International Journal on Cloud Computing: Services and Architecture, 2013
With the arrival of cloud technology, game accessibility and ubiquity have a bright future; Games... more With the arrival of cloud technology, game accessibility and ubiquity have a bright future; Games can be hosted in a centralize server and accessed through the Internet by a thin client on a wide variety of devices with modest capabilities: cloud gaming. However, current cloud gaming systems have very strong requirements in terms of network resources, thus reducing the accessibility and ubiquity of cloud games, because devices with little bandwidth and people located in area with limited and unstable network connectivity, cannot take advantage of these cloud services. In this paper we present an adaptation technique inspired by the level of detail (LoD) approach in 3D graphics. It delivers multiple platform accessibility and network adaptability, while improving user's quality of experience (QoE) by reducing the impact of poor and unstable network parameters (delay, packet loss, jitter) on game interactivity. We validate our approach using a prototype game in a controlled environment and characterize the user QoE in a pilot experiment. The results show that the proposed framework provides a significant QoE enhancement.
2013 International Conference on Cloud Computing and Big Data, 2013
Current cloud gaming systems have very strong requirements in terms of network resources. For per... more Current cloud gaming systems have very strong requirements in terms of network resources. For pervasive gaming in various environments like at home, hotels, internet cafes, or area with limited or unstable network access, it is beneficial to avoid the necessity of having a costly steady fast speed internet connection to be able to run these cloud games. We present a network aware adaptation technique based on the level of detail (LoD) approach in 3D graphics. It maintains a bidirectional multi-level quality of service for game entities at runtime, lessening the game's communication cost when it notices a decrease in network resources and maintains an optimal communication frequency otherwise. It therefore reduces the impact of poor and unstable network parameters (delay, packet loss, jitter) on game interactivity while improving user's quality of experience (QoE). The evaluation of our approach through a pilot experiment shows that the proposed technique provides a significant QoE enhancement.
PAEDIATRICS AND CHILD HEALTH 17:10 41 wheeze produced less VEGF (P < 0.01). Similar results we... more PAEDIATRICS AND CHILD HEALTH 17:10 41 wheeze produced less VEGF (P < 0.01). Similar results were found for cytokine-stimulated AECs. There were no significant differences in AEC cytokine release between children with atopic asthma and those with virus-induced wheeze. There was a non-significant trend towards atopic asthmatic AECs having a larger cytokine response to stimulation than normal AECs. There was no association between AEC cytokine release and age. Conclusions: An in vitro model of respiratory epithelium, suitable for functional studies, can be established from nasal brushings from children. There are intrinsic differences in the AECs from children with a history of wheeze compared with healthy controls. This may reflect a defect in cytokine production by asthmatic AECs in vivo or an altered state of differentiation of cultured asthmatic AECs compared with normal AECs. This study suggests that the airway epithelium is implicated in the pathogenesis of childhood wheezing, and further investigation is warranted.
AZA or 6-MP had been stopped in 36 patients (30 due to the recommendations and 6 due to intoleran... more AZA or 6-MP had been stopped in 36 patients (30 due to the recommendations and 6 due to intolerance). The withdrawal did not affect the disease activity in 25 patients whereas in 9 the activity had increased moderately, in 2 significantly. Only one of 36 patients had restarted AZA while 7 patients had been started on methotrexate. Conclusion: The recommendations to withdraw AZA and 6-MP had very little negative effect on the disease activity. The guidelines for the usage of IFX in paediatric patients were implemented to a high degree.
To assess the contribution of the 113 G--&amp;amp;gt;A missense mutation within the discs, la... more To assess the contribution of the 113 G--&amp;amp;gt;A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland. Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent). TDT analysis demonstrated a significant association with IBD (P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (&amp;amp;gt;75th centile vs &amp;amp;lt;75th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn&amp;amp;#39;s disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A (P = .001, OR = 6.92 [2.24-21.33]). DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.
