text:
- Research article
- Open Access
Matrix metalloproteinase-3 promoter polymorphisms but not dupA-H. pylori correlate to duodenal ulcers in H. pylori-infected females
© Yeh et al; licensee BioMed Central Ltd. 2010
- Received: 24 March 2010
- Accepted: 13 August 2010
- Published: 13 August 2010
This study investigated if the H. pylori dupA genotype and certain host single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), including MMP-3, MMP-7, MMP-9, TIMP-1 and TIMP-2, might correlate with ulcer risk of H. pylori- infected Taiwanese patients.
Of the 549 H. pylori- infected patients enrolled, 470 patients (265 with gastritis, 118 with duodenal ulcer, and 87 with gastric ulcer) received SNPs analysis of MMP-3-1612 6A > 5A, MMP-7-181 A > G, MMP-9exon 6 A > G, TIMP-1372 T > C and TIMP-2-418 G > C by PCR-RFLP. The 181 collected H. pylori isolates were detected for the dupA genotype by PCR. The rates of dupA-positive H. pylori infection were similar among patients with duodenal ulcer (22.8%), gastric ulcer (20.0%), and gastritis (25.5%) (p > 0.05). Males had higher rates of duodenal ulcer and gastric ulcer than females (p < 0.01). Of H. pylori-infected patients, the MMP-3 6A6A genotype were more common in patients with duodenal ulcers than in those with gastritis (87.7% vs. 74.9%, p < 0.05) in females. This genotype had a 2.4-fold (95% CI: 1.02-5.66) increased risk of duodenal ulcer, compared to those with the 5A carrier. Combining the MMP-3/TIMP-1 genotype as 6A6A/CC, the risk of duodenal ulcer increased up to 3.6 fold (p < 0.05) in H. pylori- infected females.
The MMP-3 promoter polymorphism, but not the dupA-status, may correlate with susceptibility to duodenal ulcer after H. pylori infection in Taiwanese females.
- Gastritis
- Duodenal Ulcer
- Gastric Ulcer
- Pylorus Infection
- CagA
Helicobacter pylori infection leads to chronic gastritis and in some individuals, to peptic ulcer disease or even gastric carcinoma [1]. Diverse outcomes may depend on complex interactions among bacterial virulence factors, host genetics, and environmental factors [2, 3]. In Taiwan, despite the nearly 100% prevalence of the so-called triple-genopositive cagA-vacA-babA2 virulent H. pylori infections, there is a lack of correlation to different disease outcomes [4, 5]. It will be useful for Taiwan to validate new virulence factors or any host genomic predisposition in relation to severe H. pylori-infected clinical outcomes.
Recently, a duodenal ulcer-promoting gene A (dupA) encompassing jhp0917 and jhp0918 has been suggested to lead into higher IL-8 production of epithelial cells and thus, triggering dense neutrophil infiltration and increased risk of duodenal ulcers 2[6]. However, even in such large-scale validation, those with duodenal ulcer have a nearly 55% dupA-positive infection [6]. Moreover, prevalence of dupA and relationships between dupA- positive H. pylori and clinical outcomes are different in distinct populations [7–11]. It may indicate that dupA serves a promoting role leading to duodenal ulcer after H. pylori infection. Alternatively, it is necessary to validate host factors that predispose patients to gastroduodenal ulcer, especially with dupA-negative infection.
H. pylori infection stimulates the production of pro-inflammatory cytokines, such as IL-1, which play important roles in gastric inflammation and physiology. However, IL-1 beta or IL-1RN polymorphisms are not associated with gastric ulcer in the Taiwanese population [12].
Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most extracellular matrix and correlate with ulcer formation or repairs [13]. H. pylori infection can up-regulate MMP-3, MMP-7, and MMP-9 in the gastric mucosa and even sera [14–16]. A large-scale German survey has further validated that the single-nucleotide polymorphisms (SNP) genotype as MMP-7-181 G allele and MMP-9exon 6 A allele increase the risk of gastric ulcer after H. pylori infection [17]. A deletion at MMP-3 promoter -1612, and A to G substitution at MMP-7 promoter -181 may affect transcriptional activity, leading to alterations in gene expression [18, 19]. Moreover, A to G substitution at MMP-9 exon 6 causes the amino acid change required for binding to its substrate and affects its binding ability [20].
Although MMP activity is in general counteracted by endogenous tissue inhibitors (TIMPs) [21], there remains no data to check whether TIMP-1 and TIMP-2 SNP genotypes relate to the risk of gastroduodenal ulcer after H. pylori-infection. As such, this study surveyed if the H. pylori dupA genotype and certain SNP genotypes of MMP-3, MMP-7, MMP-9, TIMP-1, and TIMP-2 predispose H. pylori-infected Taiwanese patients to ulcer risks.
Patients and study design
Five hundred and forty-nine consecutive H. pylori- infected patients documented by upper gastrointestinal endoscopy at National Cheng Kung University Medical Center, Tainan, Taiwan were enrolled. All were genetically unrelated ethnic Han Chinese from Tainan City and the surrounding regions. None had been treated with NSAIDs, proton pump inhibitor, or any antibiotics within two weeks prior to panendoscopy on enrollment, or a past history of anti-H. pylori treatment and peptic ulcer. The hospital Ethics Committee approved the study.
After obtaining informed consent, 470 patients had provided enough blood samplings for SNPs analysis of MMP-3-1612 6A > 5A, MMP-7-181 A > G, MMP-9exon 6 A > G, TIMP-1372 T > C and TIMP-2-418 G > C by PCR-RFLP. Aside from endoscopic diagnosis for clinical diseases, at least three topographic gastric biopsies were sampled for histology or H. pylori culture, one each from the antrum, corpus, and cardia. These were stained with haematoxylin and eosin and reviewed for the H. pylori-related histology by the updated Sydney's system [4, 22, 23].
