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What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases
- Jacqueline E Oliver1 and
Affiliated with
- Alan J Silman1Email author
Affiliated with
DOI: 10.1186/ar2585
© BioMed Central Ltd 2009
Published: 19 May 2009
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DOI: 10.1186/ar2585
© BioMed Central Ltd 2009
Published: 19 May 2009
This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.
Risk factors for the major rheumatic diseases over the past 10 years
Host/Environmental risk factor
Rheumatoid arthritis
Diet (caffeine and Mediterranean diet)
Juvenile idiopathic arthritis
Macrophage inhibitory factor (MIF)
Psoriatic arthritis
Rubella vaccination
Injury requiring medical consultation
Recurrent oral ulcers
Moving house
Ankylosing spondylitis
IL-1 gene cluster
Cytochrome P450 2D6 (CYP2D6) gene
Systemic lupus erythematosus
Early natural menopause
Exposure to silica or organic solvents
Familial risk
Fibrillin-1 SNP haplotypes
Foetal microchimerism
Obesity/Body mass index
IL-1 gene cluster
Physical activity
Frizzled-related protein-3 (FRZB) gene
Grip strength
Matrilin-3 gene
Previous injury
IL-4 receptor
Metalloproteinase gene ADAM12
Asporin (ASPN) gene
Estrogen receptor
High purine diet
TNF-α promoter
Dairy products
Pharmacologic agents
Fibromyalgia and chronic widespread pain
Physical trauma
Serotonin transporter gene
Familial risk
Health-seeking behaviour
Poor sleep
A number of large prospective studies have improved our knowledge of risk factors: the Framingham Study [1] and the Chingford 1000 Women Study [2] for OA, the Nurses' Health Study cohort for RA [3] and SLE [4], the European Prospective Investigation of Cancer in Norfolk (EPIC-Norfolk) for inflammatory polyarthritis [5], and the Health Professionals Follow-up Study for gout [6]. These types of studies provide valuable and robust information. Unfortunately, epidemiological data often are obtained from retrospective studies and underpowered case-control studies, resulting in contradictory findings (for example, studies on the role of caffeine in RA). Although some of the studies have found significant associations with novel risk factors, these studies often suffer from poor design. Meta-analyses have also been performed in an attempt to form conclusions from the available epidemiological data and these are also discussed.
Over the past decade, genetic research has moved from the approach of small-scale association studies, to test for candidate genes in case-control studies, to whole-genome scans of linkage based on sibling pairs which proved to be limited in the small numbers of both pairs and markers (both in the hundreds). The more recent and exciting approach has been genome-wide association studies using gene chips which have allowed hundreds of thousands of single-nucleotide polymorphisms (SNPs) to be investigated as exemplified by the Wellcome Trust Case-Control Consortium (WTCCC) study of common diseases (including RA) [7]. The advantage to this approach is clearly the opportunity to identify novel genes for the diseases; however, the disadvantage is that it results in large numbers of hints that require verification in further studies to validate the results.
In general, the studies discussed in this review identify risk factors in whole populations of patients with the disease but it is more likely that each of the individual disease phenotypes results from a number of different combinations of genetic and environmental risk factors. Thus, some risk factors may have a strong effect but only in a small proportion of patients, whereas others will have weak effects and be present in a greater number of individuals but require the involvement of other risk factors. Thus, the size of any increased risk is not a reflection of the level of its attribution to disease causation. However, the sense of strength of risk in this review has been split arbitrarily into three groups based on the typically reported strength of association: 'small' (odds ratio [OR] or relative risk [RR] of less than 2), 'moderate' (OR or RR of between 2 and 5), or 'substantial' (OR or RR of greater than 5).
Studies of environmental risk factors in RA have focused on diet, smoking, and hormones [8]. Several studies have investigated consumption of coffee/tea/caffeine as a risk factor but with mixed conclusions. Caffeine has been reported to moderately increase the risk of rheumatoid factor (RF)-positive RA, but no increased risk for RF-negative RA was found [9]. Decaffeinated coffee has been associated with a moderately increased risk of RA, whereas tea has been shown to have a protective effect [10]. The authors suggest that the decaffeination process (use of industrial solvents) and small traces of solvents may play a role in the disease whereas tea may have both anti-inflammatory and antioxidative properties [10]. However, other studies have found no association of caffeine/coffee consumption with RA [3]. Clearly, studies that are more robust are needed to verify these results.
The so-called 'Mediterranean diet' has been linked with health benefits for a number of diseases and this is also true for RA [11, 12]. High consumption of olive oil, oil-rich fish, fruit and vegetables [13], or vitamin D [14] has been shown to have a protective role in the development of RA. High consumption of red meat and meat products [5] has been associated with a moderately increased risk of inflammatory polyarthritis, but no risk was found in a more recent study [15].
Data on the link between smoking and RA are more compelling and include recent studies implicating a gene-environment interaction (see below). The duration and intensity of smoking have been linked to the development of RA in postmenopausal women [16]. Current smokers and those who had quit for 10 years or less were found to have a small increased risk of RA, whereas those who had quit for more than 10 years had no increased risk. Heavy cigarette smoking has been linked with a substantial increased risk of RA [17] (over 13-fold) and there was an increasing association between increasing pack-years of smoking and RA. Current smoking has been found to be a risk factor for RA, with the risk moderately increased in men and more so in men with seropositive RA [18]. Other studies have also shown a small increased risk due to smoking for seropositive RA in both women and men but have not shown an increased risk for seronegative RA [19]. This risk was evident in subjects who had long-term smoking habits (>20 years) and was evident even if daily smoking intensity was only moderate. Duration of smoking rather than intensity has also been found to be a risk factor in a study of female health professionals [20]. Smoking has also been linked with an increase in both the severity of RA and disease activity [21, 22], supporting a role for smoking in the development of RA. Other host factors that have been associated with RA include blood transfusion and obesity [23] and (high) birth weight [24], which have been linked with a moderate increased risk, and breast-feeding [25] and alcohol [26], which have been linked with a decreased risk/protective role. Stress has also been reported to have a role in the development of RA [27].
Genetic factors implicated in RA have been widely studied using both candidate genes and whole-genome screens [28]. Whereas the strongest genetic risk factor for RA remains the HLA DRB1 shared epitope (SE), other candidate genes have been consistently implicated. In particular, an SNP (R620W) in the protein tyrosine phosphatase (PTPN22) gene, which has regulatory activities for both T and B cells, has been associated with RA [29]; furthermore, this has been replicated in well-powered studies in different populations [30–33]. This polymorphism has been associated with other autoimmune diseases, including JIA and SLE [28]. Studies on peptidyl arginine (PADI4) have shown a significant association [34] but so far this has been replicated in one other Japanese study [35] only and not in populations from the UK [36], France [37], or Spain [38]. A recent meta-analysis of three Asian and six European studies has shown that PADI4 polymorphisms were associated with Asian populations; in European populations, only PADI4_94 had a significant association [39]. Genes such as CTLA4, FCRL3, and major histocompatibility complex 2A (MHC2A) have also been the focus of recent research [28].
The search for novel genes has been advanced by the powerful approach of genome-wide association studies as typified by the UK WTCCC. This has identified three genes with independent associations for RA: two that have been reported to have strong associations (HLA-DRB1 and PTPN22) and a further one on chromosome 7 that had different genetic effects between genders with a strong and apparently additive effect on disease status in females [7]. Further susceptibility loci are likely to be discovered using this approach. Similarly, alleles from 14 genes from over 2,300 cases and 1,700 controls from the North American Rheumatoid Arthritis Consortium (NARAC) (the US version of the WTCCC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections have supported evidence for association of RA with PTPN22, CTLA4, and PADI4 (NARAC cohort only) [40]. There is also evidence that there is a genetic overlap with other autoimmune diseases (SLE, AS, multiple sclerosis, and inflammatory bowel disease) [41]. One of the newer and possibly more exciting areas of research focuses on evidence that certain polymorphisms can predict the response of a patient to treatment [42] and this is likely to be the focus of a number of future studies.
One of the most interesting studies has shown evidence of an important gene-environment interaction between the SE and smoking [43]. This Swedish population-based case-control study showed that the risk of developing RF-positive RA substantially increased in smokers carrying double copies of SE genes (RR = 15.7) compared with smokers with no copies of SE genes (RR = 2.4). Recent research has also shown additive and multiplicative interactions between PTPN22 and heavy cigarette smoking [44]. It has also been proposed that risk factors such as smoking, alcohol and coffee consumption, obesity, and oral contraceptive use may depend on the presence or absence of autoantibodies to cyclic citrullinated peptides [45, 46].
Epidemiological studies of JIA have been hampered by a lack of standardised criteria and case ascertainment, resulting in wide-ranging results: reported prevalence ranges from 0.07 to 4.01 per 1,000 children, and annual incidence varies from 0.008 to 0.226 per 1,000 children [47]. Hopefully, the development of new diagnostic criteria will aid future studies in having results that are more consistent. Ethnicity has been studied and European descent has been associated with a moderately increased risk of JIA; additionally, JIA subtypes differed significantly between ethnic groups [48]. There have been few developments in terms of environmental risk factors, although infection remains the most favoured hypothesis.
Major advances in epidemiological studies of JIA have focused mainly on genetic aspects. A genome-wide scan in 121 families (247 affected children) confirmed linkage of juvenile RA to the HLA region [49]. In addition, early-onset polyarticular disease has been linked to chromosome 7q11 and pauciarticular disease has been linked to chromosome 19p13, suggesting that multiple genes are involved in the susceptibility to juvenile RA. Other candidate genes, including polymorphisms in the migration inhibitory factor (MIF) gene, have been associated with JIA. A study of UK JIA patients showed that patients with an MIF-173*C allele had a small increased risk of JIA [50], and serum MIF levels were also higher in patients with this allele. An SNP in the PTPN22 gene (a gene associated with both RA and SLE) has also been shown to have a novel association with JIA [30]. A recent meta-analysis has confirmed that the T allele and the T/T genotype of PTPN22 C1858T are associated with JIA [51]. Polymorphisms in the NRAMP1 gene may also play a role in the pathogenesis of JIA [52]. There is some evidence that a potentially protective CC genotype of the interleukin-6 (IL-6) gene is reduced in young patients [53].