Journal of Pediatric Gastroenterology and Nutrition, 2009
To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease p... more To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease phenotype in patients with inflammatory bowel disease (IBD). A total of 301 Scottish patients with early-onset IBD-197 Crohn disease (CD), 76 ulcerative colitis (UC), 28 indeterminate colitis (IC)-and 78 healthy control individuals were studied. ASCA status (IgA, IgG) was determined by enzyme-linked immunosorbent assay. ASCA status was then analyzed in relation to CD phenotype. Patients with CD had a higher prevalence of ASCA than patients with UC and healthy controls: 82/197 versus 12/76, odds ratio (OR) 3.80 (1.93-7.50) and 82/197 versus 6/78, OR 8.56 (3.55-20.62), respectively. Univariate analysis showed that positive ASCA status was associated with oral CD (17/25 vs 59/153, OR 3.39 [1.38-8.34]), perianal CD (39/77 vs 38/108, OR 1.89 [1.04-3.44]) and the presence of granulomata (63/132 vs 15/52, OR 2.25 [1.13-4.48]) and also with markers of disease severity: raised C-reactive protein (44/90 vs 12/49, OR 2.95[1.36-6.37]), hypoalbuminemia (44/85 vs 20/74, OR 2.28[1.19-4.37]), and surgery (27/49 vs 54/147, OR 2.11 [1.10-4.06]). From multivariate analysis, the presence of oral disease (adjusted P = 0.001, OR 22.22 [3.41-142.86]) and hypoalbuminemia (adjusted P = 0.01, OR 4.78 [1.40-16.39]) was found to be independently associated with ASCA status. No association was demonstrated between ASCA and IBD candidate genes. Patients with CD had a higher prevalence of ASCA than did other patients with IBD. ASCA status described patients with CD who had a specific phenotype, showing an association with markers of disease severity and oral CD involvement.
Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility ... more Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohn's disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood-onset CD in the high-incidence Scottish population. Methods: In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis Ͻ17 years), their parents (n ϭ 634), 855 adult IBD patients, and 345 controls were genotyped. Case-control analysis was powered to detect effect sizes with an odds ratio (OR) Ͼ1.39 in pediatric CD. Case-control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z-scores, Kruskal-Wallis test (age at diagnosis), and multifactorial genotype-phenotype analysis (Montreal classification) were performed. 7.8% of pedi-atric CD patients and 37.2% of adult CD patients had pure ileal disease. Results: We confirmed the association of the rs2241880G-allele with adult-onset CD (60.7% versus controls 53.9%, P ϭ 0.01, OR 1.32, 95% confidence interval [CI] 1.07-1.63) in contrast to childhood-onset CD (54.1% versus controls, P ϭ 0.95, OR 1.01, 95% CI 0.80-1.26). TDT analysis was negative. Genotype-phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G-allele (P ϭ 0.02, OR 1.34, 95% CI 1.03-1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P ϭ 0.03, OR 2.43, 95% CI 1.05-5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z-scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype. Conclusions: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. These contrasting effects are primarily driven by differences in disease location between early-onset and adult-onset disease.
Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The ... more Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4ϩ32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4ϩ32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4ϩ32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P Ͼ 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. Conclusions: This variant allele of NOD1/CARD4ϩ32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.
Background: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy.... more Background: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy. Filaggrin (FLG) loss-of-function variants (null-alleles) are associated with eczema and asthma in association with eczema. The aim was to assess the contribution of FLG null-alleles to pediatric IBD susceptibility and to coexistent atopy (eczema, asthma, allergic rhinitis, or food allergy). Methods: FLG variants (R501X and 2282del4) were genotyped in 403 children with IBD, 683 parents, and 996 population controls. Results: In all, 11% of IBD patients carried at least 1 FLG nullallele compared to 11% of population controls (P > 0.4). Carriage of 1 or more null-alleles in patients with atopy (present in 52% of IBD patients) differed from IBD patients without atopy (14% versus 6%, P ¼ 0.01; odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-5.1). The effect of FLG null-alleles was strongest for eczema (19% versus 7%, P ¼ 0.0003; OR 3.3, 95% CI 1.7-6.6) and food allergy (28% versus 8%, P ¼ 0.0001; OR 4.5, 95% CI 2.0-10.0). The presence of more than 1 atopic disease tended to increase the associated OR: eczema þ asthma (23% versus 7%, P ¼ 0.001; OR 3.9, 95% CI 1.6-9.1), eczema þ asthma þ allergic rhinitis (29% versus 7%, P ¼ 0.0006; OR 5.4, 95% CI 1.9-15.4) and eczema þ asthma þ allergic rhinitis þ food allergy (45% versus 6%, P < 10 À4 ; OR 12.2, 95% CI 3.2-46.3). Logistic regression analysis of IBD cases confirmed the association of carriage of an FLG null-allele with atopy (P ¼ 0.01; OR 2.4, 95% CI 1.2-5.1) and co-occurrence of different forms of atopy (P ¼ 0.003; OR 3.5, 95% CI 1.5-8.1). Conclusions: Filaggrin null-alleles have no effect on IBD susceptibility but contribute to coexistent eczema and food allergy.