In addition, the study collected 181 H. pylori isolates for the detection of dupA genotype by PCR. One hundred and three isolates were collected from randomly selected patients who had agreed to undergo SNP analysis, while 78 isolates were from patients without SNP analysis. The H. pylori culture were conducted from the two additional gastric biopsies collected during the same endoscopy and processed with the method applied in previous publications [4, 22].
For those with positive H. pylori culture, the isolates were extracted for genomic DNA to be analyzed for the dupA genotypes by PCR. The extraction of DNA was done with the same method as described previously [4, 22]. Positive H. pylori infection was defined by positive histology or culture.
Genotypes of SNPs in MMPs and TIMPs
Peripheral blood 8 ml was obtained from each subject for genomic DNA, which was extracted from peripheral blood mononuclear cells according to the manufacturer's instructions (Viogene, Taipei, Taiwan). Five SNPs in MMP-3-1612 5A/6A, MMP-7-181 A/G, MMP-9exon 6 A/G, TIMP-1372 C/T, and TIMP-2-418 G/C polymorphisms were determined by PCR-RFLP assays [18, 24–26].
The PCR primers used in the study
Primer sequence (5' →3')
Size (bp)
Restriction enzyme
Xmn I
Shibata et al, 2005
6A: 120 bp
5A: 97 bp + 23 bp
EcoR I
Jormsjö et al, 2001
A: 150 bp
G: 120 bp + 30 bp
MMP-9 exon6 A/G
Sma I
Shibata et al, 2005 *
A: 295 bp
G: 192 bp + 103 bp
Wollmer et al, 2002
T: 175 bp
C: 152 bp + 23 bp
Zhou et al, 2004
C: 253 bp + 51 bp
G: 230 bp + 51 bp + 23 bp
jhp0917 _1
Lu et al., 2005
jhp0917 _2
jhp0917 _3
This study *
jhp0917 _4
jhp0918 _1
Lu et al.,
jhp0918 _2
jhp0918 _3
This study *
jhp0918 _4
Quality control for genotyping was achieved by including in each amplification a negative PCR control sample and three positive control samples for each SNP analyzed (homozygous for allele 1, heterozygous, and homozygous for allele 2). At least 10% of the samples were run twice in separate assays to reveal 100% concordance of the genotype designation for all of the polymorphisms. For the positive controls, the genopositive products were confirmed by direct sequencing.
Detection of dupA gene by PCR
Statistical analysis
Statistical analysis was performed with the SPSS software (SPSS 12, Chicago, IL, USA). The χ2 test, Fisher's exact test or Mann-Whitney U test were used as appropriate to validate the dupA prevalence rates, histological severity, or SNP genotypes of MMPs and TIMPs between patients with and those without ulcers. A p < 0.05 was taken as significant. All test significances were validated by two-tailed analysis. The odds ratios (OR) and 95% confidence intervals (CI) were used to estimate the risk to get gastroduodenal ulcer in these H. pylori-infected subjects.
Demographic features of the study subjects
Demographic and histologic characteristics of H. pylori-infected patients with single nucleotide polymorphism analysis (n = 470)
Duodenal ulcer
Gastric ulcer
p value
(n = 265)
(n = 118)
(n = 87)
Age, mean (SD) (yr)
46.9 (13.7)
47.6 (14.0)
47.8 (11.7)
Gender, n (%)
Female: Male
183 (69.1): 82 (30.9)
57 (48.3) : 61 (51.7)
36 (41.4) : 51 (58.6)
p a < 0.05; p b < 0.05
Histology score, mean (SD)
AIS (range 1-3)
1.18 (0.99)
1.39 (0.95)
0.99 (1.03)
p c < 0.05
CIS (range 0-3)
2.34 (1.01)
2.56 (0.89)
2.05 (1.17)
p a < 0.05; p b < 0.05; p c < 0.05
AIS (range 1-3)
0.85 (0.99)
0.72 (0.95)
0.86 (1.06)
CIS (range 0-3)
2.24 (0.86)
2.15 (0.83)
2.13 (0.89)
Prevalence of dupA H. pylori infection in patients
MMP and TIMP genotypes and the H. pylori-related gastro-duodenal ulcer
The SNP genotypes of MMPs and TIMPs in the both genders with different clinical diagnoses
P a
P b
P a
P b
5A carrier
46 (25.1)
7 (12.3)
8 (22.2)
28 (34.1)
15 (24.6)
11 (21.6)
137 (74.9)
50 (87.7)
28 (77.8)
54 (65.9)
46 (75.4)
40 (78.4)
150 (82.9)
45 (80.4)
32 (91.4)
72 (88.9)
52 (86.7)
39 (76.5)
G carrier
31 (17.1)
11 (19.6)
3 (8.6)
9 (11.1)
8 (13.3)
12 (23.5)
A carrier
78 (42.6)
19 (33.3)
15 (41.7)
25 (30.5)
22 (36.1)
22 (43.1)
105 (57.4)
38 (66.7)
21 (58.3)
57 (69.5)
39 (63.9)
29 (56.9)
♀ T carrier
148 (80.9)
41 (73.2)
29 (80.6)
46 (56.8)
31 (50.8)
26 (51.0)
35 (19.1)
15 (26.8)
7 (19.4)
35 (43.2)
30 (49.2)
25 (49.0)
C carrier
54 (30.2)
17 (32.1)
10 (28.6)
27 (33.3)
20 (32.3)
13 (25.5)
125 (69.8)
36 (67.9)
25 (71.4)
54 (66.7)
42 (67.7)
38 (74.5)
Risks of combined MMP-3/TIMP-1 genotype for developing duodenal ulcer in females
Duodenal ulcer
n (%)
n (%)
5A carrier - T carrier
39 (88.6)
5 (11.4)
5A carrier - C/C
7 (77.8)
2 (22.2)
2.23 (0.36 - 13.85)
6A/6A - T carrier
109 (75.2)
36 (24.8)
2.58 (0.94 - 7.03)
28 (68.3)
13 (31.7)
3.62 (1.16 - 11.32)
This study surveyed whether the bacterial factor dupA in H. pylori or single nucleotide polymorphisms of MMPs and TIMPs correlated with the susceptibility of gastroduodenal ulcers after H. pylori infection. It shows a rather low prevalence (23.8%) of dupA-positive H. pylori infection in Taiwan. Moreover, such a low prevalence limits its association to susceptibility to gastroduodenal ulcers after H. pylori infection.