Epidemiologically, PsA is a complex disease to study as it is not simple to disentangle whether the risk factors revealed are for the complete disease phenotype of PsA or for one of its two components. Studies that compare PsA with healthy controls are not able to address this.
Studies of environmental risk factors for PsA have focused on infection-related triggers and hormones. In a recent case-control study, exposure to rubella vaccination substantially increased the risk of PsA whereas injury requiring medical consultation, recurrent oral ulcers, and moving house all moderately increased the risk of PsA [54]. The strongest associations were with trauma, adding support to the hypothesis of a 'deep Koebner phenomenon' in PsA. These data suggest that infection-related triggers may be relevant and further studies are required to verify these results. In a nested case-control study, corticosteroid use (moderate increased risk) and pregnancy (decreased risk) were both associated with PsA, suggesting that changes to the immune system may play a role in this disease [55].
Developments in the pathogenesis of PsA again have been mainly in the genetic field. There is evidence that caspase recruitment domain 15 (CARD15), a susceptibility gene for Crohn's disease, has a role in PsA, and this is supported by the fact that patients with Crohn's disease have an increased incidence of psoriasis. Initial reports suggested that over 38% of probands with PsA had at least one variant of the CARD15 gene compared with 12% of controls [56]. This pleiotropic autoimmune gene was proposed as the first non-MHC gene to be associated with PsA. Unfortunately, this has not been replicated in German [57] and Italian [58] cohorts; in these cohorts, no such association was found. A novel model that suggests that PsA susceptibility is determined by the balance of activating and inhibitory composite killer Ig-like receptor-HLA genotypes has been proposed [59]. Class I MHC chain-related gene A (MICA) may confer additional susceptibility to PsA. The MICA-A9 triplet repeat polymorphisms were present at a substantially higher frequency in PsA patients [60]. A linkage scan reported evidence that suggests that a locus on chromosome 16q is implicated in PsA; furthermore, the logarithm of the odds (LOD) score is much higher for paternal transmission than maternal transmission (4.19 and 1.03) [61]. Functional cytokine gene polymorphisms have also been associated with PsA [62], with tumour necrosis factor-alpha (TNF-α) -308 and TNF-β +252 polymorphisms being significantly associated with age at psoriasis onset, presence of joint erosions in PsA, and progression of joint erosions in early PsA. A genome-wide association study recently replicated associations of PsA with IL-23 receptor and IL-12B polymorphisms and also identified a novel locus on chromosome 4q27 [63]. A case-control study found evidence that HLA-Cw*06 and HLA-DRB1*07 are associated with the occurrence of type I psoriasis in patients with PsA, suggesting that the primary association is with age of onset of psoriasis [64].
Most of the epidemiological advances in AS have come from the ascertainment of novel genetic associations. Few environmental risk factors have been studied.
Epidemiological studies have focused on the genetics behind AS. Twin studies have estimated the influence of genetics on the aetiopathogenesis of AS, indicating that additive genetic effects account for 94% of the variance in the causation of AS [65]. Genome-wide scans have confirmed the strong linkage of the MHC with AS, which is not surprising given the overwhelming relationship between HLA B27 and AS. However, this study suggested that only 31% of the susceptibility to AS is from genes in the MHC [66]. Thus, the search for non-MHC genes has gained much interest [67]. One of the most exciting developments has been the identification of two new loci for AS from a major genetic association scan: ARTS1 and IL-23R [68]. It was calculated from these studies that these genes are responsible for 26% (ARTS1) and 9% (IL-23R) of the population-attributable risk of AS. Another strong non-MHC linkage lies on chromosome 16q (overall LOD score of 4.7) [69]. Other scans have identified regions on chromosomes 6q and 11q [70]. Combined analysis of three whole-genome scans by the International Genetics of Ankylosing Spondylitis Consortium showed that regions on chromosomes 10q and 16q had evidence suggestive of linkage. Other regions showing nominal linkage (in two or more scans) were 1q, 3q, 5q, 6q, 9q, 17q, and 19q. Evidence was also confirmed for regions previously associated with AS on chromosomes 2q (the IL-1 gene cluster) and 22q (cytochrome P450 2D6 [CYP2D6]) [71].
A linkage study of chromosome 22 in families with AS-affected sibling pairs found that homozygosity for poor-metaboliser alleles in the CYP2D6 (debrisoquine hydroxylase) gene was associated with AS. The authors of that study postulated that altered metabolism of a natural toxin or antigen by this gene may increase the susceptibility to AS [72]. AS has also been linked to the IL-1RN*2 allele [73] as have other inflammatory diseases such as ulcerative colitis and Crohn's disease.
The majority of research into environmental risk factors for SLE has focused on the role of hormones due to the higher prevalence of this disease in women. In a recent population case-control study, breast-feeding was found to be associated with a reduced risk of SLE, with a trend for the number of babies fed and total weeks of breast-feeding [74]. Women who developed SLE had an earlier natural menopause whereas there was little association with current use or duration of use of hormonal replacement therapy or oral contraceptive pill and no association with the use of fertility drugs. The authors of that study proposed that early natural menopause may be a marker for susceptibility to SLE. However, another study has shown that risk of SLE or discoid lupus was moderately increased among current users of estrogens who had exposure of at least 2 years [75]. A prospective cohort study of women found no relationship between oral contraceptive use, either with duration or time since first use [4].
There has been a long-standing interest in the role of chemical exposures causing SLE. An interesting association has been found with lipstick use and SLE [76]. Researchers found that using lipstick 3 days per week was significantly associated with a small increased risk of SLE and this may be worth replicating in future studies on environmental risk factors. The authors suggest that chemicals (these include eosin, 2-octynoic acid [a xenobiotic], and phthalate isomers) present in lipsticks may be absorbed across the buccal mucosa and have a biological effect on disease development. Other risk factors associated with an increased risk of SLE include history of hypertension, drug allergy, type I/II sun-reactive skin type, and blood transfusions (all moderately increasing the risk) and family history substantially increasing the risk of SLE [77]. Consumption of alcohol has been inversely associated with the risk of SLE [77]. A small increased risk was found with smoking, but exposure to estrogen or hair-colouring dyes, both of which previously have been proposed as risk factors, was not associated.
There has been a major increase in the understanding of the genetics behind SLE, particularly over the last year, and this topic is concisely summarised in a recent review [78]. Two high-density case-control genome-wide association analyses have been published [79, 80]. From these studies, overwhelming evidence for the association of various genes with SLE (MHC, ITGAM, IRF5, BLK, and STAT4 [79, 80]) and strong evidence for a role for PTPN22 and FCGR2A [51, 79, 81] have emerged. Other genes for which there is evidence of an association, including the TNF superfamily gene [82], in which the upstream region of TNFSF4 contains a single risk haplotype for SLE, have also emerged. Gene copy number variation may lead to variation in disease susceptibility as highlighted in studies on the complement component C4 in which patients with SLE had a lower gene copy number of total C4 and C4A [83]. Zero copies or one copy of the C4A gene increased the risk of disease susceptibility, whereas three or more copies appeared to have a protective role. The risk of SLE was substantially greater in subjects with only two copies of total C4, but those with five or more copies of C4 had a reduced risk of disease. Another area of research focus has been on the role of sex chromosomes in the development of SLE, especially given the high incidence in females. An interesting observation was the increased incidence of Klinefelter's syndrome (47, XXY) in male patients with SLE, in whom the frequency was substantially increased (14-fold) compared with men without SLE, suggesting that the susceptibility to SLE could be due to an X-chromosome gene-dose effect [84].
Epidemiological studies of Scl have focused on the role for toxic environmental exposures. Specifically, studies have carefully investigated silica and organic solvents as both are thought to stimulate the immune system and cause inflammation and increase antibody production. Recent reports show that occupational silica exposure moderately increases the risk of Scl, with medium exposure increasing the risk twofold and high exposure increasing the risk fourfold [85]. There is still interest in the relationship of silicone breast implants and Scl. However, a recent meta-analysis of nine cohorts, nine case-control studies, and two cross-sectional studies found no association with Scl or other connective tissue diseases [86]. Exposure to organic solvents remains a moderate risk factor and the presence of anti-Scl-70 autoantibodies may be an effect modifier as the association was stronger in patients with these antibodies [87]. However, such studies are difficult to undertake as exposure to other chemicals cannot be controlled.
There is increasing evidence for a genetic role in Scl development [88]. The familial risk of Scl has been investigated in three large US cohorts with a significant increase in risk observed: 2.6% in families with Scl compared with 0.026% in the general public [89]. Studies of HLA alleles suggest that the DQA1*0501 allele is significantly increased in men with Scl compared with healthy men. This allele was found to be moderately associated with diffuse Scl in men but not with limited Scl [90]. HLA associations have also been studied in mutually exclusive autoantibody subgroups, lending support to the theory that Scl in subgroups are actually separate diseases [91]. Transforming growth factor-beta (TGF-β) and connective tissue growth factor may have roles in Scl but further studies are required [92, 93]. Increased expression of TGF receptors may account for the increased production of collagen type I by Scl fibroblasts [94]. Fibrillin-1 SNPs haplotypes have been strongly associated with Scl in Choctaw and Japanese populations [95]. Long-term foetal microchimerism is also still being investigated as a potential risk factor [96, 97].
