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1.  NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma 
Oncogene  2015;34(39):5069-5079.
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
doi:10.1038/onc.2014.429
PMCID: PMC4802362  PMID: 25579177
2.  EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment† 
Annals of Oncology  2014;26(2):407-414.
This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.
Background
Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response.
Patients and methods
Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m2, doxorubicin 75 mg/m2, methotrexate 12 g/m2 × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken.
Results
Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3–4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen.
Conclusions
New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future.
The trial is registered as NCT00134030 and ISRCTN 67613327.
doi:10.1093/annonc/mdu526
PMCID: PMC4304379  PMID: 25421877
osteosarcoma; randomised controlled trial; trial conduct; international collaboration
3.  Protective skin care behaviors in cancer survivors 
Current Oncology  2014;21(4):e531-e540.
Purpose
Research suggests that physicians neglect preventive care for cancer survivors. A survivor’s self-motivation with respect to preventive care is unknown. Using protective skin care as a proxy, our aims were to characterize preventive care in cancer survivors and to identify factors associated with appropriate prevention.
Methods
Using data from the 2009 U.S. Health Information National Trends Survey, we compared preventive skin care patterns in cancer survivors and non-cancer patients. Primary endpoints were the use of sunscreens, long-sleeved shirts, hats, and shade.
Results
We identified 179 early cancer survivors (<5 years), 242 intermediate cancer survivors (5–10 years), 412 long-term cancer survivors (>10 years), and 5951 non-cancer patients. The use of sunscreens (60%), long-sleeved shirts (88%), hats (58%), and shade (68%) was suboptimal. Overall, cancer survivors were not more likely to adhere to preventive care (p = 0.89). A composite score showed a significant difference between the cancer survivor groups (p < 0.01) whereby intermediate survivors reported the best preventive practices.
Conclusions
A prior diagnosis of cancer does not appear to increase personal compliance with cancer prevention. Reasons for this poor engagement are not clear. Targeted strategies to increase self-motivation might improve preventive practices in cancer survivors.
doi:10.3747/co.21.1893
PMCID: PMC4117620  PMID: 25089104
Cancer survivors; skin; sun; prevention; protection
4.  Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca2+ Signaling in Spines 
The Journal of Neuroscience  2014;34(3):869-879.
The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca2+ permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca2+ signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca2+ permeation and Ca2+ signaling in spines. Activation of β-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca2+ permeation, synaptic currents, and Ca2+ rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca2+ signaling at synapses and regulated by the emotional response to stress.
doi:10.1523/JNEUROSCI.4538-13.2014
PMCID: PMC3891964  PMID: 24431445
5.  Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222 
British Journal of Cancer  2013;108(10):2178-2185.
Background:
Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma.
Methods:
To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.
Results:
The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10−24, minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.
Conclusion:
Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3′-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.
doi:10.1038/bjc.2013.155
PMCID: PMC3670481  PMID: 23571737
inherited susceptibility; glioma; risk
6.  Differential Gender And Species Specific Formation Of Aneurysms Using A Novel Method Of Inducing Abdominal Aortic Aneurysms 
The Journal of surgical research  2012;178(2):1038-1045.
Background
The objective of this study was to test a novel model of inducing AAA in different mouse strains and genders.
Materials and Methods
Male and female C57BL/6 and B6129 mice (N=5 per group) underwent peri-aortic dissection and porcine pancreatic elastase (30μl) or inactivated elastase application (5 min) to aorta. Aortic measurements were taken on day 0 and 14. Aortic samples were analyzed for histology, and zymography for MMP activity. Comparison statistics performed using unpaired t-test.