The negative finding is consistent with several studies worldwide [8, 10, 11] but differs from Lu et al., who support the promoting role of H. pylori dupA [6]. In their positive report [6], dupA-positive prevalence is nearly 50% and it can be attributed as the promoting role of ulceration. Their data suggest that there should be some other bacterial virulence factor of H. pylori as CagA, babA2, vacA, or host factors, which determine the susceptibility of ulceration. In Taiwan, there is nearly a 100% prevalence of CagA, babA2, vacA triple-positive infection [4, 15]. The current study area should be a good place to validate the host factor predisposing to ulcer risk.
In the in vitro promoter functional assay of fibroblasts and vascular smooth muscle cells, the MMP-3 -1612 as 5A allele has greater promoter activities than the 6A allele [19]. This implies that patients carrying the lower promoter activity genotype 6A6A in the MMP-3 promoter are accompanied by lower MMP-3 expressions of the gastric mucosa. This study discloses the host genotype MMP-3 -1612 as 6A6A, which expresses lower MMP-3 carries a 2.4-fold risk of having duodenal ulcers among females after H. pylori infection (p < 0.05) (Table 3). Moreover, TIMP-1 372, as CC, contributes a higher risk of duodenal ulcers to MMP-3 -1612 6A6A (Table 4). This data suggests that patients with higher MMP-3 expression may have lower ulcer risk, but the reasons remain uncertain.
In general, MMP-3 can degrade a wide range of substrates, including fibronectin, type IV, V, IX, and X collagens, elastin, laminins, gelatin, and proteoglycan core proteins, and is thus helpful during wound healing of the skin [27–29]. Moreover, the gastric mucosa at the ulcer site also has significantly higher expression of MMP-3 than those in the antrum [30], which suggests MMP-3 is abundant in the ulcer part, and this may help the process of re-epithelialization and contribute to wound healing.
Hellmig et al. disclose the positive associations of MMP-7 promoter -181 and MMP-9 exon 6 SNPs to the presence of gastric ulcer among Germans [17]. However, this may be due to distinct ethnic or racial variations and such positive linkage is not disclosed in the current study from Taiwan.
This is the first report to show that there is no direct association between the genotypes of TIMP-1 372 at exon 5 and TIMP-2 at promoter -418, and the presence of gastroduodenal ulcers (Table 3). However, because TIMP-1 genotypes may modulate MMP-3 activity, further testing if the MMP-3-1612 /TIMP-1372 Combined genotypes contribute to increased risk of duodenal ulcers shows that the combined MMP-3/TIMP-1 genotype as 6A6A/CC has a 3.6-fold increased risk of duodenal ulcer (p < 0.05) in H. pylori- infected females. This data suggests that TIMP-1 may also have a supportive role in interacting with MMP-3 during ulcerogenesis by H. pylori infection, especially in females.
However, the exact reason why such a combined MMP-3/TIMP-1 genotype as 6A6A/CC has just an increased risk of duodenal ulcer in H. pylori- infected females, but not in male, remains uncertain. If such a regulation between MMP-3 and TIMP-1 play a role in female's ulceration, our data at least imply some other host or environment factors in male should be more dominant than such combined genotype.
The study has a limitation of just providing 181 isolates for the analysis of the dupA status of H. pylori, which disclose a rather low 20% dupA-positive prevalence rate. Accordingly, the study became limited to only 103 patients to provide both analyses on the infected isolate's dupA status and the host's SNPs (Figure 2). It thus cannot provide an adequate statistical power to determine the exact impact of MMP-3 SNPs under dupA-negative specific conditions.
In conclusion, this study provides evidence that host promoter polymorphisms of MMP-3 contribute to increased individual susceptibility to duodenal ulcers in females after H. pylori infection in Taiwan. The MMP-3 promoter genotypes may serve to screen out patients at risk and target for H. pylori eradication in order to stop the ulceration process among H. pylori-infected patients without ulcers yet.
This study was supported by grants from the National Science Council, Taiwan (95-2314-B-006-029-MY3 and 98-2628-B-006-013-MY3), NHRI-EX99-9908BI from the National Health Research Institute, and DOH99-TD-C-111-003 from Department of Health, Taiwan. The authors also thank Miss Hunt-Wen Wu for her assistance.