Studies on environmental risk factors for OA have focused on obesity, physical activity, and prior joint injury, all of which may increase stress on the joints. There have been several major cohort studies of OA, including the Framingham Study [1], the Chingford 1000 Women Study [2], Bristol OA 500 [98], and the North Staffordshire Osteoarthritis Project (NorSTOP) [99]. From these and other studies, a number of risk factors, including high body mass index (BMI), previous injury, and regular sports participation, have been found [100, 101]. The main preventable risk factor, and hence the subject of many reports, is obesity, which has been shown to substantially increase the risk of knee OA [100, 102]. A moderate influence of obesity has also been found with hip OA [103]. Data from adult twins (St. Thomas' Hospital Adult Twin Registry) have shown a moderate association between high BMI and knee OA (OR = 3.9) [104]. Manek and colleagues, who gathered those data, also concluded that this association was not influenced by shared genetic factors. Other influences have been the effect of physical activity on OA [105]. One study found a moderate association between heavy physical workload and hip OA [106]. High levels of physical activity were found to be a moderate risk factor for OA of the knee/hip joints in men younger than 50 years [107].
Men with maximal grip strength have been found to have a moderately increased risk of OA in the proximal interphalangeal, metacarpophalangeal (MCP), and thumb base joints, and women with maximal grip strength have been found to have a moderately increased risk of OA in the MCP joints [108]. There is some evidence that occupation can increase the risk of hand OA. A recent case-control study showed that occupations involving repetitive thumb use and jobs in which there were perceived to be insufficient breaks were associated with OA of the carpometacarpal (CMC) joints [109]. However, not all studies agree and a cross-sectional study found no association with occupation, physical activity, or sports participation but found a moderate increase in risk for hand OA for self-reported digital fracture [110].
Genetic studies in female twins have estimated that the genetic contribution to radiographic hip OA is 58% for OA overall and 64% for joint space narrowing [111]. Studies have revealed that disease risk differs for males and females at different sites and thus there may be specific genes rather than a single OA phenotype [112]. The IL-1 gene cluster is a key regulator in a number of chronic disease processes, and within this cluster, haplotypes such as IL1A-IL1B-IL1RN, which confers a moderate increase in the risk of OA, and IL1B-IL1RN, which confers a fivefold reduced risk, have been identified [113]. This cluster has also been proposed to confer susceptibility for knee OA but not hip OA [114]. Functional polymorphisms in the frizzled motif associated with bone development (FRZB) genes have been found to confer susceptibility to hip OA in females [115]. Radiographic OA is also associated with genotypes of the insulin-like growth factor I gene [116].
Data from the Rotterdam study showed that polymorphisms in the estrogen receptor-alpha (ESR1) gene are associated with radiographic knee OA in elderly men and women [117]. In a case-control study, several candidate genes were investigated: the strongest associations with clinical knee OA were found with a haplotype in ADAM12 (a disintegrin and metalloproteinase domain 12) and ESR1 in women [118] and again with ADAM12 in men along with the CILP (cartilage intermediate layer protein) haplotype. There is also evidence that the cyclooxygenase-2 enzyme encoded by PTGS2 has a role in the pathogenesis of knee OA [119]. The iodothyronine-deiodinase enzyme type 2 (DIO2) gene has been identified as a new susceptibility locus for OA, using a genome-wide linkage scan [120]. A meta-analysis of more than 11,000 individuals provided evidence for an SNP in GDF5 having a positive association with knee OA in both European and Asian cohorts [121]. Other genes so far implicated include the IL-1 gene cluster, matrilin-3 gene, IL-4 receptor, frizzled-related protein-3 (FRZB) gene, metalloproteinase gene ADAM12, and the asporin (ASPN) gene [122]. An ambitious study that will screen over 8,000 people with hip or knee OA and 6,000 healthy controls – arcOGEN (Arthritis Research Campaign Osteoarthritis GENetics) [123] – has been recently been announced and is likely to lead to the identification of further genes associated with OA.
The Dutch GARP (Genetics, Arthrosis, and Progression) study has shown that there is a moderate increased risk for familial aggregation of both hand and hip OA whereas there was no increased risk for knee OA [124]. That there should be greater genetic effects on OA of the hand compared with other sites is not surprising given the relatively weaker role for environmental (including mechanical) factors. The familial risk of hand OA has shown a moderate increase in risk in sisters of women affected with hand OA and this risk was substantially increased with the severity of the disease, with sisters of those with severe first CMC OA having an RR of 6.9 [125]. Whole-genome linkage scans on female twins have shown significant linkage of distal interphalangeal (DIP) OA on chromosome 2 and Tot-KL (Kellgren-Lawrence score for both hands) on chromosome 19 [126]. Polymorphisms in the vitamin D receptor (VDR) gene have also been associated with symmetrical hand OA, with a novel finding of a joint effect of low calcium intake and VDR polymorphisms (aT haplotype) having a moderate increased risk of symmetrical hand OA [127]. Data from the Framingham Study have shown that several chromosomes (DIP joint on chromosome 7, first CMC joint on chromosome 15, and two sites in the female DIP joint on chromosome 1 and first CMC joint on chromosome 20) contain susceptibility genes for hand OA and that a joint-specific approach rather than a global approach to hand OA may be more useful in further investigations of these regions [128]. Genome-wide scans have also revealed linkage peaks on chromosomes 4q, 3p, and the short arm of chromosome 2 for idiopathic hand OA [129]. Genome-wide significance was reached for a locus on chromosome 2 for first CMC and DIP joints coinciding with the MATN3 gene, which encodes the extracellular matrix protein, matrilin-3.
Studies on environmental risk factors for gout have focused mainly on the long-established risk factors of high purine diet and diuretic use. The incidence of gout is increasing [130] and high alcohol consumption is no longer the only risk factor for the disease [131]. Other risk factors that have been proposed include longevity, metabolic syndromes [132], and use of certain pharmacologic agents [133]. The high incidence in some ethnic groups has no obvious host factor, and genetic factors may be implicated in these groups.
Dietary factors have a strong association with gout. Much of the research in this area has been conducted by Choi and colleagues [6, 134–137]. As part of a large prospective study in men (the Health Professionals Follow-up Study), a number of factors were associated with an increased risk of gout. Higher adiposity, hypertension, and diuretic use were all moderate risk factors, whereas weight loss had a protective role [136]. High intake of sugar-sweetened drinks and high fructose intake from fruit juice and fruit have been associated with a small increased risk of gout [137]. High meat intake and seafood intake (purine intake) have also been positively associated with gout with a small increase in risk [6]. In the same study, long-term coffee consumption was inversely associated with gout [138]. Consumption of low-fat dairy products has been shown to decrease the risk of gout [6]; milk proteins (casein and lactalbumin) can reduce serum uric acid levels in healthy individuals.
Advances in the genetic factors behind gout have included a variation in the SLC2A gene, which appears to make it more difficult for uric acid to be removed from the blood [139]. A polymorphism in the TNF-α promoter gene has been shown to be significantly associated with gout [140]. Genetic studies have included families with purine metabolism defects and case-control studies of isolated aboriginal cohorts with primary gout [133].
These poorly defined conditions are nonetheless the target of many investigations seeking to unravel risk factors for their causation or severity.
Studies on environmental risk factors for FM and CWP have focused on physical trauma and psychosocial factors. Physical trauma in the months prior to disease onset has been significantly associated with FM [141]. FM was found to be 13 times more likely in patients who had a prior injury to the cervical spine compared with those with injuries to the lower extremities [142]. In a population-based prospective study, three psychosocial factors independently predicted a moderate increased risk of the development of CWP: somatisation, health-seeking behaviour, and poor sleep [143].
Subjects with all three factors had a substantial increased risk of developing CWP.
There may be biologically based risk factors. Thus, abnormalities in the hypothalamic-pituitary-adrenal (HPA) stress-response system may predict the onset of CWP. In a recent study, high levels of cortisol after dexamethasone and high levels in evening saliva moderately increased the risk of CWP [144]. Low levels in morning saliva were also associated with a small increase in risk. These factors were both independent and additive predictors of CWP, with over 90% of new-onset cases of CWP being identified by one or more of these HPA factors.
Perhaps surprisingly, there have been some interesting suggestions of a genetic basis to FM. FM has been shown to aggregate strongly in families: the odds of FM in a relative of a proband with FM versus the odds of FM in a relative of a proband with RA was 8.5 [145]. Genotypes in the promoter region of the serotonin transporter gene (5-HTT) were analysed in FM patients. A higher frequency of the S/S genotype was found in patients compared with controls [146], supporting the hypothesis of altered serotonin metabolism in FM patients. Family studies have also shown significant genetic linkage of the HLA region to FM [147]. Polymorphisms in the gene encoding the COMT (catechol-O-methyltransferase) enzyme may also have a role in FM as certain genotypes combined are higher in patients than controls and a third genotype was significantly lower in control groups [148].
Over the last 10 years, there have been some major epidemiological advances, particularly in the field of genetic risk factors, in which new candidate genes have been identified and useful gene-environment interactions have been studied. Studying lone environmental factors has been less fruitful. The problem epidemiologically is that these factors often explain only a small number of cases, and on their own, they are not sufficient to cause the disease; both of these issues present considerable epidemiological challenges. The hope is that, as we begin to understand more about the genetics behind the diseases and genetic studies become more technically practical, it will enable stratification by genetic subgroups to identify environmental triggers (such as smoking). However, in other disease areas, progress has been very slow and we still understand very little.
a disintegrin and metalloproteinase domain 12
ankylosing spondylitis
body mass index
caspase recruitment domain 15
chronic widespread pain
cytochrome P450 2D6
distal interphalangeal
frizzled-related protein-3
juvenile idiopathic arthritis
logarithm of the odds
major histocompatibility complex
class I major histocompatibility complex chain-related gene A
migration inhibitory factor
North American Rheumatoid Arthritis Consortium
odds ratio
peptidyl arginine
psoriatic arthritis
protein tyrosine phosphatase
rheumatoid arthritis
rheumatoid factor
relative risk
shared epitope
systemic lupus erythematosus
single-nucleotide polymorphism
transforming growth factor
tumour necrosis factor
vitamin D receptor
Wellcome Trust Case-Control Consortium