Gaslrostomy tube placement has become a common procedure in children with neurodevelopmental dela... more Gaslrostomy tube placement has become a common procedure in children with neurodevelopmental delay and swallowing disorders. We report a spectrum of gastric mucosal injury from inflatable type G-tubes (1GT) in four children. The ages were 1.5-9 yrs (mean 4.5), weight 10-26 kg (mean 15). All had neurodevelopmental delay and the G-tube was placed surgically with Nissen fandoplication. These patients (4) had a Button| type G-tube and this was replaced with IGT for ease of insertion/removal. The presenting symptoms were upper GI bleeding (4) and retching and gagging (3) which occurred 1-3 month after the IGT was put in. The endoscopic findings show n below were seen in the distal body of the stomach just opposite to the tip of the Gtube.
Page 1. Stereochemical congruence of Baeyer-Villigerases ~ David R. Kelly,*&quot; Christopher... more Page 1. Stereochemical congruence of Baeyer-Villigerases ~ David R. Kelly,*&quot; Christopher J. Knowles,b Jassem G. Mahdi,&quot; Michael A. Wright,b Ian N. Taylor,b Stanley M. Roberts,c Peter WH Wan,c Gideon Grogan,d Sandrine Pedragosa-Moreaud and Andrew J. Willettsd ...
Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chron... more Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chronic lymphocytic leukaemia (CLL) cells, but the molecular mechanisms that underpin this observation have not been fully elucidated. Here, we have analysed the effect two novel aspirin analogues, 2-hydroxy benzoate zinc (2HBZ) and 4-hydroxy benzoate zinc (4HBZ), on primary CLL samples. Cytotoxic effects of 2HBZ and 4HBZ were analysed in primary CLL cells derived from 52 patients, and normal B- and T-lymphocytes. Mechanisms of action of these agents were also elucidated. Both analogues induced apoptosis in a dose-dependent and time-dependent manner. Apoptosis was associated with activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor (Z-LEHD.fmk). Importantly, both agents demonstrated preferential cytotoxicity in CLL cells when compared to normal B- and T-lymphocytes. In terms of their molecular mechanisms of action, 4HBZ and 2HBZ inhibited COX-2 transcription and protein expression and this was associated with upstream inhibition of transcription factor Rel A. Co-culture of CLL cells with CD40 ligand-expressing mouse fibroblasts significantly increased COX-2 expression and inhibited spontaneous apoptosis. Importantly, the most potent analogue, 4HBZ, overcame pro-survival effects of the co-culture system and significantly repressed COX-2. Finally, elevated COX-2 expression was associated with poor prognostic subsets and increased sensitivity to 4HBZ. Our results demonstrate therapeutic potential of 4HBZ and are consistent with a mechanism involving suppression of Rel A nuclear translocation and inhibition of COX-2 transcription.
... When Bax and Whitmore carried out their studies this was probably true, but with greater soph... more ... When Bax and Whitmore carried out their studies this was probably true, but with greater sophistication of diagnosis and management ... ROSEMARY JONES FIONA FINLAY VIV CROUCH SUE ANDERSON Bath & West Community NHS Trust, Bath NHS House, Child Health ...