Authors' Affiliations
- Labigne A, de Reuse H: Determinants of Helicobacter pylori pathogenicity. Infect Agents Dis. 1996, 5 (4): 191-202.PubMedGoogle Scholar
- Maeda S, Mentis AF: Pathogenesis of Helicobacter pylori infection. Helicobacter. 2007, 12 (Suppl 1): 10-14. 10.1111/j.1523-5378.2007.00529.x.View ArticlePubMedGoogle Scholar
- Prinz C, Schwendy S, Voland P: H. pylori and gastric cancer: shifting the global burden. World J Gastroenterol. 2006, 12 (34): 5458-5464.PubMed CentralPubMedGoogle Scholar
- Sheu BS, Odenbreit S, Hung KH, Liu CP, Sheu SM, Yang HB, Wu JJ: Interaction between host gastric Sialyl-Lewis X and H. pylori SabA enhances H. pylori density in patients lacking gastric Lewis B antigen. Am J Gastroenterol. 2006, 101 (1): 36-44. 10.1111/j.1572-0241.2006.00358.x.View ArticlePubMedGoogle Scholar
- Lai CH, Kuo CH, Chen YC, Chao FY, Poon SK, Chang CS, Wang WC: High prevalence of cagA- and babA2-positive Helicobacter pylori clinical isolates in Taiwan. J Clin Microbiol. 2002, 40 (10): 3860-3862. 10.1128/JCM.40.10.3860-3862.2002.PubMed CentralView ArticlePubMedGoogle Scholar
- Lu H, Hsu PI, Graham DY, Yamaoka Y: Duodenal ulcer promoting gene of Helicobacter pylori. Gastroenterology. 2005, 128 (4): 833-848. 10.1053/j.gastro.2005.01.009.PubMed CentralView ArticlePubMedGoogle Scholar
- Schmidt HM, Andres S, Nilsson C, Kovach Z, Kaakoush NO, Engstrand L, Goh KL, Fock KM, Forman D, Mitchell H: The cag PAI is intact and functional but HP0521 varies significantly in Helicobacter pylori isolates from Malaysia and Singapore. Eur J Clin Microbiol Infect Dis. 2010, 29 (4): 439-451. 10.1007/s10096-010-0881-7.View ArticlePubMedGoogle Scholar
- Nguyen LT, Uchida T, Tsukamoto Y, Kuroda A, Okimoto T, Kodama M, Murakami K, Fujioka T, Moriyama M: Helicobacter pylori dupA gene is not associated with clinical outcomes in the Japanese population. Clin Microbiol Infect. 2010, 16 (8): 1264-1269. 10.1111/j.1469-0691.2009.03081.x.View ArticlePubMedGoogle Scholar
- Hussein NR: The association of dupA and Helicobacter pylori-related gastroduodenal diseases. Eur J Clin Microbiol Infect Dis. 2010, 29 (7): 817-821. 10.1007/s10096-010-0933-z.View ArticlePubMedGoogle Scholar
- Gomes LI, Rocha GA, Rocha AM, Soares TF, Oliveira CA, Bittencourt PF, Queiroz DM: Lack of association between Helicobacter pylori infection with dupA-positive strains and gastroduodenal diseases in Brazilian patients. Int J Med Microbiol. 2008, 298 (3-4): 223-230. 10.1016/j.ijmm.2007.05.006.View ArticlePubMedGoogle Scholar
- Argent RH, Burette A, Miendje Deyi VY, Atherton JC: The presence of dupA in Helicobacter pylori is not significantly associated with duodenal ulceration in Belgium, South Africa, China, or North America. Clin Infect Dis. 2007, 45 (9): 1204-1206. 10.1086/522177.View ArticlePubMedGoogle Scholar
- Chang YT, Wu MS, Shun CT, Lin MT, Chang MC, Lin JT: Association of polymorphisms of interleukin-1 beta gene and Helicobacter pylori infection with the risk of gastric ulcer. Hepatogastroenterology. 2002, 49 (47): 1474-1476.PubMedGoogle Scholar
- Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003, 92 (8): 827-839. 10.1161/01.RES.0000070112.80711.3D.View ArticlePubMedGoogle Scholar
- Yeh YC, Sheu BS, Cheng HC, Wang YL, Yang HB, Wu JJ: Elevated serum matrix metalloproteinase-3 and -7 in H. pylori-related gastric cancer can be biomarkers correlating with a poor survival. Dig Dis Sci. 2010, 55 (6): 1649-1657. 10.1007/s10620-009-0926-x.View ArticlePubMedGoogle Scholar
- Mori N, Sato H, Hayashibara T, Senba M, Geleziunas R, Wada A, Hirayama T, Yamamoto N: Helicobacter pylori induces matrix metalloproteinase-9 through activation of nuclear factor kappaB. Gastroenterology. 2003, 124 (4): 983-992. 10.1053/gast.2003.50152.View ArticlePubMedGoogle Scholar
- Crawford HC, Krishna US, Israel DA, Matrisian LM, Washington MK, Peek RM: Helicobacter pylori strain-selective induction of matrix metalloproteinase-7 in vitro and within gastric mucosa. Gastroenterology. 2003, 125 (4): 1125-1136. 10.1016/S0016-5085(03)01206-X.View ArticlePubMedGoogle Scholar
- Hellmig S, Ott S, Rosenstiel P, Robert Folsch U, Hampe J, Schreiber S: Genetic variants in matrix metalloproteinase genes are associated with development of gastric ulcer in H. pylori infection. Am J Gastroenterol. 2006, 101 (1): 29-35. 10.1111/j.1572-0241.2005.00348.x.View ArticlePubMedGoogle Scholar
- Jormsjo S, Whatling C, Walter DH, Zeiher AM, Hamsten A, Eriksson P: Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2001, 21 (11): 1834-1839. 10.1161/hq1101.098229.View ArticlePubMedGoogle Scholar
- Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM: Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996, 271 (22): 13055-13060. 10.1074/jbc.271.22.13244.View ArticlePubMedGoogle Scholar
- Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM: The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. J Biol Chem. 1996, 271 (8): 4335-4341. 10.1074/jbc.271.8.4335.View ArticlePubMedGoogle Scholar
- Clark IM, Swingler TE, Sampieri CL, Edwards DR: The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008, 40 (6-7): 1362-1378. 10.1016/j.biocel.2007.12.006.View ArticlePubMedGoogle Scholar
- Sheu BS, Sheu SM, Yang HB, Huang AH, Wu JJ: Host gastric Lewis expression determines the bacterial density of Helicobacter pylori in babA2 genopositive infection. Gut. 2003, 52 (7): 927-932. 10.1136/gut.52.7.927.PubMed CentralView ArticlePubMedGoogle Scholar
- Dixon MF, Genta RM, Yardley JH, Correa P: Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996, 20 (10): 1161-1181. 10.1097/00000478-199610000-00001.View ArticlePubMedGoogle Scholar
- Shibata N, Ohnuma T, Higashi S, Usui C, Ohkubo T, Kitajima A, Ueki A, Nagao M, Arai H: Genetic association between matrix metalloproteinase MMP-9 and MMP-3 polymorphisms and Japanese sporadic Alzheimer's disease. Neurobiol Aging. 2005, 26 (7): 1011-1014. 10.1016/j.neurobiolaging.2004.09.004.View ArticlePubMedGoogle Scholar