Results
AAA phenotype (50% aortic increase), occurred in external elastase treated males (100%) and females (90%). No control animals developed AAAs. The aortic diameter was larger in C57BL/6 and B6129 elastase treated versus control males (p=0.0028 and p=<0.0001, respectively) and females (p<0.0001 and p=0.0458, respectively). Histology verified phenotype via disrupted internal elastic laminae. Macrophage counts in elastase treated animals were >6 fold higher than in controls (all groups significant). MMP9 activity was greater in elastase treated males and females in C57BL/6 (p=0.0031, p=0.0004) and B6129 (p=0.025, p=0.2) mice; MMP2 activity was greater in C57BL/6 vs. B6129 ME.
Conclusions
This rodent model produced AAAs in both genders and strains of mice. This model is simple, has little variability, and occurs in the infrarenal aorta, substantiating the external elastase model for future studies.
doi:10.1016/j.jss.2012.04.073
PMCID: PMC3442138  PMID: 22651981
7.  Activity-dependent regulation of inhibition via GAD67 
The Journal of Neuroscience  2012;32(25):8521-8531.
Alterations in network activity trigger compensatory changes in excitation and inhibition that restore neuronal firing rate to an optimal range. One example of such synaptic homeostasis is the downregulation of inhibitory transmission by chronic inactivity, in part, through the reduction of vesicular transmitter content. The enzyme glutamic acid decarboxylase 67 (GAD67) is critical for GABA synthesis, but its involvement in homeostatic plasticity is unclear. We explored the role of GAD67 in activity-dependent synaptic plasticity using a mouse line (Gad1−/−) in which GAD67 expression is disrupted by genomic insertion of the green fluorescent protein (GFP). Homozygous deletion of Gad1 significantly reduced miniature inhibitory postsynaptic current (mIPSC) amplitudes and GABA levels in cultured hippocampal neurons. The fractional block of mIPSC amplitude by a low affinity, competitive GABAA receptor antagonist was higher in GAD67-lacking neurons, suggesting that GABA concentration in the synaptic cleft is lower in knockout animals. Chronic suppression of activity by the application of tetrodotoxin (TTX) reduced mIPSC amplitudes and the levels of GAD67 and GABA. Moreover, TTX reduced GFP levels in interneurons, suggesting that GAD67 gene expression is a key regulatory target of activity. These in vitro experiments were corroborated by in vivo studies in which olfactory deprivation reduced mIPSC amplitudes and GFP levels in glomerular neurons in the olfactory bulb. Importantly, TTX-induced downregulation of mIPSC was attenuated in Gad1−/− neurons. Altogether, these findings indicate that activity-driven expression of GAD67 critically controls GABA synthesis and, thus, vesicular filling of the transmitter.
doi:10.1523/JNEUROSCI.1245-12.2012
PMCID: PMC3388776  PMID: 22723692
8.  Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity 
Biochemical Society transactions  2009;37(Pt 6):1369-1374.
NMDARs (N-methyl-d-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca2+ influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca2+ signalling in dendritic spines is not static, but can be remodelled in a cell- and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca2+ permeability of neuronal NMDARs, NMDAR-mediated Ca2+ signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral–CA1 synapses are under control of the cAMP/PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca2+ influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca2+ signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.
doi:10.1042/BST0371369
PMCID: PMC3501105  PMID: 19909278
calcium; N-methyl-d-aspartate receptor (NMDAR); protein kinase; signalling; synaptic plasticity
9.  SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking 
The Journal of Neuroscience  2010;30(1):242-254.
Protein kinase C (PKC) enhances NMDA receptor (NMDAR) channel opening rate and promotes NMDAR delivery to the cell surface via SNARE-dependent exocytosis. Although the mechanisms of PKC potentiation are established, the molecular target of PKC is unclear. Here we show that synaptosomal-associated protein of 25 kDa (SNAP-25), a SNARE protein, is functionally relevant to PKC-dependent NMDAR insertion and identify serine residue-187 as the molecular target of PKC phosphorylation. Constitutively active PKC delivered via the patch pipette potentiated NMDA (but not AMPA) whole-cell currents in hippocampal neurons. Expression of RNAi targeting SNAP-25 or mutant SNAP-25(S187A) and/or acute disruption of the SNARE complex by treatment with BoNT A, BoNT B or SNAP-25 C-terminal blocking peptide abolished NMDAR potentiation. A SNAP-25 peptide and function-blocking antibody suppressed PKC potentiation of NMDA EPSCs at mossy fiber-CA3 synapses. These findings identify SNAP-25 as the target of PKC phosphorylation critical to PKC-dependent incorporation of synaptic NMDARs and document a postsynaptic action of this major SNARE protein relevant to synaptic plasticity.
