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1.  Optimisation of an automated drusen-quantifying software for the analysis of drusen distribution in patients with age-related macular degeneration 
Eye  2013;27(4):554-560.
Purpose
The purpose of this study is to optimise the settings of the Retinal Image Analysis Laboratory (RIALAB), a semi-automatic drusen quantification software, in planning for high-throughput quantification of drusen in clinical studies of age-related macular degeneration (AMD).
Patients and methods
A comparison of five different settings in RIALAB was made on 67 images from the Rotterdam eye study (population-based study) and 56 images from the fellow eye of patients with active neovascular AMD in King's College Hospital, London (hospital-based study).
Results
The ‘Few Outer' setting was the best setting, with it being most appropriate for 52 (77.6%) of the Rotterdam cohort and 47 (83.9%) for the London cohort. Pearson's χ2-test revealed both results to be statistically significant (P<0.0001).
Conclusions
RIALAB is a viable algorithm and software package that can detect, quantify, and analyse drusen efficiently in both population-based and hospital-based studies. We have shown that the ‘Few Outer' drusen setting can be employed as the default setting, with fine-tuning only needed in a minority of cases, thus helping to speed up workflow.
doi:10.1038/eye.2012.292
PMCID: PMC3625998  PMID: 23306729
age-related macular degeneration; automated drusen delineation; image processing
2.  Normal Heart Ventricular Tachycardia Associated with Pregnancy: Successful Treatment with Catheter Ablation 
Background
Normal heart ventricular arrhythmia occurring during pregnancy has been previously described. Whilst there are established reports of catheter ablation to treat supraventricular arrhythmia during pregnancy, there are no reports of ablation to treat ventricular tachycardia.
Case
We present the case of a 36 year old women, 31 weeks into an otherwise uncomplicated pregnancy, experiencing significant, troublesome and drug refractory tachycardia emanating from the right ventricular outflow tract.
Conclusion
We describe a successful radio frequency ablation in the third trimester of pregnancy.
PMCID: PMC3952613  PMID: 24669106
Ventricular tachycardia; Right ventricular outflow tract; Pregnancy; Catheter ablation; Verapamil
3.  Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis 
Nature communications  2013;4:1957.
Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract in which alterations to the bacterial community contribute to disease. Adherent-invasive E. coli (AIEC) are associated with human Crohn’s disease, however their role in intestinal immunopathology is unclear due to the lack of an animal model compatible with chronic timescales. Here we establish chronic AIEC infection in streptomycin-treated conventional mice (CD-1, DBA/2, C3HeN, 129e, C57BL/6), enabling the study of host response and immunopathology. AIEC induces an active Th17 response, heightened levels of proinflammatory cytokines and fibrotic growth factors, with transmural inflammation and fibrosis. Depletion of CD8+ T cells increases cecal bacterial load, pathology and intestinal fibrosis in C57BL/6 mice suggesting a protective role. Our findings provide evidence that chronic AIEC infections result in immunopathology similar to that seen in Crohn’s disease. With this model, research into the host and bacterial genetics associated with AIEC-induced disease becomes more widely accessible.
doi:10.1038/ncomms2957
PMCID: PMC3938456  PMID: 23748852 CAMSID: cams3948
4.  The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia 
The Journal of Experimental Medicine  2013;210(8):1545-1557.
miR-223 is upregulated by the transcription factor TAL1 in human T-ALL cells and suppress the FBXW7 tumor suppressor.
The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.
doi:10.1084/jem.20122516
PMCID: PMC3727321  PMID: 23857984
5.  Isoflurane decreases death of hESC-derived Nkx2.5+ cardiac progenitor cells 
Acta anaesthesiologica Scandinavica  2011;55(9):10.1111/j.1399-6576.2011.02509.x.
Background
Cardiac progenitor cells (CPCs) derived from human embryonic stem cells (hESCs) can multiply and generate cardiomyocytes offering their tremendous potential for cardiac regenerative therapy. However, poor survival under stressful conditions is a major hurdle in the regeneration. We investigated whether isoflurane-induced preconditioning can increase hESC-derived CPCs survival under oxidative stress.