- Zhou Y, Yu C, Miao X, Tan W, Liang G, Xiong P, Sun T, Lin D: Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes. Carcinogenesis. 2004, 25 (3): 399-404. 10.1093/carcin/bgh020.View ArticlePubMedGoogle Scholar
- Wollmer MA, Papassotiropoulos A, Streffer JR, Grimaldi LM, Kapaki E, Salani G, Paraskevas GP, Maddalena A, de Quervain D, Bieber C: Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease. Psychiatr Genet. 2002, 12 (3): 155-160. 10.1097/00041444-200209000-00006.View ArticlePubMedGoogle Scholar
- Bullard KM, Mudgett J, Scheuenstuhl H, Hunt TK, Banda MJ: Stromelysin-1-deficient fibroblasts display impaired contraction in vitro. J Surg Res. 1999, 84 (1): 31-34. 10.1006/jsre.1999.5599.View ArticlePubMedGoogle Scholar
- Saarialho-Kere UK: Patterns of matrix metalloproteinase and TIMP expression in chronic ulcers. Arch Dermatol Res. 1998, 290 (Suppl): S47-54. 10.1007/PL00007453.View ArticlePubMedGoogle Scholar
- Madlener M: Differential expression of matrix metalloproteinases and their physiological inhibitors in acute murine skin wounds. Arch Dermatol Res. 1998, 290 (Suppl): S24-29. 10.1007/PL00007450.View ArticlePubMedGoogle Scholar
- Tomita M, Ando T, Minami M, Watanabe O, Ishiguro K, Hasegawa M, Miyake N, Kondo S, Kato T, Miyahara R: Potential role for matrix metalloproteinase-3 in gastric ulcer healing. Digestion. 2009, 79 (1): 23-29. 10.1159/000203637.View ArticlePubMedGoogle Scholar
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AlphaNinja - If the Nasdaq closes positive today, it will be 12days in a row...The longest streak since 1992. Nucking Futs.
The Dow Jones Industrial Avergae is above 9,000 this morning, after bottoming (not sayin' that was THE bottom...) at 6500ish in March. As I'll detail later today, even after this big run the index is not very expensive.
Thanks to Bristol-Myers' shall we say "aggresive" (I think a 90% premium to the previous close indicates they want to avoid a bidding war...) bid for Medarex (MEDX), top 10 gainers are beating losers by 42% -->>I've never seen such a disparity.
Thursday, July 23, 2009
Another big day for US stocks
Posted by Brendan Wagner at 9:02 AM
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I was greeted by the world's most wonderful news this morning. [CAPSLOCK] ROYCE IS OPENING IN MANILA! [/CAPSLOCK] Yes, that nyummy Japanese chocolate store that's made of all things fine, delectable and unforgettable will be here. To give us our Nama Chocolate fix! Anytime! *hyperventilates*
Scheduled to open in Rockwell this coming November, this Manila flagship store will carry their complete line of more than 20 products, including the Nama chocolates I'm absolutely crazy about and their Chocolate Potatochip.
They'll be accepting advance corporate and bulk orders just in time for Christmas starting October 10 so place your orders. Personally, I can't think of a better gift to receive.
For inquiries and reservations, email Royce at firstname.lastname@example.com.


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St John's (14th Farnworth) Cubs Closed in April 2017
St John's Cubs in the 2000's
Beavers, Cubs and Scouts 'Flower Festival' Display September 2001.
The 14th Farnworth (St John's) Beavers, Cubs and Scouts sponsored a floral arrangement, depicting the hymn 'O Jesus I Have Promised', at the church's Flower Festival celebrating the 175th birthday of St John's Church. The event was held from Friday 7th September to Sunday 9th September 2001.
St George's Day Service at St John's Church on Sunday 27th April 2014.
Beavers, Cubs and Scouts, from Bolton South with Farnworth District took part in the St George's Day Parade, which started at 2.00pm at the Cenotaph in Farnworth Park. They then paraded up Market Street, turning left onto Church Street, before being welcomed at St John Church. The service was conducted by Rev'd Carol Pharaoh and was attended by over 230 members of the Scout movement, friends and parents.
During the service Johnny Lewis, who has been involved in Scouting for over 70 years, was presented with the 'Silver Wolf,' the highest award in Scouting, by Colin Hilton. All the Beavers from the newly formed 12th Bolton (Rosehill) Beavers were invested.
Keith Entwistle - Leader in Charge
Thankyou to John Entwistle for the photos.
The 14th Farnworth (St John's) Beavers, Cubs and Scouts display at the 'Waterloo Open Weekend' held at St John's Church on Saturday 10th and Sunday 11th October 2015.
14th Farnworth (St John's) Scout Group
The Scout Group was very active during the year with eight Beavers, eight Cubs and five Scouts. We also had five leaders/helpers.
They were involved in a variety of activities such as map reading, knot work, cooking, crafts, first aid and a hike. However, as the year went on, numbers began to decrease and we lost leaders and helpers as well. We contacted several people who had expressed interest in joining the group but unfortunately this did not materialise.
After Christmas we were down to FIVE members with 1 leader and 1 helper. The District Commissioner was aware of our situation and came to discuss our plight. He reluctantly concluded that we would have to close the group, particularly as there was no 'back-up' committee in place.
It was with great sadness, that after so many years, 14th Farnworth (St John's) Scout Group would close and for the first time since 1954, there will be no scout group associated with St John's church.
Yours in Scouting,
Graham and Heather
Church Magazine May 2017
Our Cubs' History
We believeSt John's Cubs were originally formed in the 1930's
The 14th Farnworth (St John's) group met, to take part in the 1997 St Georges Day Parade, at Silcoms car park, which is at the junction of Albert Road/ Kildare Street. They then paraded up Albert Road before turning onto Longcauseway on their way to St Peter's church.