doi:10.1523/JNEUROSCI.4933-08.2010
PMCID: PMC3397691  PMID: 20053906
Synaptic plasticity; ion channels; synaptic transmission; exocytosis; phosphorylation; trafficking
10.  A Novel Approach to Assess Oral Feeding Skills of Preterm Infants 
Neonatology  2011;100(1):64-70.
Background
There is no well-defined means to identify the level of oral feeding skills (OFS) in preterm infants.
Objective
To determine whether OFS as reflected by the combination of proficiency (PRO, %ml taken during the first 5 min/ml prescribed) and rate of milk transfer (RT, ml/min) correlates with gestational age (GA), oral feeding performance (OT, %ml taken during a feeding/ml prescribed) and days from start to independent oral feeding (SOF-IOF). Our working premises are that PRO is reflective of infants’ actual feeding skills when fatigue is minimal and RT, monitored over an entire feeding session, reflects their overall skills when fatigue comes into play.
Methods
Infants (26–36 weeks GA) with prematurity as their principal diagnosis were recruited and monitored at their first oral feeding. GA was divided into 3 strata, 26–29, 30–33, and 34–36 weeks GA. OFS was divided into 4 levels delineated by PRO (≥ or <30%) and RT (≥ or <1.5 ml/min). ANOVA with post-hoc Bonferroni and multiple regression analyses were used.
Results
OFS levels were correlated with GA. OT, PRO, and days from SOF-IOF were associated with OFS and GA, whereas RT was only correlated with OFS levels.
Conclusions
OFS is a novel objective indicator of infants’ feeding ability that takes into account infants’ skills and endurance. As a clinical tool, it can help caretakers monitor infants’ skills as they transition to oral feeding and identify oral feeding issues arising from immature skills and/or poor endurance.
doi:10.1159/000321987
PMCID: PMC3023010  PMID: 21212698
Very low birth weight; Bottle feeding; Prematurity; Oral feeding evaluation
11.  Quantification of the healthy worker effect: a nationwide cohort study among electricians in Denmark 
BMC Public Health  2011;11:571.
Background
The healthy worker effect (HWE) is a well-known phenomenon. In this study we used the extensive registration of all Danish citizens to describe the magnitude of HWE among all Danish electricians and evaluated strategies for minimizing HWE bias of the association between occupation and mortality.
Methods
All Danish male citizens aged 26-56 years in the period 1984-1992 were followed for three years in several registers. We evaluated HWE bias among electricians because they were unexposed to detrimental occupational exposures. We compared electricians to three reference groups (general population, construction industry and carpenters/brick layers) and utilized analytical methods for minimizing HWE bias (lag time analyses, age-stratified analyses, marginal structural model and restriction to employed, newly employed or long-term workers).
Results
The mortality rate was higher among electricians, who the year following active employment received incapacity benefits or were on long-term sick leave. Electricians receiving incapacity benefits, on long-term sick leave, unemployed, or with increased comorbidity index had lower odds of re-employment. Electricians had lower mortality rate (rate ratio,0.60;95%CI,0.52-0.69) compared to the general population, while electricians leaving employment had increased mortality (1.90;1.50-2.40). Adjusting for several social events slightly attenuated the estimates, while the marginal structural model did not minimize bias. Electricians had the same mortality as the construction industry and carpenters/brick layers. Mortality was comparable to the general population after three or more years of lag time.