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Mon., June 8, 2015 12:04pm
Tasers Used 195 Times At Chatham Co. Jail Last Year
Taser use at the Chatham County Detention Center has come under scrutiny following the death in custody of Matthew Ajibade, ruled a homicide.
Fri., May 31, 2013 12:27pm
Chatham County Bomb-Sniffing Dog Retires
Sheriff's officials say a joint injury is forcing the dog to retire after more than six years on the job. A ceremony in honor of the 8-year-old black Labrador retriever named Corporal Aldo is scheduled for Friday.
©Copyright 2015, Georgia Public Broadcasting. All Rights Reserved
Georgia Public Radio®


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"Running for a Reason" is putting together a 5-K run that will raise money for the group this weekend.
The run will raise money for a general fund that the group will use for community members who are experiencing financial hardships. In the past, they've held running events when they heard of people in need. They hope this run will help them provide financial assistance quicker.
"It's kind of a fundraiser in itself, and we can establish an account so that if a situation comes up and we would like to make a donation, we have that money on hand rather than having to do a fundraiser and wait a month or two before we can actually donate money," said run organizer, Carrie Harvala.
The run will start at 906 Cross Fit in Ishpeming. Runners will head down the Iron Ore Heritage Trail. For more information on the run, including how to register, click here.


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2 years ago
Both of these guys are so hot. I'd love to be sucking that cock and feeling the younger guy sucking mine at the same time.
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3 years ago
nice circumcised cock
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I don't pay for it, BUT I'd pay for him!
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Laptop storage?
Comments (9)
Following. I don't even use a laptop, but I've got an iPad that gets tossed around in much the same manner once I get home from work. On the nightstand, on the buffet in the kitchen, on the bookshelf in the basement. I need a good home for it!
Angela, DS K1 4/09 and DD K2 5/11. Ask me about dogs, my journey to minimalism, and coping with a full-time career, MCDK and SCAD!
1mrsM, thanks so much for the link! The rail isn't exactly what I had in mind, but in the pics below it, there is a beautiful standing magazine file! Something sturdy like that would allow me to toss it in whenever I need to and can move the location if the file holder to whichever room I am in. I'm inspired! Thanks to you both!
I'm no help. DH keeps his laptop in his backpack (which gets left in the living room), I keep my work laptop in the bag by the front door (I have to take it home every night), and our iPad gets kept on the nightstand.
leanna(28) + dh(31) =
nora addison(5) ayla elaine(3) clark james(July 18)
BS2: 79% done
Mom to Thomas David 10/19/06 and Rebecca Paige (aka Becca) 7/15/09 and Dance Studio owner.
25.88% of the way to being debt free! (5 Year Plan)
2007 ~ 2010 ~ 2013 ~ 2015
I keep mine in a low boy looking thing that is dedicated to art and school supplies on one side, and the other side is all computer cords and computer parts and disks. It's our "work" space, and it's near the dinning room since we do homework and everything else at the kitchen table. Our kitchen table doubles as a desk when no one is eating.
Momma to 5 Girls and 1 Toddler Boy!