Methods
Undifferentiated hESCs were cultured in suspension with 20% FBS and 20 ng/ml of BMP-4 to form embryoid bodies and grown onto Matrigel-coated plates for 2-3 wks. To characterize the differentiated CPCs, immunostaining for Nkx2.5 and Isl-1 was performed. hESC-derived CPCs were exposed to oxidative stress induced by H2O2 and FeSO4. For anaesthetic preconditioning, CPCs were exposed to isoflurane (0.25, 0.5, 1.0 mM). CPCs survival was determined by trypan blue exclusion. A mitoKATP channels inhibitor, 5-hydroxydecanoic acid (200 μM) and an opener, diazoxide (100 μM) were used to investigate the involvement of mitoKATP channels.
Results
hESC-derived CPCs stained with Nkx2.5 were 95 ± 3% of total cell number. Isoflurane (0.5 and 1.0 mM)-preconditioned CPCs showed a significantly lower death rate compared with control (0.5 mM: 30.6 ± 10.7% and 1.0 mM: 28.5 ± 6.2% vs control: 43.2 ± 9.9%). Inhibition of mitoKATP channels with 5-HD completely abolished the protective effects of isoflurane. Diazoxide significantly decreased CPC death (29.5 ± 12.4%). However, when diazoxide was applied to CPC preconditioned with isoflurane, CPC death did not decrease further (28.7 ± 10.9%).
Conclusion
Isoflurane increased hESC-derived Nkx2.5+ CPCs survival under oxidative stress and mitoKATP channels may be involved in the protective effect.
doi:10.1111/j.1399-6576.2011.02509.x
PMCID: PMC3859137  PMID: 22092211
6.  Tying Payment Incentives to Quality Measurement 
Journal of Oncology Practice  2013;9(3):119-121.
The most important lesson from this program has been that collaboration, data, and measured performance are all possible for cancer care.
doi:10.1200/JOP.2013.000975
PMCID: PMC3651554  PMID: 23942485
7.  Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T-cell Acute Lymphoblastic Leukemia 
Cancer cell  2012;22(2):209-221.
SUMMARY
The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T-cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3 and RUNX1. We show that TAL1 forms a positive interconnected auto-regulatory loop with GATA3 and RUNX1, and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.
doi:10.1016/j.ccr.2012.06.007
PMCID: PMC3422504  PMID: 22897851
8.  Maternal height and child growth patterns from birth to adulthood1, 2 
The Journal of pediatrics  2013;163(2):549-554.e1.
Objective
To examine associations between maternal height and child growth during four developmental periods: intrauterine, birth to age 2y, age 2y to mid-childhood, and mid-childhood to adulthood.
Study Design
Pooled analysis of maternal height and offspring growth using 7630 mother-child pairs from five birth cohorts (Brazil, Guatemala, India, Philippines and South Africa). We used conditional height measures that control for collinearity in height across periods. We estimated associations between maternal height and offspring growth using multivariate regression models adjusted for household income, child sex, birth order and study site.
Results
Maternal height was associated with birthweight and with both height and conditional height at each age examined. The strongest associations with conditional heights were for adulthood and 2y. A 1 cm increase in maternal height predicted a 0.024 (95%CI: 0.021 - 0.028) SD increase in offspring birthweight, a 0.037 (95%CI: 0.033 – 0.040) SD increase in conditional height at 2 y, a 0.025 (95%CI: 0.021 – 0.029 SD increase in conditional height in mid-childhood, and a 0.044 (95%CI: 0.040-0.048) SD increase in conditional height in adulthood. Short mothers (< 150 cm) were more likely to have a child who was stunted at 2 years (PR=3.20 (95% CI: 2.80–3.60) and as an adult (PR=4.74, (95% CI: 4.13-5.44). There was no evidence of heterogeneity by site or sex.
Conclusion
Maternal height influences offspring linear growth over the growing period. These influences likely include genetic and non-genetic factors, including nutrition-related intergenerational influences on growth that prevent the attainment of genetic height potential in low and middle income countries.
doi:10.1016/j.jpeds.2013.02.002
PMCID: PMC3711792  PMID: 23477997
Maternal height; Child; Conditional Growth; Intergenerational Influences; COHORTS
9.  Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme 
Diabetologia  2013;56(8):1716-1725.