Conclusions
In this nationwide study, employment as electricians had marked effect on mortality. Appropriate reference selection and lag time analyses minimized the HWE bias.
doi:10.1186/1471-2458-11-571
PMCID: PMC3154868  PMID: 21767353
12.  Severe plaque prolapse after stenting a lesion with large areas of necrotic core 
BMJ Case Reports  2009;2009:bcr2006104190.
doi:10.1136/bcr.2006.104190
PMCID: PMC3105836  PMID: 21687188
intravascular ultrasonography; virtual histology; vulnerable plaque
13.  The preterm piglet – a model in the study of oesophageal development in preterm neonates 
Rasch S, Sangild PT, Gregersen H., Schmidt M., Omari T, Lau C. The Preterm Piglet – an Animal Model for the Oesophageal Maturation in Preterm Neonates. Acta Paediatr ...... Stockholm. ISSN ......
Aim
Preterm infants have difficulty attaining independent oral feeding. This can ensue from inadequate sucking, swallowing, and/or respiration. In impeding bolus transport, immature oesophageal motility may also be a cause. As studies on the development of oesophageal motility are invasive in preterm infants, the preterm piglet was investigated as a potential research model.
Methods
Oesophageal motility (EM) of term (n=6) and preterm (n=15) piglets were monitored by manometry for 10 min immediately following bottle feeding on days 1-2 and 3-4 of life.
Results
Piglets’ oral feeding performance and EM were similar to those of their human counterparts. Term piglets readily completed their feeding whereas their preterm counterparts did not. They also presented with greater peristaltic activity and propagating velocity. Peristaltic activity remained unchanged over time in preterm piglets, but an increase in synchronous and decrease in incomplete motor activity were noted. Preterm piglets that developed symptoms analogous to necrotizing enterocolitis (NEC) demonstrated uncharacteristic oesophageal activity.
Conclusion
Immature EM may cause oral feeding difficulties. NEC-like symptoms may adversely affect EM. The piglet is a valid research model for studying human infant oral feeding and oesophageal development.
doi:10.1111/j.1651-2227.2009.01564.x
PMCID: PMC2848287  PMID: 19878132
oral feeding; prematurity; oesophageal motility
14.  Severe plaque prolapse after stenting a lesion with large areas of necrotic core 
Heart  2007;93(11):1350.
doi:10.1136/hrt.2006.104190
PMCID: PMC2016932  PMID: 17933990
intravascular ultrasonography; virtual histology; vulnerable plaque
15.  SNAP-25 Is a Target of Protein Kinase C Phosphorylation Critical to NMDA Receptor Trafficking 
The Journal of Neuroscience  2010;30(1):242-254.
Protein kinase C (PKC) enhances NMDA receptor (NMDAR)-mediated currents and promotes NMDAR delivery to the cell surface via SNARE-dependent exocytosis. Although the mechanisms of PKC potentiation are established, the molecular target of PKC is unclear. Here we show that synaptosomal-associated protein of 25 kDa (SNAP-25), a SNARE protein, is functionally relevant to PKC-dependent NMDAR insertion, and identify serine residue-187 as the molecular target of PKC phosphorylation. Constitutively active PKC delivered via the patch pipette potentiated NMDA (but not AMPA) whole-cell currents in hippocampal neurons. Expression of RNAi targeting SNAP-25 or mutant SNAP-25(S187A) and/or acute disruption of the SNARE complex by treatment with BoNT A, BoNT B or SNAP-25 C-terminal blocking peptide abolished NMDAR potentiation. A SNAP-25 peptide and function-blocking antibody suppressed PKC potentiation of NMDA EPSCs at mossy fiber-CA3 synapses. These findings identify SNAP-25 as the target of PKC phosphorylation critical to PKC-dependent incorporation of synaptic NMDARs and document a postsynaptic action of this major SNARE protein relevant to synaptic plasticity.
doi:10.1523/JNEUROSCI.4933-08.2010
PMCID: PMC3397691  PMID: 20053906
16.  Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese 
Genes and Immunity  2009;10(5):414-420.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 × 10−9; TNFSF4, rs844648, OR=1.22, P=2.47 × 10−3; TNFSF4, rs2205960, OR=1.30, P=2.41 × 10−4). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 × 10−3). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 × 10−8, respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 × 10−3), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.
doi:10.1038/gene.2009.16
PMCID: PMC2834352  PMID: 19357697
SLE; BANK1; TNFSF4; Chinese; genetic association
18.  Raloxifene protects endothelial cell function against oxidative stress 
British Journal of Pharmacology  2008;155(3):326-334.