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amazing eyes............
What a fantastic picture.
if you stare at the eyes more than few second,your heart may skip a beat : )
great work!
great work!
more than awesome
Favorited. Beautiful eyes
she has beautiful eyes, very well done
Oh Yeah! Thisone is so amazing! Really like those eyes!
I like this pictzue so much, the eyes are way amazing. I was spending a couple minutes examining, but I see you copied one side. But the eyes are my favourite, that's why the whole picture is so attractive.
great shot!
You have beautiful eyes, but this photo is absolutely stunning! Very, very nice work!!
wow.....really nice
and great gallery!!!
and great gallery!!!
Amazing well donex
Amazing well donex
very beautiful.I love green
How beautiful! The model face is really beautiful even covered.
its really striking!
love the eyes
They're mirrored... >.> I'd like to see a little variation in the eyelashes. But it's a gorgeous pic! Almost playful.
very pretty (:
absolutely gorgeous, gorgeous, GORGEOUS eyes
Hey...um...is it alright if I paint this or draw this??
Totally understand if you say no!
Totally understand if you say no!
Yes, of course. If you show me the painting/drawing when you are finished.
Beautiful eyes.. and her face? Is amazing too?
Beautiful eyes!!


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News for Monday, April 2, 2012
2012 Masters: Breaking down Tiger vs. Phil
Tale of the tape
Tiger Woods and Phil Mickelson have combined for seven victories in the Masters. So who plays Augusta National better? Here are the numbers:
Notes: Kaymer's ace a sign of change in fortune?
Notes: Kaymer's turn?
Masters notebook: Martin Kaymer picked up a hole-in-one on Monday, and he is hoping that it is a sign that his luck is changing at Augusta National, where he never has made the cut.
Aussies lament likely Tour conflicts
Professional or personal?
When the PGA Tour rolls out its anticipated schedule changes in the fall of 2013, the Aussies will face a quandary: play the season-opening U.S. events or return Down Under for their country's version of major championships (Australian Open, Australian PGA and JBWere Masters).
McCabe: No one way to prepare for the Masters
McCabe on Masters prep
Adam Scott and Nick Watney try to treat Masters week like any other. Scott Stallings can't practice enough. Tiger and Phil have their own traditions. Does anyone have the secret? Nope.
Senden could be 2012's Masters surprise
says John Senden could record the first win by an Australian in the history of the year's first major.
John Senden could record the first win by an Australian in the history of the year's first major.
2012 Masters: The Monday awards go to . . .
Achenbach: Monday's best
Jim Achenbach: The Masters is all about tradition. Continuing an honored tradition that started, well, last year, here are Monday's award winners from the Masters.
Winner's Circle: March 26 - April 1, 2012
See what the winners had in their bags this week.
RBC extends sponsorship of Canadian Open
RBC lengthens sponsorship
Canada's largest bank solidified its extensive investment in the PGA Tour, lengthening its title sponsorship of the RBC Canadian Open through 2017.
Golf 2.0 bolsters player-development staff
Grow the game personnel
Golf 2.0, the PGA of America-led initiative to grow the game, continues to build its field staff to help golf facilities in key markets attract players.
Lewis, 54, oldest to make a Masters debut
Lewis' Masters debut
Randal Lewis won the U.S. Mid-Amateur to earn a spot in the Masters field, and is taking advantage of his first opportunity to play Augusta National.
Las Vegas makes Tiger the favorite at Masters
Tiger is Vegas' pick
The final odds - which can be updated - came out of Las Vegas last night and Tiger Woods at 9-2 is a slight favorite over Rory McIlroy at 5-1 to win the 2012 Masters.
Player of the week: Jennifer Kirby, Alabama
The Crimson Tide junior opened play at the Liz Murphey Collegiate Classic with a 6-under 66 and then backed that up with rounds of 72-71 to win her first college title.
Team of the week: UCLA
The Bruins won for the fifth time in eight starts with a 12-shot victory over Arizona State at the Ping/ASU Invitational.
Player of the week: Julien Brun, TCU
The Horned Frogs freshman posted rounds of 68-65-69 against a field of many of the nation's top college players to win the Insperity Augusta State Invitational.
Team of the week: Oregon
The Ducks won a pair of titles last week, claiming its own Duck Invitational on March 27 and the U.S. Intercollegiate hosted by Stanford on April 1.
Kent State sets record in Irish Creek win
The Kent State men's team shot 12-under 272 in Sunday's final round of the Irish Creek Collegiate, giving the Golden Flashes a school-record 27-under 825 total and handing head coach Herb Page his 75th career victory.
LSU rallies past Iowa to win at home
Austin Gutgsell shot 7-under 65 in the final round of the LSU National Invitational on Sunday to win his second college title and lead the LSU men's team to a two-shot victory over Iowa at its home event.