Aims/hypothesis
The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly retinopathy screening.
Methods
This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy.
Results
The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years.
Conclusions/interpretation
Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2928-7) contains peer reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-013-2928-7
PMCID: PMC3699707  PMID: 23689796
Diabetes; Diabetic retinopathy; Maculopathy; Retinal screening; Screening intervals
10.  Adverse skin reactions following intravitreal bevacizumab injection 
BMJ Case Reports  2011;2011:bcr0220102753.
The authors describe two separate cases of skin eruption following intravitreal bevacizumab injection with evidence to suggest that these were adverse drug reactions to bevacizumab. The authors also discuss how each case was treated and report on the final outcome.
doi:10.1136/bcr.02.2010.2753
PMCID: PMC3062049  PMID: 22715260
11.  Unsupported off-label chemotherapy in metastatic colon cancer 
Background
Newer systemic therapies have the potential to decrease morbidity and mortality from metastatic colorectal cancer, yet such therapies are costly and have side effects. Little is known about their non-evidence-based use.
Methods
We conducted a retrospective cohort study using commercial insurance claims from UnitedHealthcare, and identified incident cases of metastatic colon cancer (mCC) from July 2007 through April 2010. We evaluated the use of three regimens with recommendations against their use in the National Comprehensive Cancer Center Network Guidelines, a commonly used standard of care: 1) bevacizumab beyond progression; 2) single agent capecitabine as a salvage therapy after failure on a fluoropyridimidine-containing regimen; 3) panitumumab or cetuximab after progression on a prior epidermal growth factor receptor antibody. We performed sensitivity analyses of key assumptions regarding cohort selection. Costs from a payer perspective were estimated using the average sales price for the entire duration and based on the number of claims.
Results
A total of 7642 patients with incident colon cancer were identified, of which 1041 (14%) had mCC. Of those, 139 (13%) potentially received at least one of the three unsupported off-label (UOL) therapies; capecitabine was administered to 121 patients and 49 (40%) likely received it outside of clinical guidelines, at an estimated cost of $718,000 for 218 claims. Thirty-eight patients received panitumumab and six patients (16%) received it after being on cetuximab at least two months, at an estimated cost of $69,500 for 19 claims. Bevacizumab was administered to 884 patients. Of those, 90 (10%) patients received it outside of clinical guidelines, at an estimated costs of $1.34 million for 636 claims.
Conclusions
In a large privately insured mCC cohort, a substantial number of patients potentially received UOL treatment. The economic costs and treatment toxicities of these therapies warrant increased efforts to stem their use in settings lacking sufficient scientific evidence.
doi:10.1186/1472-6963-12-481
PMCID: PMC3544564  PMID: 23272659
Colorectal cancer; Off-label; Evidence-based medicine; Physician practice patterns
12.  Change in waist circumference over 11 years and current waist circumference independently predict elevated CRP in Filipino women 
C-reactive protein, a marker of chronic, low-grade inflammation, is strongly associated with current central adiposity, and has been linked to elevated risk of cardiovascular disease. Less is known about the contribution of longitudinal change in waist circumference to current inflammation. We evaluated the extent to which current waist circumference and change over an 11-year interval contribute independently to low-grade systemic inflammation measured in a group of 1,294 women, 35–69 years, participating in the Cebu Longitudinal Nutrition and Health Survey in the Philippines. Waist circumference was measured at the time of blood draw for CRP analysis in 2005 and during an earlier survey in 1994. A waist circumference delta variable was constructed by subtracting current circumference from past circumference. We used logistic regression models to predict having an elevated plasma CRP concentration (3 mg/L
doi:10.1002/ajhb.20986
PMCID: PMC3511826  PMID: 19856425
Cell stem cell  2011;9(3):219-232.