Background and purpose:
Maintaining a delicate balance between the generation of nitric oxide (NO) and removal of reactive oxygen species (ROS) within the vascular wall is crucial to the physiological regulation of vascular tone. Increased production of ROS reduces the effect and/or bioavailability of NO, leading to an impaired endothelial function. This study tested the hypothesis that raloxifene, a selective oestrogen receptor modulator, can prevent endothelial dysfunction under oxidative stress.
Experimental approach:
Changes in isometric tension were measured in rat aortic rings. The content of cyclic GMP in aortic tissue was determined by radioimmunoassay. Phosphorylation of endothelial NOS (eNOS) and Akt was assayed by Western blot analysis.
Key results:
In rings with endothelium, ACh-induced relaxations were attenuated by a ROS-generating reaction (hypoxanthine plus xanthine oxidase, HXXO). The impaired relaxations were ameliorated by acute treatment with raloxifene. HXXO suppressed the ACh-stimulated increase in cyclic GMP levels; this effect was antagonized by raloxifene. The improved endothelial function by raloxifene was abolished by ICI 182,780, and by wortmannin or LY294002. Raloxifene also protected endothelial cell function against H2O2. Raloxifene increased the phosphorylation of eNOS at Ser-1177 and Akt at Ser-473; this effect was blocked by ICI 182,780. Finally, raloxifene was not directly involved in scavenging ROS, and neither inhibited the activity of xanthine oxidase nor stimulated that of superoxide dismutase.
Conclusion and implications:
Raloxifene is effective against oxidative stress-induced endothelial dysfunction in vitro through an ICI 182,780-sensitive mechanism that involves the increased phosphorylation and activity of Akt and eNOS in rat aortae.
doi:10.1038/bjp.2008.262
PMCID: PMC2567878  PMID: 18574454
raloxifene; nitric oxide; reactive oxygen species; endothelial dysfunction
19.  The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels 
British Journal of Pharmacology  2008;155(3):365-373.
Background and purpose:
Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels.
Experimental approach:
Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes.
Key results:
Ketanserin blocked hERG current (IhERG) in a concentration-dependent manner (IC50=0.11 μM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 μM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K+ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC50s of 0.84±0.2 and 1.7±0.4 μM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2–59 fold) by ketanserin.
Conclusions and implications:
These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin.
doi:10.1038/bjp.2008.261
PMCID: PMC2567890  PMID: 18574455
ketanserin; human ether-à-go-go-related gene (hERG) potassium channels; open channel block; long QTs
20.  Triage rapid initial assessment by doctor (TRIAD) improves waiting time and processing time of the emergency department 
Emergency Medicine Journal : EMJ  2006;23(4):262-265.
Aim
To evaluate the effect of triage rapid initial assessment by doctor (TRIAD) on waiting time and processing time of an emergency department (ED) without extra staff.
Method
A senior emergency doctor was put into triage instead of a consultation cubicle for seven shifts of 9 hours each. All the patients were assessed and necessary interventions started at the time of triage. Waiting time and processing time of various categories of patients were compared with a control group that was sampled during the week before the trial period.
Results
In total, there were 1310 cases in the trial period and 1355 controls. Over a quarter (27%) of the patients received triage doctor interventions. The average waiting time was reduced by 38% and the average processing time by 23%. Patients without triage intervention also had a 24% shorter waiting time because of overall improvement in efficiency. Trauma patients and patients needing radiography particularly benefited from the new system. The waiting time and processing time of category 4 and 5 patients improved significantly as a result of more efficient processing of more urgent cases.