St John's Cubs in the 1990's
St John's Cubs in the 1980's
An article from the Bolton News – 18th August 2016
Click on the image below to be able to read the fullB.E.N. article
St John's Cubs in the 1940's
St John's Cubs in the 1930's
'Guard of Honour'
The cubs formed a 'Guard of Honour' outside St John's Church, at the marriage of Kitty Toms to Jim Tattersall, on 15th July 1939.
St John's cubs held their weekly meetings in Church House, situated in the front basement of the school, until the outbreak of the Second World War in September 1939 when they were disbanded. The cubs were re-formed in 1954, when Rev Philip Arthur Wrigley was appointed vicar, and registered as the 14th Farnworth (St John's) Cubs.
Photograph courtesy of Joan Hall (nee Tattersall)
St John's Cubs during a visit to Kearsley Park in the late 1930's.
This photograph was taken in the late 1930's, during a cub's excursion to Kearsley Park. Kearsley Mill can be seen in the background, together with the spire of Trinity Church, Prestolee.
The Cub Leader on the left of the photograph is Kitty Tattersall (nee Toms).
Photograph courtesy of Joan Hall (nee Tattersall)


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1. What are the thread states in java ?
|A thread that has not yet started is in this state.
|A thread executing in the Java virtual machine is in this state.
|A thread that is blocked waiting for a monitor lock is in this state.
|A thread that is waiting indefinitely for another thread to perform a particular action is in this state.
|A thread that is waiting for another thread to perform an action for up to a specified waiting time is in this state.
|A thread that has exited is in this state.
2. List all the inner classes ?
|Class Type
|static inner class
|the static inner class can only access the static fields of the enclosing class and define its own static fields.
|non static inner class
|the inner class can access all the fields of the enclosing class, they can define there own fields but these can not be static.
|local class
|This is a class inside a method, the local inner class can access all the fields from the enclosing class and all final parameters from the enclosing method, they can define there own fields but these can not be static.
|anonymous class
3. How to increase the heap memory of the JVM ?
-Xmx (maximum heap size)
4. Name three JVMs ?
Windows JVM
5. What is the quickest type of HashMap ?
6. How do you redirect the System.out ( "standard" output stream ) to a file ?
7. A class that supports serializarion must implement serializable, if its base class is not serizable then what must it have. ?
A default constructor
8. Which method should you override when writing a Customer Class Loader ?
you should override the findClass() method, see example below :
class CustomClassLoader extends ClassLoader { String host; int port; public Class findClass(String name) { byte[] b = loadClassData(name); return defineClass(name, b, 0, b.length); } private byte[] loadClassData(String name) { // load the class data from the connection } } // then to load your class Class r = new CustomClassLoader().findClass("com.x.MyClass"); or Class.forName("com.x.MyClass",true,new CustomClassLoader());
9. Name the standard class loaders ?
10. What is the signature of readResolve() and what is it used for ?
The read resolve method will be called ( if exists ) to create the object. Note : the constructor of the object does not get called is read resolve is called ( so this is one way to create an object without calling its constructor )
ANY-ACCESS-MODIFIER Object readResolve() throws ObjectStreamException;
11. Other than using externizable, how can you handle custom sterilization?
Just provide the following methods in your class being serialized. note: the private access modifiers.
private void writeObject(java.io.ObjectOutputStream out) throws IOException private void readObject(java.io.ObjectInputStream in) throws IOException, ClassNotFoundException;
12. In java 6, how can you see the assembly code that the JIT is creating ?
13. Name 10 Ways to Reduce Lock Contention in Threaded Programs ?
1.Protect data, not code.
2.Get rid of expensive calculations while in locks.
3.Use lock striping.
4.Employ interlocked / atomic operations.
5.Use synchronized data structures.
6.Use Reader-Writer Locks where applicable.
7.Use Read-Only data whenever possible.
8.Avoid Object Pooling.
9.Use local variables or thread-local storage.
10. Avoid hotspots.
14. List 4 Collection Classes and 4 Collection Interfaces ?
(some of them are listed below )
15. How do you create an array using reflection
use Array.newInstance(String.class, 10);
import java.lang.reflect.*; public class array1 { public static void main(String args[]) { try { Class cls = Class.forName( "java.lang.String"); Object arr = Array.newInstance(cls, 10); Array.set(arr, 5, "this is a test"); String s = (String)Array.get(arr, 5); System.out.println(s); } catch (Throwable e) { System.err.println(e); } } }
15. Describethe following exceptions : CloneNotSupportedException, ClassNotFoundException, ArrayStoreException, ClassCastException, ConcurrentModificationException, IllegalMonitorStateException, UnsupportedOperationException.
Checked Exceptions
CloneNotSupportedException Thrown to indicate that the clone method in class Object has been called to clone an object, but that the object's class does not implement the Cloneable interface.
ClassNotFoundException Thrown when an application tries to load in a class through its string name, and this fails.
Runtime Exceptions
ArrayStoreException Thrown to indicate that an attempt has been made to store the wrong type of object into an array of objects.
ClassCastException Thrown to indicate that the code has attempted to cast an object to a subclass of which it is not an instance.
IllegalMonitorStateException Thrown to indicate that a thread has attempted to wait on an object's monitor or to notify other threads waiting on an object's monitor without owning the specified monitor.
UnsupportedOperationException Thrown to indicate that the requested operation is not supported.
16 With java collections, whats the difference between Offer(E e) and Add(E e).
generally the following is true :
|Throws exception
|Special value
Add(E e) Inserts the specified element into this queue if it is possible to do so immediately without violating capacity restrictions, returning true upon success and throwing an Exception if no space is currently available.
Offer() Inserts the specified element into this queue if it is possible to do so immediately without violating capacity restrictions. When using a capacity-restricted queue, this method is generally preferable to add(E), which can fail to insert an element only by throwing an exception. It is implemented in Queue and Deque.