Summary
Using mouse skin, where bountiful reservoirs of synchronized hair follicle stem cells (HF-SCs) fuel cycles of regeneration, we explore how adult SCs remodel chromatin in response to activating cues. By profiling global mRNA and chromatin changes in quiescent and activated HF-SCs and their committed, transit-amplifying (TA) progeny, we show that polycomb-group(PcG)-mediated H3K27-trimethylation features prominently in HF-lineage progression by mechanisms distinct from embryonic-SCs. In HF-SCs, PcG represses non-skin lineages and HF-differentiation. In TA-progeny, non-skin regulators remain PcG-repressed, HF-SC regulators acquire H3K27me3-marks and HF-lineage regulators lose them. Interestingly, genes poised in embryonic-SCs, active in HF-SCs and PcGrepressed in TA-progeny, encode not only key transcription factors, but also signaling regulators. We document their importance in balancing HF-SC quiescence, underscoring the power of chromatin mapping in dissecting SC behavior. Our findings explain how HF-SCs cycle through quiescent and activated states without losing stemness, and define roles for PcG-mediated repression in governing a fate switch irreversibly.
doi:10.1016/j.stem.2011.07.015
PMCID: PMC3166618  PMID: 21885018
Neuroscience  2010;171(3):788-793.
Excitatory amino acid transporters (EAAT) uptake extracellular glutamate, the major excitatory neurotransmitter in the brain. EAAT type 3 (EAAT3), the main neuronal EAAT, is expressed widely in the central nervous system. We have shown that the volatile anesthetic isoflurane increases EAAT3 activity and trafficking to the plasma membrane. Thus, we hypothesize that EAAT3 mediates isoflurane-induced anesthesia. To test this hypothesis, the potency of isoflurane to induce immobility and hypnosis, two major components of general anesthesia, was compared in the CD-1 wild-type mice and EAAT knockout mice that had a CD-1 strain gene background. Hypnosis was assessed by loss of righting reflex in this study. The expression of EAAT1 and EAAT2, two widely expressed EAATs in the central nervous system, in the cerebral cortex and spinal cord was not different between the EAAT3 knockout mice and wild-type mice. The concentration required for isoflurane to cause immobility to painful stimuli, a response involving primarily reflex loops in the spinal cord, was not changed by EAAT3 knockout. However, the EAAT3 knockout mice were more sensitive to isoflurane-induced hypnotic effects, which may be mediated by hypothalamic sleep neural circuits. Interestingly, the EAAT3 knockout mice did not have an altered sensitivity to the hypnotic effects caused by ketamine, an intravenous anesthetic that is a glutamate receptor antagonist and does not affect EAAT3 activity. These results suggest that EAAT3 modulates the sensitivity of neural circuits to isoflurane. These results, along with our previous findings that isoflurane increases EAAT3 activity, indicate that EAAT3 may regulate isoflurane-induced behavioral changes, including anesthesia.
doi:10.1016/j.neuroscience.2010.09.044
PMCID: PMC3401886  PMID: 20875840
anesthesia; glutamate transporter; gene expression; hypnosis; isoflurane
Diabetologia  2012;55(9):2335-2342.
Aims/hypothesis
The aim of this study was to examine the prevalence of and risk factors for diabetic retinopathy in people with newly diagnosed type 2 diabetes mellitus, using Scottish national data.
Methods
We identified individuals diagnosed with type 2 diabetes mellitus in Scotland between January 2005 and May 2008 using data from the national diabetes database. We calculated the prevalence of retinopathy and ORs for risk factors associated with retinopathy at first screening.
Results
Of the 51,526 people with newly diagnosed type 2 diabetes mellitus identified, 91.4% had been screened by 31 December 2010. The median time to first screening was 315 days (interquartile range [IQR] 111–607 days), but by 2008 the median was 83 days (IQR 51–135 days). The prevalence at first screening of any retinopathy was 19.3%, and for referable retinopathy it was 1.9%. For individuals screened after a year the prevalence of any retinopathy was 20.5% and referable retinopathy was 2.3%. Any retinopathy at screening was associated with male sex (OR 1.19, 95% CI 1.14, 1.25), HbA1c (OR 1.07, 95% CI 1.06, 1.08 per 1% [11 mmol/mol] increase), systolic BP (OR 1.06, 95% CI 1.05, 1.08 per 10 mmHg increase), time to screening (OR for screening >1 year post diagnosis = 1.12, 95% CI 1.07, 1.17) and obesity (OR 0.87, 95% CI 0.82, 0.93) in multivariate analysis.