Conclusion
The waiting time and processing time of the ED were greatly reduced by TRIAD without extra manpower.
doi:10.1136/emj.2005.025254
PMCID: PMC2579496  PMID: 16549569
triage; waiting time; processing time
21.  Heparan sulphate synthetic and editing enzymes in ovarian cancer 
British Journal of Cancer  2007;96(10):1544-1548.
Several angiogenic growth factors including fibroblast growth factors 1 and 2 (FGF1 and FGF2) depend on heparan sulphate (HS) for biological activity. We previously showed that all cellular elements in ovarian tumour tissue synthesised HS but biologically active HS (i.e. HS capable of binding FGF2 and its receptor) was confined to ovarian tumour endothelium. In this study, we have sought to explain this observation. Heparan sulphate sulphotransferases 1 and 2 (HS6ST1 and HS6ST2) attach sulphate groups to C-6 of glucosamine residues in HS that are critical for FGF2 activation. These enzymes were strongly expressed by tumour cells, but only HS6ST1 was found in endothelial cells. Immunostaining with the 3G10 antibody of tissue sections pretreated with heparinases indicated that HS proteoglycans were produced by tumour and endothelial cells. These results indicated that, in contrast to the endothelium, HS produced by tumour cells may be modified by cell-surface heparanase (HPA1) or endosulphatase (SULF). Protein and RNA analysis revealed that HPA1 was strongly expressed by ovarian tumour cells in eight of ten specimens examined. HSULF-1, which removes specific 6-O-sulphate groups from HS, was abundant in tumour cells but weakly expressed in the endothelium. If this enzyme was responsible for the lack of biologically active HS on the tumour cell surface, we would expect exogenous FGF2 binding to be preserved; we showed previously that this was indeed the case although FGF2 binding was reduced compared to the endothelium and stroma. Thus, the combined effects of heparanase and HSULF could account for the lack of biologically active HS in tumour cells rather than deficiencies in the biosynthetic enzymes.
doi:10.1038/sj.bjc.6603747
PMCID: PMC2359940  PMID: 17437011
ovarian cancer; HS; FGF; heparanase; HSULF-1
22.  Effects of magnesium on atrial fibrillation after cardiac surgery: a meta-analysis 
Heart  2005;91(5):618-623.
Objectives: To assess the efficacy of the administration of magnesium as a method for the prevention of postoperative atrial fibrillation (AF) and to evaluate its influence on hospital length of stay (LOS) and mortality.
Methods: Literature search and meta-analysis of the randomised control studies published since 1966.
Results: 20 randomised trials were identified, enrolling a total of 2490 patients. Study sample size varied between 20 and 400 patients. Magnesium administration decreased the proportion of patients developing postoperative AF from 28% in the control group to 18% in the treatment group (odds ratio 0.54, 95% confidence interval (CI) 0.38 to 0.75). Data on LOS were available from seven trials (1227 patients). Magnesium did not significantly affect LOS (weighted mean difference −0.07 days of stay, 95% CI −0.66 to 0.53). The overall mortality was low (0.7%) and was not affected by magnesium administration (odds ratio 1.22, 95% CI 0.39 to 3.77).
Conclusion: Magnesium administration is an effective prophylactic measure for the prevention of postoperative AF. It does not significantly alter LOS or in-hospital mortality.
doi:10.1136/hrt.2004.033811
PMCID: PMC1768903  PMID: 15831645
magnesium; atrial fibrillation; surgery
23.  Maturation of oral feeding skills in preterm infants 
Aim
Safe and successful oral feeding requires proper maturation of sucking, swallowing and respiration. We hypothesized that oral feeding difficulties result from different temporal development of the musculatures implicated in these functions.