International Journal on Cloud Computing: Services and Architecture, 2013
With the arrival of cloud technology, game accessibility and ubiquity have a bright future; Games... more With the arrival of cloud technology, game accessibility and ubiquity have a bright future; Games can be hosted in a centralize server and accessed through the Internet by a thin client on a wide variety of devices with modest capabilities: cloud gaming. However, current cloud gaming systems have very strong requirements in terms of network resources, thus reducing the accessibility and ubiquity of cloud games, because devices with little bandwidth and people located in area with limited and unstable network connectivity, cannot take advantage of these cloud services. In this paper we present an adaptation technique inspired by the level of detail (LoD) approach in 3D graphics. It delivers multiple platform accessibility and network adaptability, while improving user's quality of experience (QoE) by reducing the impact of poor and unstable network parameters (delay, packet loss, jitter) on game interactivity. We validate our approach using a prototype game in a controlled environment and characterize the user QoE in a pilot experiment. The results show that the proposed framework provides a significant QoE enhancement.
2013 International Conference on Cloud Computing and Big Data, 2013
Current cloud gaming systems have very strong requirements in terms of network resources. For per... more Current cloud gaming systems have very strong requirements in terms of network resources. For pervasive gaming in various environments like at home, hotels, internet cafes, or area with limited or unstable network access, it is beneficial to avoid the necessity of having a costly steady fast speed internet connection to be able to run these cloud games. We present a network aware adaptation technique based on the level of detail (LoD) approach in 3D graphics. It maintains a bidirectional multi-level quality of service for game entities at runtime, lessening the game's communication cost when it notices a decrease in network resources and maintains an optimal communication frequency otherwise. It therefore reduces the impact of poor and unstable network parameters (delay, packet loss, jitter) on game interactivity while improving user's quality of experience (QoE). The evaluation of our approach through a pilot experiment shows that the proposed technique provides a significant QoE enhancement.
PAEDIATRICS AND CHILD HEALTH 17:10 41 wheeze produced less VEGF (P < 0.01). Similar results we... more PAEDIATRICS AND CHILD HEALTH 17:10 41 wheeze produced less VEGF (P < 0.01). Similar results were found for cytokine-stimulated AECs. There were no significant differences in AEC cytokine release between children with atopic asthma and those with virus-induced wheeze. There was a non-significant trend towards atopic asthmatic AECs having a larger cytokine response to stimulation than normal AECs. There was no association between AEC cytokine release and age. Conclusions: An in vitro model of respiratory epithelium, suitable for functional studies, can be established from nasal brushings from children. There are intrinsic differences in the AECs from children with a history of wheeze compared with healthy controls. This may reflect a defect in cytokine production by asthmatic AECs in vivo or an altered state of differentiation of cultured asthmatic AECs compared with normal AECs. This study suggests that the airway epithelium is implicated in the pathogenesis of childhood wheezing, and further investigation is warranted.
AZA or 6-MP had been stopped in 36 patients (30 due to the recommendations and 6 due to intoleran... more AZA or 6-MP had been stopped in 36 patients (30 due to the recommendations and 6 due to intolerance). The withdrawal did not affect the disease activity in 25 patients whereas in 9 the activity had increased moderately, in 2 significantly. Only one of 36 patients had restarted AZA while 7 patients had been started on methotrexate. Conclusion: The recommendations to withdraw AZA and 6-MP had very little negative effect on the disease activity. The guidelines for the usage of IFX in paediatric patients were implemented to a high degree.
To assess the contribution of the 113 G--&amp;amp;gt;A missense mutation within the discs, la... more To assess the contribution of the 113 G--&amp;amp;gt;A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland. Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent). TDT analysis demonstrated a significant association with IBD (P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (&amp;amp;gt;75th centile vs &amp;amp;lt;75th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn&amp;amp;#39;s disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A (P = .001, OR = 6.92 [2.24-21.33]). DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.