17 Can a top level class be have a protected class modifier
No, only inner class can have protected class modifier access.
more coming soon….


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Black and white and colour printing are available from all library computers. Students can use their WatCard to print. You will need to have funds available on your card. You can add money to your WatCard account online or at the Circulation desk.
Faculty, staff and external borrowers (this includes research and visiting scholars) can print using uPrint guest card. You will need to create an account in uPrint and purchase a uPrint guest card. The uPrint guest cards are sold at the Circulation desk in denominations of $2, $5, and $10.
Printer locations
- Davis Library: Main floor across from the Circulation desk
- Dana Porter Library: Main floor across from the Circulation desk and in the alcove
- Witer Learning Resource Centre, School of Optometry
- Musagetes Architecture Library
How to print
You can use uPrint to print from your laptop or from a library computer. Library computers have a default black and white printer. If you want to print in colour or single-sided, adjust the printing options before sending your document to the printer. To print from a library computer:
- Send your document to the printer: choose "Print" from the "File" menu, or click on the "Print" icon in the "Print" dialogue box.
- In the "Login" dialogue box, enter your WatIAM credentials and click "OK".
- Please wait until you see the following dialogue box before going to the Release Stations to print your job.
- Release your print job: at the print station, swipe your WatCard or type in your WatIAM credentials.
- Highlight the job(s) from the list and select print. If you have enough money on your card to pay for the printout, it is printed and the price is deducted from your card. If you don't have enough money on your card, the printout remains in the queue for two hours, so you can add funds to your card.
Faculty, staff, and external borrowers
Create an account:
- Go to uwaterloo.ca/uprint, then click on "Register as guest card user"
After filling in your full name, email address (UWaterloo, Gmail, Yahoo …etc), user name, and password), click on "Register"
You will get a message that confirms your registration and includes your registration details. Now you can click on the "login" link at the bottom of this message.
- To login, enter your user name and the password that you create in the registration , then click on "Log in"
Add funds to your account:
- Purchase a uPrint card from the Circulation desk. They are sold in amounts of $2, $5, $10.
- Login to your account. You'll see the summary page that shows your username, balance, total print jobs, and total pages.
- From the left menu of the page click on "Redeem card"; enter the access number printed on the uPrint card; then click on "Redeem card".
- You should see a message saying "The value associated with this card has been successfully applied to your account"
- To make sure that the fund has been successfully added to your account, click on "Summary" in the left menu. Now you can see the amount added beside the "Balance".
Print your job:
- Once the account is created, you can print from the library public computers. To release your job using the library's release stations, you will need to type in your uPrint account username and password.
- To print from your laptop, you will need to login into uPrint using your uPrint account username and password.
Cost and refunds
All costs below are tax included
- Black & White printing:
- 8.5 x 11 Single (one sided): $0.10
- 8.5 x 11 Duplex (double sided): $0.14
- Colour printing:
- 8.5 x 11 Single (one sided): $0.45
- 8.5 x 11 Duplex (double sided): $0.70
Refund requests should be submitted through uPrint. Approved refund amounts will be made available for future print jobs (refunds will not be added back to your WatCard or uPrint guest card). There is no service fee for refunds. For more details, please visit the uPrint frequently asked questions page.
- Before you re-boot the library computer, save your work to a USB (memory key) or email your work.
- If you are printing an Excel document in colour you must first save it as a PDF.
- If you have trouble printing a huge file try printing a few pages at a time, or save the document as an .xps file and print using that format.
- Review the printing frequently asked questions.


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Ambush Board Co. Reviews
We always strive to offer the best Customer experience. Here are some real, verified reviews that our Customers have left about us:
Burton pioneered a lifestyle into the mountain landscape during 1977 that became the mantle of innovation and progression – whether it's the product or the perspective. With a stable of world-class snowboarders like Danny Davis, Mark McMorris, Shaun White and Kelly Clark, Burton collaborates with incredible talent for sure, but equally attracts those with a passion for the life. Burton is synonymous with snowboarding, and has driven its reputation through iconic products like the Feelgood and Custom snowboards and equally timeless pieces like the Day Hiker Pack. The craftsmanship of their product transcends seasons to their Durable Goods collection of bags, clothing and camping gear with the adventurous soul in mind. Regardless if your journey takes you far from home, or deep into the night Burton is there with an unapologetic commitment to having fun.


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PROVO, Utah (AP) BYU has accepted an invitation to the Las Vegas Bowl.
BYU finished 9-3, including wins against Nebraska and Boise State. The Cougars were ranked as high as No. 19 in The Associated Press poll, but fell out in Week 5 and never returned.
The bowl has a tie-in with the Pac-12 and is expected to announce the other participant Sunday.
BYU has played in the Las Vegas Bowl five times, most recently in 2009. This will be the 11th consecutive bowl for the Cougars under coach Bronco Mendenhall.


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Emergency Medication Needs: Hurricane Katrina
Dear AIDS Drug Assistance Program Directors:
In response to the emergency medication needs of HIV-positive individuals displaced by Hurricane Katrina, Gilead Sciences will donate, free of charge, replacement medications for Truvada® (emtricitabine and tenofovir disoproxil fumarate), Viread® (tenofovir disoproxil fumarate), Emtriva® (emtricitabine) and Hepsera® (adefovir dipivoxil) provided by the state AIDS Drug Assistance Programs in Texas, Arkansas, Georgia, Tennessee, Florida, Louisiana, Mississippi and Alabama to out-of-state, displaced individuals.
In order to receive donated product, please fax a letter of request on state letterhead to Kristie Banks at Gilead Sciences at 1-800-693-9009. To reach Kristie directly by phone, please call 650-522-5279. The letter should clearly state that you are requesting donated replacement medications for Gilead products dispensed by your program to out-of-state individuals displaced by Hurricane Katrina. Please include full contact information for your program and your Federal Tax ID Number.