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Details and Shopping
Customer Favorite
- FP Exclusive :
- Only sold thru Free People
Sheer gauzy printed top with a gathered waistband and wrists. Lace-up V-Neck with tiny tassel details. Dolman sleeves.
*100% Cotton
*Machine Wash Cold
*Machine Wash Cold
Measurements for Small:Bust: 67"
Length: 22"
Sleeve Length (from neck): 25 1/2"


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Snug n Chunky Cable Knit Hat
By: Bernat
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This knit hat from Bernat Yarns with thick cables goes well with casual outfits, or dress it up with an overcoat when you brave the cold! Intermediate skill level.
- Bernat® Alpaca
- (100 g /3.5 oz; 110 m/120 yds)
- 1 ball of (93531 Tomato).
- Knitting Needles: sizes 5.5 mm (U.S. 9) and 6 mm (U.S. 10) or size needed to obtain gauge.
- Cable needle.
One size to fit average lady.
15 sts and 20 rows = 4 ins [10 cm] with larger needles in stocking st.
With smaller needles, cast on 73 sts.
Work 1½ ins [4 cm] in (K1. P1) ribbing, ending with a WS row.
Next row: (RS-Inc row). K3. *M1. K2. M1. K3. Rep from * to end of row. 101 sts.
Change to larger needles and purl 1 row.
1st row: (RS). K5. *Slip next 4 sts onto a cable needle and leave at front of work. K4, then K4 from cable needle – C8F made. K4. Rep from * to end of row.
Beg with a purl row, work 7 rows in stocking st.
9th row: (RS). K1. *Slip next 4 sts onto a cable needle and leave at back of work. K4, then K4 from cable needle – C8B made. K4. Rep from * to last 4 sts. K4.
Beg with a purl row, work 7 rows in stocking st.
Rep 1st to 9th rows once more.
Next row: Purl.
Shape top: 1st row: (RS). K1. *K2tog. K3. Rep from * to end of row. 81 sts.
2nd and alt rows: Purl.
3rd row: K1. *K2tog. K2. Rep from * to end of row. 61 sts.
5th row: K1. *K2tog. K1. Rep from * to end of row. 41 sts.
7th row: K1. *K2tog. Rep from * to end of row. 21 sts. Break yarn, leaving a long end. Thread yarn
through rem sts and fasten securely.
Sew back seam.
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Bask in the view of sparkling waterfalls that glint in the sunshine and cascade down the mountainside into the pure turquoise river rushing along below. You're watching this breathtaking scenery from the comfort of a glass-domed observation car as your train winds through the remote wilderness of mountain passes, glacial river gorges and pristine forest. A pair of golden eagles wheel overhead.
Your reverie is interrupted by the announcement that lunch is served in the dining car downstairs. White linen, sparkling silver, fresh-cut flowers, impeccable service and delicious gourmet food prepared from regional cuisine by award-winning chefs – what's not to like? The most difficult decision you'll have to make today is whether to have the bison tenderloin or the wild Pacific salmon.
Experience the Canadian Rockies by train and see why UNESCO declared them a World Heritage Site. Glimpse wildlife you would rarely see from the road. Step off at a vintage railway station and discover the magic of Jasper or Banff.
For an unforgettable day trip, take an antique steam train across the wide open prairie. Engaging themes are played out on board, from murder mysteries to train robberies. Travellers of all ages will be mesmerized by the timeless vistas of Alberta by rail.
"Fantastic holiday in every way. We have travelled the world and this was one, if not the best, experience we have ever had...100% total marvel at breathtaking views, and wonderful wildlife and passenger care, a journey second to none!"
R. & A. Cole, England


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"Adventure Time with Finn & Jake Theme Song - Lyrics"
Finn and Jake! They come to town
Come to save the Princess Bubblegum
The Ice King put her away
Now the children don't play
But they will when Finn and Jake save the day
Adventure Time!
Now Finn, fill up your hearts
So you can shoot your sword with power
And when you're feeling all down
Jake will come around
So you'll be brave
And not a sissy coward
Now Finn and Jake have saved the day
For the Ice King is in his grave
So now Bubblegum is free
And now our hero shall be
Finn and Jake, I think your name shall go down into history
Adventure Time Song - Lyrics by ian2x4Watch
©2010-2016 ian2x4
Hello, everyone! As you all know, this is the fanmade theme song from Cartoon Network's new original series, Adventure Time with Finn & Jake. This is the parody song from System of A Down's The Legend of Zelda Theme Song.


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Respond to Review of CLOSED: InSpiral Lounge
by hundert
Review: ... you can find this lovely place on your way to the camden lock market. the food is awesome, the price is still in the "ok-range". thanks to a lot of category icons on the menu, it's very clear if the food fits your needs (marked as: gluten free, vegan, raw food, organic etc..). it's self service and a little chaotic, but i would definitely go there again when i'm in the area. first i thought i wouldn't need the quite loud music (too much input anyway in this area!), but after a time it changed to a very calm and chilled downtempo electro, which fitted perfectly. the meals are very customizable (you can choose between a lot of (all vegan!) sides), what makes it almost too complicated for tourists with slight language barriers (my mom didn't understand all the questions of the staff).
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text: I know that graphene is a far more superb conductor than copper, but I'm trying to compare their weight difference. I mean, lets take an example: A copper busbar that is 7kg with resistance of 2 micro-Ω can carry a lot of current(in kA), I assume a much lighter(possible less than a kg) graphene conductor can conduct the same current range and is much much lighter? Trying to grasp more about this amazing material.


text:
HP Original CE980A Toner Collection Unit in Retail Packaging
Original CE980A HP toner collectors allow for error-free print jobs and can lend your printer a longer life. Avoid unwanted future hassles when you purchase the HP CE980A for your HP printer!
Compatible Printers:
Color LaserJet Enterprise
|OEM Number
Page Yield
Page Yield is an approximation of the number of standard pages that can be printed with one cartridge, usually measured at 5% page coverage. 5% coverage is a standard 8.5 x 11 inch page with a light letterhead, address and three paragraphs of text double spaced. If you print mixed text and graphics or WebPages your page coverage is closer to 15% and therefore the number of pages printed with each cartridge will be less. If you are printing photos your page coverage is close to 100% and the number of printed photos will be much less than the amount the number of pages you would be able to print if you were just printing standard text documents.
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|Cost Per Page
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|0.03 cents
|24 Months


text:
Members' Spotlight
Howe, Jude
Standing Form - 40cm fused, tack fused and slumped
Open Form - kiln formed glass with stainless steel
Resistance (detail) fused, tack fused and slumped
Red/Orange Form - kiln formed glass and glazed stoneware
Aqua - fused and slumped
Spring Green Form 40cm - fused and slumped
Wingbeats - fused and slumped
Resistance - fused, tack fused and slumped
Red Plant Form - kiln formed glass, glazed stoneware and stainless steel
Ms. Jude Howe
My work is based around the experience of living in East Yorkshire, very close to the sea . The colours, textures and sensual properties of the shore and surrounding environment are portrayed in mixed media pieces. Translucent kiln formed glass reflects the coastal light.
Technique:Kiln work
Discipline:Decorative, Fine art, Sculptural
Areas of Interest:Competitions, Exhibition, Workshops


text:
Runzheimer International® Launches Runzheimer Mobile™ with Salesforce® Integration Mobile application helps sales and service teams manage itineraries, plan routes, track business mileage and capture expenses in the field with Salesforce CRM integration.
WATERFORD, Wis., Aug. 22, 2013 /PRNewswire/ -- Runzheimer International®, the global leader in Total Employee Mobility® solutions, today announced the availability of Runzheimer Mobile™ Version 2.1, featuring integration to Salesforce® and the ability to access client and prospect information via smartphone in the field.
(Photo: http://photos.prnewswire.com/prnh/20130822/CG67792)
The application enables route planning, expense tracking, mileage and trip capture. The new release features two-way communication and integration with Salesforce, allowing field sales and service workers to manage itineraries, contacts and activities in the cloud, self-schedule in real-time and easily locate nearby Accounts, Contacts, Leads and Opportunities via map-based searches with the added ability to enter notes.
For back office operations, trip data is available in the cloud, providing concurrent visibility to back-end administrators and increased visibility into planned versus actual field activity. Data can be used to optimize resource deployment and territory planning along with visibility into driver behaviors and trip costs.
"Interfacing with Salesforce really sets Runzheimer Mobile apart from other mobile applications to help connect with customers in the field," said Donna Koppensteiner, VP of Business Development for Runzheimer International. "We listened to our clients and delivered a powerful tool to give mobile workers the edge and be more productive while working on the go."
The Runzheimer Mobile application requires an enterprise level license from Runzheimer International. To learn more, visit www.runzheimer.com/runzheimermobile.
About Runzheimer International
Founded in 1933, Runzheimer International serves 60 percent of the Fortune 500 and numerous government agencies. Recognized for providing innovative solutions relating to Total Employee Mobility, Runzheimer is the global leader in workforce mobility programs including business vehicles, business travel, routing and logistics, employee relocation and compensation, and mobile device expense management.
SOURCE Runzheimer International