Methods
Sixteen medically stable preterm infants (26 to 29 weeks gestation, GA) were recruited. Specific feeding skills were monitored as indirect markers for the maturational process of oral feeding musculatures: rate of milk intake (mL/min); percent milk leakage (lip seal); sucking stage, rate (#/s) and suction/expression ratio; suction amplitude (mmHg), rate and slope (mmHg/s); sucking/swallowing ratio; percent occurrence of swallows at specific phases of respiration. Coefficients of variation (COV) were used as indices of functional stability. Infants, born at 26/27- and 28/29-week GA, were at similar postmenstrual ages (PMA) when taking 1–2 and 6–8 oral feedings per day.
Results
Over time, feeding efficiency and several skills improved, some decreased and others remained unchanged. Differences in COVs between the two GA groups demonstrated that, despite similar oral feeding outcomes, maturation levels of certain skills differed.
Conclusions
Components of sucking, swallowing, respiration and their coordinated activity matured at different times and rates. Differences in functional stability of particular outcomes confirm that maturation levels depend on infants’ gestational rather than PMA.
doi:10.1111/j.1651-2227.2007.00548.x
PMCID: PMC2289993  PMID: 18052999
Bottle feeding; Prematurity; Sucking skills; Suck-swallow-respiration; Swallowing skills; Very low birth weight
24.  Ethnic/racial diversity, maternal stress, lactation and very low birthweight infants 
Objective
(1) To compare maternal characteristics and psychological stress profile among African-American, Caucasian and Hispanic mothers who delivered very low birthweight infants. (2) To investigate associations between psychosocial factors, frequency of milk expression, skin-to-skin holding (STS), and lactation performance, defined as maternal drive to express milk and milk volume.
Study Design
Self-reported psychological questionnaires were given every 2 weeks after delivery over 10 weeks. Milk expression frequency, STS, and socioeconomic variables were collected.
Result
Infant birthweight, education, and milk expression frequency differed between groups. Trait anxiety, depression and parental stress in a neonatal intensive care unit (PSS:NICU) were similar. African-American and Caucasian mothers reported the lowest scores in state anxiety and social desirability, respectively. Maternal drive to express milk, measured by maintenance of milk expression, correlated negatively with parental role alteration (subset of PSS:NICU) and positively with infant birthweight and STS. Milk volume correlated negatively with depression and positively with milk expression frequency and STS.
Conclusion
Differences between groups were observed for certain psychosocial factors. The response bias to self-reported questionnaires between groups may not provide an accurate profile of maternal psychosocial profile. With different factors correlating with maintenance of milk expression and milk volume, lactation performance can be best enhanced with a multi-faceted intervention program, incorporating parental involvement in infant care, close awareness and management of maternal mental health, and encouragement for frequent milk expression and STS.
doi:10.1038/sj.jp.7211770
PMCID: PMC2282065  PMID: 17592486
prematurity; milk expression; milk production; maternal stress; depression; anxiety; social desirability
25.  Recurrent acute heart failure caused by sliding hiatus hernia 
Siu, C | Jim, M | Ho, H | Chu, F | Chan, H | Lau, C | Tse, H
Postgraduate Medical Journal  2005;81(954):268-269.
The case is reported of a 75 year old woman who presented with recurrent nocturnal episodes of acute pulmonary oedema. The cause was uncertain as she had normal cardiothoracic ratio on chest radiography and normal left ventricular systolic and diastolic function by transthoracic echocardiogram. Another transthoracic echocardiogram was repeated when she was recumbent for an hour and had a full stomach. It showed a striking finding of severe left atrial compression by an external structure. Computed tomography of the thorax showed an intrathoracic mass behind the left atrium causing external compression of the left atrium suggestive of a sliding hiatus hernia. Cardiac catheterisation confirmed the diagnosis by showing a pronounced rise of pulmonary capillary wedge pressure in the recumbent position compared with the sitting up position.
doi:10.1136/pgmj.2004.023416
PMCID: PMC1743244  PMID: 15811895

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