PMC3330682  PMID: 22187084
time constraints; trade-off; full-sib/half-sib design
20.  Small bowel perforation secondary to enteric Salmonella paratyphi A infection 
BMJ Case Reports  2011;2011:bcr0820103272.
A patient of Pakistani-origin was admitted to Bradford Royal Infirmary, UK, following a 3-week history of cough, headache and general malaise. He had recently spent 10 weeks in Pakistan and on return had been diagnosed in the community with Swine flu. He developed abdominal pain and diarrhoea in the week prior to admission, and presented to hospital with fever, tachycardia and raised inflammatory markers. He deteriorated rapidly, developing signs of peritonism and Salmonella paratyphi A was grown from blood cultures. CT demonstrated a small volume of free fluid within the abdomen and the patient underwent laparotomy. A small bowel perforation was resected and a side to side anastomosis fashioned. Treatment with intravenous antibiotics was completed and the patient was discharged 9 days postoperatively.
doi:10.1136/bcr.08.2010.3272
PMCID: PMC3082069  PMID: 22696633
21.  Congenital Diverticular Disease of the Entire Colon 
Case Reports in Surgery  2013;2013:319026.
Congenital or true colonic diverticulosis is a rare condition typified by the preservation of the colonic wall architecture within the diverticular outpouching. Cases of multiple jejunal diverticula have been reported as well as cases of solitary giant diverticula of the colon. There have been no reports in the literature of pancolonic congenital diverticulosis.
doi:10.1155/2013/319026
PMCID: PMC3639703  PMID: 23662238
22.  Analysis of intraprostatic therapeutic effects in prostate cancer patients using [11C]-choline pet/ct after external-beam radiation therapy 
Current Oncology  2013;20(2):104-110.
Purpose
The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [11C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur.
Methods
The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [11C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt.
Results
Analysis of [11C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt.
Conclusions
Our study demonstrated that intraprostatic [11C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [11C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [11C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [11C]-choline pet changes as a possible, but currently unproven, biomarker of response.
doi:10.3747/co.20.1217
PMCID: PMC3615852  PMID: 23559873
External-beam radiation therapy; ebrt; positron-emission tomography; pet; [11C]-choline
23.  Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism 
Diabetologia  2011;55(2):331-339.
Aims/hypothesis
Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.
Methods
We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n=16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.
Results
The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p=1×10−4), nominally greater at GCK and SLC30A8 (p<0.05) and nominally smaller at IGF2BP2 (p=0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.
Conclusions/interpretation
Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.
doi:10.1007/s00125-011-2353-8
PMCID: PMC3589986  PMID: 22038522
Common genetic variants; Diabetes mellitus; Genetics; Glycaemic progression; Impaired fasting glucose; Normal fasting glucose; Single nucleotide polymorphism; Type 2 diabetes
24.  A swallowed foreign body that uncovered an undiagnosed bowel pathology 
BMJ Case Reports  2011;2011:bcr0720103175.
This report details a unique presentation of Crohn's disease in a patient who inadvertently swallowed the cap of a USB mass storage device and subsequently developed intestinal obstruction and underwent a limited right hemicolectomy. Imaging, photographs and histology are described with discussion of surgical outcomes.
doi:10.1136/bcr.07.2010.3175
PMCID: PMC3062052  PMID: 22715222
25.  Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia 
Blood Cancer Journal  2013;3(1):e101-.
Pediatric leukemia survival rates have improved dramatically over the past decades. However, current treatment protocols are still largely ineffective in cases of relapsed leukemia and are associated with a significant rate of chronic health conditions. Thus, there is a continued need for new therapeutic options. Here, we show that mer receptor tyrosine kinase (MerTK) was abnormally expressed in approximately one half of pediatric T-cell leukemia patient samples and T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Stimulation of MerTK by the ligand Gas6 led to activation of the prosurvival proteins Erk 1/2 and Stat5, and MerTK-dependent activation of the STAT pathway in leukemia represents a novel finding. Furthermore, inhibition of MerTK expression increased the sensitivity of T-ALL cells to treatment with chemotherapeutic agents and decreased the oncogenic potential of the Jurkat T-ALL cell line in a methylcellulose colony-forming assay. Lastly, inhibition of MerTK expression significantly increased median survival in a xenograft mouse model of leukemia (30.5 days vs 60 days, P<0.0001). These results suggest that inhibition of MerTK is a promising therapeutic strategy for the treatment of leukemia and may allow for dose reduction of currently used chemotherapeutics resulting in decreased rates of therapy-associated toxicities.
doi:10.1038/bcj.2012.46
PMCID: PMC3556576  PMID: 23353780
MerTK; receptor tyrosine kinase; T-cell leukemia; xenograft mouse model

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