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With Aion patch 2.7 going live on October 19th, we've teamed up with NCsoft to give you some helpful hints to guide your way through Padmarashka's Cave. This new instance will test your fortitude as you battle Sematariux and Padmarashka with 47 of your closest friends. Yep, that's right, a 48-man raid! Will you be able to take down the monstrosities that lurk in Padmarashka's Cave? Read on to find out the best ways to approach this mammoth instance.
Padmarashka's Cave is a new 48-man Instanced Dungeon introduced in Aion Patch 2.7, based on the Dramata world boss encounters (Sematariux and Padmarashka) that were introduced in Aion Patch 2.0 (which will be removed for 2.7).
Tiamat and Siel, the Dramata, and the Assault on Balaurea
The Balaur have begun to withdraw from Inggison and Gelkmaros, marking the assault on Balaurea a success. However, this was not the Empyrean Lords' first attack on the Balaur homeland. Before the Cataclysm, Siel's Spear Legion entered Balaurea to put a stop to the horrors of the Udas Temple, a torture den dedicated to Dragon Lord Beritra. The attack culminated in a colossal battle between Dragon Lord Tiamat and Siel….
…Tiamat heaved forward, crushing Siel beneath its scaly hide. The Lady of Time tried to escape, but Tiamat slammed down its claws, pinning her. The Dragon Lord reared back, a blaze building in its throat, as another fire ignited deep within Siel. Tiamat's head lurched forward, flames licking through the cracks between its teeth. The Dragon Lord opened its maw, and Siel exploded in a brilliant light. Radiance burst forth from the Lady of Time, hurling Tiamat back. The earth cracked and buckled, opening chasms at Siel's feet, and for an instant the whole of Balaurea was consumed in light… .
Centuries after Siel's death in the Cataclysm, the children of the ten remaining Empyrean Lords entered Balaurea, determined to take the fight to Balaur once again. Tiamat's forces were to be the first line of defense, but soon fell back, unable to stem the tide of Daevas flooding into Balaurea. Tiamat has since ordered the Balaur to retreat, including Sematariux and Padmarashka, the two Dramata. Sematariux and Padmarashka are each responsible for fostering thousands of Drakan children, and are crucial to the Balaur war effort. While Sematariux abandoned its eggs without hesitation, Padmarashka remained despite Tiamat's orders—a disparate mother devoted to its children.
With the Balaur in retreat, Padmarashka now stands as the final obstacle to conquering Inggison and Gelkmaros. Confront Padmarashka, and secure the path to inner Balaurea where Tiamat awaits!
Entering Padmarashka's Cave
The entrance to Padmarashka's Cave is located in both Inggison and Gelkmaros. To enter Padmarashka's Cave, each player in the Alliance will need the Padmarashka's Cave Key, which can be obtained from the Balaur outside the entrance to Padmarashka's Cave in both Inggison and Gelkmaros.
Only one Padmarashka's Cave Key can be carried in the player's cube, however, an infinite number of Padmarashka's Cave Keys can be deposited in a Pet Bag, allowing players to carry more than one.
When entering Padmarashka's Cave, the key is consumed, and should the player want to re-enter, they will need another key.
Padmarashka's Cave
Padmarashka's Cave is split into three areas: Reian Foothold, Padmarashka's Cave, and Padmarashka's Nest. At the Reian Foothold, players can collect a few Quests from the Reians, and purchase basic supplies.
Continue from the Reian Foothold into Padmarashka's Cave, where Padmarashka's Balaur defenders roam. Clear through the area and proceed to Padmarashka's Nest.
Padmarashka's Nest is the final area of Padmarashka's Cave, and upon entering, players will notice that Padmarashka is protected by a shield. This shield grants Padmarashka the Protective Slumber buff, rendering it invincible to all attacks and also causing all attacks to be reflected.
To dispel this shield, defeat the four Heroic monsters with the Padmarashka's Protector title located in front of Padmarashka. These four monsters are Padmarashka's Chief Medic, Padmarashka Sartip, Padmarashka's Elite Captain, and Padmarashka's Elite Commander. With these four defeated, Padmarashka can be engaged. The Dramata are horrific foes with powers that rival even the Dragon Lords, and Padmarashka is no exception. Wielding enormous teeth and claws with more than a dozen devastating skills at its disposal, Padmarashka could be the most fearsome encounter in all of Aion.
The Padmarashka encounter can be broken down into three phases, and the effects of the previous phase will carry over into the next phase. To succeed, the Alliance will need to manage the unique circumstances of each phase in addition to Padmarashka (which can be quite a handful in of itself).
Padmarashka begins the encounter with two main skills—Destructive Claw and Venomous Claw. Padmarashka alternates attacking with these two abilities, both of which inflict massive damage, and also apply a debuff. The Destructive Claw debuff will cause Venomous Claw to inflict additional damage, and the Venomous Claw debuff will cause Destructive Claw to inflict additional damage. To combat this, either have two tanks on Padmarashka bouncing enmity between the Destructive Claw and Venomous Claw attacks, or use a single tank with well timed cooldowns and several dedicated healers (however, depending on the tank's experience and equipment, this might not be feasible).
Padmarashka will unleash more abilities as the encounter wears on, including Padmarashka's Roar, an area of effect attack which inflicts massive damage, and Chilling Gaze, which paralyzes all targets in an area of effect for 10 seconds.
Padmarashka applies numerous debuffs, some of which can be dispelled, and others which cannot. The Padmarashka encounter is healing intensive on both the tanks and the Alliance, and thus it is important to bring several healers and ensure those healers know who to heal and remain in range of their healing targets.
In addition to Padmarashka itself, there are three different phases to the Padmarashka encounter that each present their own unique challenges.
Phase I
In the first Phase, Padmarashka begins summoning additional monsters to the battle. Padmarashka summons Balaur warriors from the instance entrance, and hatchers and eggs containing Neonate Drakan at the back of Padmarashka's Nest.
It is best to defeat these enemies as soon as possible or the Alliance risks being overwhelmed. To accomplish this, consider splitting the Alliance into separate Groups and assigning those Groups to attack the monsters spawning in different areas.
Phase II
In this phase, Padmarashka begins summoning huge eggs containing Veteran Drakan, which can inflict colossal damage and wreak havoc if allowed to hatch from their eggs.
When a huge egg is summoned, a system message displays "The huge hidden egg is finally revealed," at which point a huge egg will spawn in one of the sand pits located around Padmarashka's Nest. Destroy the eggs and their guardians as soon as possible to avoid being overwhelmed.
Phase III
When Padmarashka is at low health, the ceiling of the cave collapses around the edges of the room, necessitating that the Alliance moves to the center.
When the ceiling caves in, a system message displays "The cave starts to crumble from Padmarashka's might," at which point areas around the cave will be affected with Cave Collapse.
In this phase, it's important that all players remain aware of their surroundings, and ensure that no one is standing in a Cave Collapse, the Padmarashka tank or tanks in particular!
Expect the Padmarashka encounter to last some time, and while the damage and sheer scale of the encounter can be overwhelming, the key to success is assigning players to handle the different phase mechanics, while the tank (or tanks), healers, and a handful of damage dealers work on Padmarashka itself.