Please submit an invoice labeled "request for donated medications -- Hurricane Katrina" for the number of bottles of Truvada, Viread, Emtriva or Hepsera dispensed by your program for which you are seeking replacement. Please include full shipping and contact information on the invoice.
Gilead will offer replacement medications through October 31, 2005. At that time we will evaluate the need for continued support and the availability of alternative resources. All invoices for medications dispensed September 1, 2005 - October 31, 2005 must be submitted to Gilead by November 30, 2005.
For patients not accessing emergency medication coverage through one of the state ADAPs listed above, Gilead will offer expedited enrollment in our "Advancing Access" Patient Assistance Program via telephone, waiving the standard documentation requirements for individuals displaced by Hurricane Katrina who are in need of Truvada, Viread, Emtriva, or Hepsera. Patients will be provided with one original 30-day prescription and one 30-day refill. After the initial 60-day period, patients should formally enroll in the Advancing Access Program. We will continue to evaluate patient needs at that time. The telephone number for the Advancing Access program is 1-800-226-2056.
Please do not hesitate to contact me on my mobile phone at 650-787-2162 over the weekend if you have any questions about the assistance Gilead is offering.
Coy A. Stout, II, M.S.W.
Senior Director, National Accounts
Gilead Sciences


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I love a good story – how about you?
My name is Tracey Dowdy and even though I sometimes speak before I think, I love to think before I write.
Words have power. As a journalist, I understand that power and want to tell stories that change lives and truly make a difference.
Over the years, I've been a speaker, counselor, and leader in my local community. As a freelance journalist, I've written on topics as varied as parenting, education, technology, faith and even mental health. Moving back to Fairfax, Virginia means I've added coverage of events in Washington, D.C. to my beat.
I'm a regular contributor to The Online Mom and I serve as editorial assistant to New York Times best-selling author David R. Stokes.
Good stories connect us – there's nothing like that moment when you're reading and think "Me too!" Some of those nearest and dearest to my heart are authors I've never met. Some of the most powerful influences in my life have been stories crafted by journalists who saw beyond the moment and told a compelling story about the people behind the headline.
I hope you feel that way when you read my work.
Follow me on Twitter here or connect with me on LinkedIn here, or if you're interested in connecting with me for editing or freelance services, you can email me at firstname.lastname@example.com.
The following links take you to recent samples of my work:
The National Plumbing, Heating and Cooling Contractors Association 2017 Legislative Conference on Capitol Hill
5 Reasons Why You Should Be Talking to Your Kids About "13 Reasons Why" – via The Online Mom
Who's a Lucky Dog? LUCKY DOGS PARTICIPATE IN ALEXANDRIA'S ST. PATRICK'S DAY DOG SHOW
If you'd like more information on my work or what services I offer, click on the link below to review my Media Kit.


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Kitty Caps for Cats provides a safe and human alternative to surgical declawing and help prevent damage to furniture caused by your pet's natural desire to scratch. kitty Caps are made from a safe and nontoxic natural vinyl resin. They are durable and easy to apply. After application, you pet's claws can extend and retract without any disturbance. Kitty Caps will fall off as you cats nails grow and shed generally 4-8 weeks after application.
Combo Kits - 20 of each tip color for a total of 40 tips .. Clear Kits - 40 clear tips
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Getting enough sleep can be difficult for many juggling the demands of work, leisure and family.
But experts said yesterday that those who clock up seven hours of shut-eye a night can slash the risk of health problems.
Those who manage fewer hours double the risk of heart problems, warn researchers.
Sleeping yourself to good health: those people who can clock up seven hours of shut-eye a night can slash the risk of health problems
Long-term studies show that those who drop down to five hours or fewer face a 70 per cent extra risk of dying from all causes.
They also face twice the risk of death from a cardiovascular problem.
However, getting more than seven hours can also be a risk, according to the study by the University of Warwick and University College London.
Those who slept for eight hours or more a night were more than twice as likely to die as those who had not changed their habits.
The study looked at how sleep patterns affected death rates among 10,308 subjects, mainly white-collar civil servants.
Researchers examined data for 1985-8 and for those still alive in 1992-3.
Once adjustments were made for factors such as age, smoking and illness, the study was able to isolate the effect of changes in sleep patterns.
The average night's sleep is seven hours but around a third of adults in Britain regularly sleep five hours or fewer a night.
Professor Francesco Cappuccio, of the University of Warwick medical school, said: "Fewer hours of sleep and greater levels of sleep disturbance have become widespread in industrialised societies.
"This change, largely the result of sleep curtailment to create more time for leisure and shiftwork, has meant that reports of fatigue, tiredness and excessive daytime sleepiness are more common. Sleep represents the daily process of physiological restitution and recovery, and lack of sleep has far-reaching effects.
"Our findings indicate that consistently sleeping around seven hours per night is optimal for health."
He said insufficient sleep was a risk factor in weight gain, high blood pressure and type 2 diabetes.
But it is unclear how sleeping too long could cause ill-health, he added, although possible causes included depression and low socio-economic status.
Last week, researchers showed that children who did not get enough sleep were more likely to become obese as adults.


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Cast13 // RB2 (Price per wheel)
Product Details
Cast13's RB2 features a laced multi-spoke design and has been engineered with a concave face, again more noticeable in the wider sizes. The RB2 will suit a wide range of vehicles; the no lip design helps compliment the smooth lines of the wheel. The wheel is finished in impact silver then lacquered for cutting edge looks. Each wheel features our unique signature 3D chrome centre cap and is tyre pressure sensor compatible.
All Cast13 wheels are subjected to the highest standards in manufacture, finish, testing and quality control, meeting ISO9001 standards and have been JWL (Japan Light alloy wheel standard) and VIA (Vehicle inspection Association of Japan) approved.
When purchasing a set of Cast13 alloy wheels you will receive all the necessary hardware needed for mounting your wheels. We include a complete set of brand new wheel bolts, four top quality metal wheel valves and a set of spigot rings (if required).