Conclusions/interpretation
The prevalence of retinopathy at first screening is lower than in previous UK studies, consistent with earlier diagnosis of diabetes. Most newly diagnosed type 2 diabetic patients in Scotland are screened within an acceptable interval and the prevalence of referable disease is low, even in those with delayed screening.
doi:10.1007/s00125-012-2596-z
PMCID: PMC3411303  PMID: 22688348
Diabetic retinopathy; Diabetic retinopathy screening; Scotland; Type 2 diabetes
Cell Death and Differentiation  2011;18(6):1046-1056.
Stress protein mortalin is a multifunctional protein and is highly expressed in cancers. It has been shown to interact with tumor suppressor protein-p53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells. In the present study, we found that, unlike most of the cancer cells, HepG2 hepatoma lacked mortalin–p53 interaction. We demonstrate that the mortalin–p53 interaction exists in cancer cells that are either physiologically stressed (frequently associated with p53 mutations) or treated with stress-inducing chemicals. Targeting mortalin–p53 interaction with either mortalin small hairpin RNA or a chemical or peptide inhibitor could induce p53-mediated tumor cell-specific apoptosis in hepatocellular carcinoma; p53-null hepatoma or normal hepatocytes remain unaffected.
doi:10.1038/cdd.2010.177
PMCID: PMC3131943  PMID: 21233847
stress; mortalin–p53 interaction; cancer; target; therapy
The British Journal of Radiology  2011;84(1002):518-525.
Objective
Klebsiella pneumoniae is one of the organisms most commonly isolated from pyogenic liver abscesses in Asian populations. We compared CT findings in liver abscesses caused by K. pneumoniae with those caused by other bacterial pathogens.
Methods
Of 214 patients with liver abscesses examined over a 5 year period, 129 patients with positive blood or aspirate cultures were enrolled. The patients were divided into two groups: the K. pneumoniae monomicrobial liver abscess (KLA) group (n = 59) and the non-K. pneumoniae monomicrobial or polymicrobial liver abscess (non-KLA) group (n = 70). Two radiologists blinded to the culture results evaluated the CT images, recording the number, size, location and configuration of abscesses, the thickness of the abscess wall, the pattern of rim enhancement, septal enhancement, the double target sign, internal necrotic debris, internal gas bubbles and underlying biliary disease. The presence of diabetes and metastatic infection was also compared between groups. Statistical analyses were performed using univariate (Student's t-test and χ2 test) and multivariate analyses.
Results
Multivariate analysis showed that a thin wall, necrotic debris, metastatic infection and the absence of underlying biliary disease were the most significant predictors of KLA. When three of the four criteria were used in combination, a specificity of 98.6% was achieved for the diagnosis of KLA.
Conclusion
A thin-walled abscess, internal necrotic debris, the presence of metastatic infection and the absence of underlying biliary disease may be useful CT findings in the early diagnosis of K. pneumoniae liver abscesses.
doi:10.1259/bjr/23004588
PMCID: PMC3473636  PMID: 21081584
Cell  2011;147(3):577-589.
Summary
BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, while expression of the erythroid regulator GATA1 directs SMAD1 loss on non-erythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity.
doi:10.1016/j.cell.2011.09.044
PMCID: PMC3219441  PMID: 22036566
Cell  2011;144(2):296-309.
While many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly co-expressed genes, some of which are restricted to a single lineage, but most are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.
doi:10.1016/j.cell.2011.01.004
PMCID: PMC3049864  PMID: 21241896
Diabetologia  2011;55(4):981-995.
Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2370-7
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
Journal of Oncology Practice  2011;7(3 Suppl):60s-61s.
doi:10.1200/JOP.2011.000309
PMCID: PMC3092453  PMID: 21886521
Background
Diastolic dysfunction of the right ventricle (RV) is common after repair of tetralogy of Fallot. While restrictive physiology in late diastole has been well known, dysfunction in early diastole has not been described. The present study sought to assess the prevalence and mechanism of early diastolic dysfunction of the RV defined as delayed onset of the tricuspid valve (TV) flow after TOF repair.