Journal of Pediatric Gastroenterology and Nutrition, 2009
To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease p... more To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease phenotype in patients with inflammatory bowel disease (IBD). A total of 301 Scottish patients with early-onset IBD-197 Crohn disease (CD), 76 ulcerative colitis (UC), 28 indeterminate colitis (IC)-and 78 healthy control individuals were studied. ASCA status (IgA, IgG) was determined by enzyme-linked immunosorbent assay. ASCA status was then analyzed in relation to CD phenotype. Patients with CD had a higher prevalence of ASCA than patients with UC and healthy controls: 82/197 versus 12/76, odds ratio (OR) 3.80 (1.93-7.50) and 82/197 versus 6/78, OR 8.56 (3.55-20.62), respectively. Univariate analysis showed that positive ASCA status was associated with oral CD (17/25 vs 59/153, OR 3.39 [1.38-8.34]), perianal CD (39/77 vs 38/108, OR 1.89 [1.04-3.44]) and the presence of granulomata (63/132 vs 15/52, OR 2.25 [1.13-4.48]) and also with markers of disease severity: raised C-reactive protein (44/90 vs 12/49, OR 2.95[1.36-6.37]), hypoalbuminemia (44/85 vs 20/74, OR 2.28[1.19-4.37]), and surgery (27/49 vs 54/147, OR 2.11 [1.10-4.06]). From multivariate analysis, the presence of oral disease (adjusted P = 0.001, OR 22.22 [3.41-142.86]) and hypoalbuminemia (adjusted P = 0.01, OR 4.78 [1.40-16.39]) was found to be independently associated with ASCA status. No association was demonstrated between ASCA and IBD candidate genes. Patients with CD had a higher prevalence of ASCA than did other patients with IBD. ASCA status described patients with CD who had a specific phenotype, showing an association with markers of disease severity and oral CD involvement.
Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility ... more Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohn's disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood-onset CD in the high-incidence Scottish population. Methods: In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis Ͻ17 years), their parents (n ϭ 634), 855 adult IBD patients, and 345 controls were genotyped. Case-control analysis was powered to detect effect sizes with an odds ratio (OR) Ͼ1.39 in pediatric CD. Case-control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z-scores, Kruskal-Wallis test (age at diagnosis), and multifactorial genotype-phenotype analysis (Montreal classification) were performed. 7.8% of pedi-atric CD patients and 37.2% of adult CD patients had pure ileal disease. Results: We confirmed the association of the rs2241880G-allele with adult-onset CD (60.7% versus controls 53.9%, P ϭ 0.01, OR 1.32, 95% confidence interval [CI] 1.07-1.63) in contrast to childhood-onset CD (54.1% versus controls, P ϭ 0.95, OR 1.01, 95% CI 0.80-1.26). TDT analysis was negative. Genotype-phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G-allele (P ϭ 0.02, OR 1.34, 95% CI 1.03-1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P ϭ 0.03, OR 2.43, 95% CI 1.05-5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z-scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype. Conclusions: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. These contrasting effects are primarily driven by differences in disease location between early-onset and adult-onset disease.
Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The ... more Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4ϩ32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4ϩ32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4ϩ32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P Ͼ 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. Conclusions: This variant allele of NOD1/CARD4ϩ32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.
Background: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy.... more Background: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy. Filaggrin (FLG) loss-of-function variants (null-alleles) are associated with eczema and asthma in association with eczema. The aim was to assess the contribution of FLG null-alleles to pediatric IBD susceptibility and to coexistent atopy (eczema, asthma, allergic rhinitis, or food allergy). Methods: FLG variants (R501X and 2282del4) were genotyped in 403 children with IBD, 683 parents, and 996 population controls. Results: In all, 11% of IBD patients carried at least 1 FLG nullallele compared to 11% of population controls (P > 0.4). Carriage of 1 or more null-alleles in patients with atopy (present in 52% of IBD patients) differed from IBD patients without atopy (14% versus 6%, P ¼ 0.01; odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-5.1). The effect of FLG null-alleles was strongest for eczema (19% versus 7%, P ¼ 0.0003; OR 3.3, 95% CI 1.7-6.6) and food allergy (28% versus 8%, P ¼ 0.0001; OR 4.5, 95% CI 2.0-10.0). The presence of more than 1 atopic disease tended to increase the associated OR: eczema þ asthma (23% versus 7%, P ¼ 0.001; OR 3.9, 95% CI 1.6-9.1), eczema þ asthma þ allergic rhinitis (29% versus 7%, P ¼ 0.0006; OR 5.4, 95% CI 1.9-15.4) and eczema þ asthma þ allergic rhinitis þ food allergy (45% versus 6%, P < 10 À4 ; OR 12.2, 95% CI 3.2-46.3). Logistic regression analysis of IBD cases confirmed the association of carriage of an FLG null-allele with atopy (P ¼ 0.01; OR 2.4, 95% CI 1.2-5.1) and co-occurrence of different forms of atopy (P ¼ 0.003; OR 3.5, 95% CI 1.5-8.1). Conclusions: Filaggrin null-alleles have no effect on IBD susceptibility but contribute to coexistent eczema and food allergy.