Methods
The study population consisted of 31 children with repaired TOF (mean age ± SD, 12.3 ± 4.1 years) who underwent postoperative cardiovascular magnetic resonance (CMR). The CMR protocol included simultaneous phase-contrast velocity mapping of the atrioventricular valves, which enabled direct comparison of the timing and patterns of tricuspid (TV) and mitral (MV) valve flow. The TV flow was defined to have delayed onset when its onset was > 20 ms later than the onset of the MV flow. The TV and MV flow from 14 normal children was used for comparison. The CMR results were correlated with the findings on echocardiography and electrocardiography.
Result
Delayed onset of the TV flow was observed in 16/31 patients and in none of the controls. The mean delay time was 64.81 ± 27.07 ms (8.7 ± 3.2% of R-R interval). The delay time correlated with the differences in duration of the TV and MV flow (55.94 ± 32.88 ms) (r = 0.90, p < 0.001). Delayed onset was associated with prolongation of the RV ejection time in 9 and delayed onset and cessation of the pulmonary arterial flow in 4. Delayed onset was not associated with timing changes in the pulmonary artery in 3. The patients with delayed onset showed reduced RV ejection fraction (p = 0.01). However, the two groups did not show significant differences in TV E/A ratio, ventricular end-diastolic volumes, left ventricular ejection fraction, pulmonary regurgitant fraction, heart rate, PR interval and QRS duration.
Conclusions
Early diastolic dysfunction with delayed onset of TV flow is common after TOF repair, and is associated with reduced RV ejection fraction. It is a further manifestation of interventricular dyssynchrony and represent an additional mechanism of ventricular diastolic dysfunction.
doi:10.1186/1532-429X-13-43
PMCID: PMC3173350  PMID: 21864332
tetralogy of Fallot; delayed onset of tricuspid valve flow; phase-contrast magnetic resonance; right ventricular function; diastolic dysfunction
mBio  2011;2(1):e00342-10.
Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.
IMPORTANCE
Isolates of Cryptococcus gattii are currently causing an outbreak of cryptococcosis in western North America, and most of the cases occurred in the absence of coinfection with HIV. This pattern is therefore in stark contrast to the current global burden of one million annual cases of cryptococcosis, caused by the related species Cryptococcus neoformans, in the HIV/AIDS population. The genome sequences of two outbreak-associated major genotypes of C. gattii reported here provide insights into genome variation within and between cryptococcal species. These sequences also provide a resource to further evaluate the epidemiology of cryptococcal disease and to evaluate the role of pathogen genes in the differential interactions of C. gattii and C. neoformans with immunocompromised and immunocompetent hosts.
doi:10.1128/mBio.00342-10
PMCID: PMC3037005  PMID: 21304167
Journal of geophysical research  2006;111(C11003):1-46.
[1] Independent data from the Gulf of Mexico are used to develop and test the hypothesis that the same sequence of physical and ecological events each year allows the toxic dinoflagellate Karenia brevis to become dominant. A phosphorus-rich nutrient supply initiates phytoplankton succession, once deposition events of Saharan iron-rich dust allow Trichodesmium blooms to utilize ubiquitous dissolved nitrogen gas within otherwise nitrogen-poor sea water. They and the co-occurring K. brevis are positioned within the bottom Ekman layers, as a consequence of their similar diel vertical migration patterns on the middle shelf. Upon onshore upwelling of these near-bottom seed populations to CDOM-rich surface waters of coastal regions, light-inhibition of the small red tide of ~1 ug chl l–1 of ichthytoxic K. brevis is alleviated. Thence, dead fish serve as a supplementary nutrient source, yielding large, self-shaded red tides of ~10 ug chl l–1. The source of phosphorus is mainly of fossil origin off west Florida, where past nutrient additions from the eutrophied Lake Okeechobee had minimal impact. In contrast, the P-sources are of mainly anthropogenic origin off Texas, since both the nutrient loadings of Mississippi River and the spatial extent of the downstream red tides have increased over the last 100 years. During the past century and particularly within the last decade, previously cryptic Karenia spp. have caused toxic red tides in similar coastal habitats of other western boundary currents off Japan, China, New Zealand, Australia, and South Africa, downstream of the Gobi, Simpson, Great Western, and Kalahari Deserts, in a global response to both desertification and eutrophication.
doi:10.1029/2004JC002813
PMCID: PMC2856968  PMID: 20411040

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