Gaslrostomy tube placement has become a common procedure in children with neurodevelopmental dela... more Gaslrostomy tube placement has become a common procedure in children with neurodevelopmental delay and swallowing disorders. We report a spectrum of gastric mucosal injury from inflatable type G-tubes (1GT) in four children. The ages were 1.5-9 yrs (mean 4.5), weight 10-26 kg (mean 15). All had neurodevelopmental delay and the G-tube was placed surgically with Nissen fandoplication. These patients (4) had a Button| type G-tube and this was replaced with IGT for ease of insertion/removal. The presenting symptoms were upper GI bleeding (4) and retching and gagging (3) which occurred 1-3 month after the IGT was put in. The endoscopic findings show n below were seen in the distal body of the stomach just opposite to the tip of the Gtube.
Page 1. Stereochemical congruence of Baeyer-Villigerases ~ David R. Kelly,*&quot; Christopher... more Page 1. Stereochemical congruence of Baeyer-Villigerases ~ David R. Kelly,*&quot; Christopher J. Knowles,b Jassem G. Mahdi,&quot; Michael A. Wright,b Ian N. Taylor,b Stanley M. Roberts,c Peter WH Wan,c Gideon Grogan,d Sandrine Pedragosa-Moreaud and Andrew J. Willettsd ...
Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chron... more Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chronic lymphocytic leukaemia (CLL) cells, but the molecular mechanisms that underpin this observation have not been fully elucidated. Here, we have analysed the effect two novel aspirin analogues, 2-hydroxy benzoate zinc (2HBZ) and 4-hydroxy benzoate zinc (4HBZ), on primary CLL samples. Cytotoxic effects of 2HBZ and 4HBZ were analysed in primary CLL cells derived from 52 patients, and normal B- and T-lymphocytes. Mechanisms of action of these agents were also elucidated. Both analogues induced apoptosis in a dose-dependent and time-dependent manner. Apoptosis was associated with activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor (Z-LEHD.fmk). Importantly, both agents demonstrated preferential cytotoxicity in CLL cells when compared to normal B- and T-lymphocytes. In terms of their molecular mechanisms of action, 4HBZ and 2HBZ inhibited COX-2 transcription and protein expression and this was associated with upstream inhibition of transcription factor Rel A. Co-culture of CLL cells with CD40 ligand-expressing mouse fibroblasts significantly increased COX-2 expression and inhibited spontaneous apoptosis. Importantly, the most potent analogue, 4HBZ, overcame pro-survival effects of the co-culture system and significantly repressed COX-2. Finally, elevated COX-2 expression was associated with poor prognostic subsets and increased sensitivity to 4HBZ. Our results demonstrate therapeutic potential of 4HBZ and are consistent with a mechanism involving suppression of Rel A nuclear translocation and inhibition of COX-2 transcription.
... When Bax and Whitmore carried out their studies this was probably true, but with greater soph... more ... When Bax and Whitmore carried out their studies this was probably true, but with greater sophistication of diagnosis and management ... ROSEMARY JONES FIONA FINLAY VIV CROUCH SUE ANDERSON Bath & West Community NHS Trust, Bath NHS House, Child Health ...
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