text:
Connect With Us800-299-9470
The G-Max System offers outstanding commercial grade technology. This low consumption toilet received high ratings during ANSI/ASME testing at independent laboratories. Designed with a powerful siphon jet flushing action, the bowl offers a large water surface and a 100% glazed trapway for superior performance.
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Products & ServicesSee also: Categories | Featured Products | Technical Articles | More Information
Supplier: OMEGA Engineering, Inc.
Description: The R44 Series are industrial pressure regulators for use with compressed air and inert gases such as carbon dioxide, argon helium, krypton, neon nitrogen and xenon. The R83 models are for primary high pressure regulation, while the R44 models are for secondary low pressure regulation
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- Valve Size: 1.5 inch
- Pressure Rating: 250 psi
- Connection: Threaded
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Description: Features Used in electric welding for on/off control of argon and water
- Media: Other
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- Pressure Rating: 75 to 100 psi
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Supplier: Clark Cooper Div. Magnatrol Valve Corp.
Description: ; leads APPLICATION: To control the flow of Steam, Hot Liquids, Hot Gases, Cryogenics** and any other fluids not reactive with construction materials and free of sediment. Cryogenic fluids include Liquid Oxygen (-297°F), Liquid Argon (-303°F) and Liquid Nitrogen (-320°F). Valve operates from
- Media: Gasoline / Diesel Fuel, LP - Gas, Natural Gas, Specialty / Corrosive Gases
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- Media: LP - Gas, Natural Gas
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- Media: High Purity Gas
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Description: changes as are pneumatic control valves. Applications State-Of-The-Art Air Sampling Systems Chlorine metering Petrochemical plants Semi-Conductor Process Gas Blending Control of Argon and Helium in welding Pilot plants Aluminum and Steel Industry Key Features Rugged integrated design 2-wire
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Description: VALVE,CYLINDER,GAS,ARGON,OIL-FREE,3/4"INLET
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Description: of gas volume will be used rather than approximately 80% when utilizing the glass flasks. The EGL Gas Transfer System provides uninterrupted flow of pure Neon, Argon or special gas mixtures into tubes for neon signs, cold cathode, etc. A precision-made filling valve eliminates the use of two glass
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Description: REGULATOR FOR ARGON GAS
Gas Compressors and Gas Compressor Systems - HX/HN: Oil-free reciprocating piston compressors, 30-560 kW / 40-750 hp. -- 1528404Supplier: Atlas Copco USA
Description: Atlas Copco's HX/HN oil-free reciprocating compressors are extremely reliable solutions for air, nitrogen, C0/C02, methane, hydrogen and argon. Designed for 24/24 industrial service, with minimal maintenance cost and long overhaul intervals, HX/HN compressors can work in a most efficient
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Description: and manufacturing of compressors for the inflator filling of air bags and isostatic presses. Diaphragm compressors are used for lubricant-free compression of different gases, such as e. g. nitrogen, hydrogen, helium, argon, ethylene, NF3, hydrosulphide, chlorine gas, oxygen, monosilan etc., as well
Supplier: Union Process, Inc.
Description: be applied. Cover seals can be provided for conditions where dust control is desired, or where grinding must be done under a closed inert gas system. Torque meter is available including torque and speed sensor read-out. Media discharge valves can also be installed. Variable frequency drives
Welding, Brazing, and Soldering Equipment - Miller Millermatic 180 Autoset 230V 60HZ 1PH - 907312 -- 907312Supplier: U.S. Welding & Safety Supply Co.
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SC Hydraulic Engineering Corporation
Self Contained Air Driven Gas Boosters
SC air driven gas boosters are self contained units, using a cycling spool and pilot valve to provide automatic reciprocating action when air or gas is supplied to the air drive inlet. The drive consists of a large piston and valve assembly directly connected to a hydrocarbon-free pumping piston with self lubricating seals cycling in a stainless barrel that has an integral check valve. The working surface area of the drive piston exceeds the working surface area of the pump piston, thereby... (read more)
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TESCOM ™ SG Series - compact, lightweight, high purity regulators for specialty, flammable and industrial gas flows. Sensitive, extra long-life metal diaphragm ensures gas purity and integrity. User-friendly model number enables the specifier to select optional gauges, relief and shut-off valves, and cylinder connections as part of the regulator assembly. Applications: Laboratory and Point-of-Use Gas Systems in medical, pharmaceutical, food and beverage and other high purity applications... (read more)
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E+E Elektronik
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The EE771 is a thermal mass flow meter for compressed air and gases. Irrespective of pressure and temperature, the EE771 flow meter registers mass flow, volumetric flow or standard flow. The flow meter can measure the consumption of compressed air, nitrogen, oxygen, CO2, helium, argon or other non-corrosive gases. The ball valve permits eady installation and removal with only a short interruption of the flow. EE771 flow meter employs the well proven E+E hot-film sensor element with high... (read more)
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AM250 Additive: Design today, build tomorrow
hopper – particularly useful for materials development or use of a range of materials. To enhance productivity, a valve interlock on the AM250 allows the addition of extra powder while the process is running. Safe processing of reactive materials, such as titanium and aluminum, is ensured with features such as a gas knife that clears away reactive, sooty emissions, and a heated build plate. The system provides 250 x 250 x 300 mm (X-Y-Z) with Z axis extendable to 360 mm and a 200 or 400 W... (read more)
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Conduct Research Top
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to commissioning. However, during routine fab operations, an inadvertent error by a process tool operator or the failure of a delivery system component such as a valve or pressure regulator can cause gas contamination, which, if not detected in a timely manner, can result in a significant amount of scrapped
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Multipurpose sodium sampler for LMFBR's: design and operation
The MS gas pressure is adjusted to '^1 psig above the sodium supply system pressure and the argon gas valve is closed.
Argon gas valve .
CO2 gas sensitivity of sputtered zinc oxide thin films
Then the argon gas valve with fine controlling was adjusted carefully until the pressure reached the desired value.
The effect of ITER-like wall on runaway electron generation in JET
The temperature and density profiles were obtained from Thomson scattering, right before the argon gas valve was triggered.
Adapting the Duoplasmatron EUV light source for use entirely within vacuum
The argon gas valve is then closed.
Combustion synthesis of nonoxide ceramic and composite preforms for liquid-metal infiltration
'opening argon gas valve setenoJd LOCATE'12, 1: PRXNT"CHAHBER-PRESSURXZATXONpPEoXGNITXONSEQUENCEINXTIATED" LOCATE13, 5: PRINT "Shutting down vacuumpump.........
Engineering techniques to obtain uniform heating of spherical metal objects in an induction furnace
Liquid-liquid mixing for the breakup of accelerating drops
The argon gas valve was opened k, obtain the desired void fraction in the column.
The effect of ITER-like wall on runaway electron generation in JET
The temperature and density profiles were obtained from Thomson scattering, right before the argon gas valve was triggered.
Calibration Facilities for High Temperature Radiation Thermometers at NMIJ
The setting temperature and the argon gas valve can be controlled and the present temperature and the gas flow rate can be monitored by a computer through an RS 232C interface.
pulsed gas valve argon puffing location .
Process synthesis and optimization for the production of carbon nanostructures
After 10 min, the argon flow was stopped by closing the argon gas main valve .
Deposition process, microstructure and mechanical behaviours of RF magnetron sputtered (Ti,Al)N thin films
1: vacuum chamber; 2: rotating holder; 3: nitrogen gas inlet; 4: argon gas inlet; 5: nitrogen gas inlet valve; 6: argon gas inlet valve ; 7: high vacuum valve; 8: low vacuum valve; 9: turbo pump valve; 10: rotary pump valve; 11: turbo …
Proceedings of SCANNING 2000 May 9–12, 2000 San Antonio, Texas, USA
Further investigation of the deposition tool found that the argon gas pressure valve , which is used to supply argon to transfer heat to the wafer from the heating block, was not opening completely due to a bad solenoid.


text:
Depeche Mode Compilation Albums
A selection of articles related to depeche mode compilation albums.
Original articles from our library related to the Depeche Mode Compilation Albums. See Table of Contents for further available material (downloadable resources) on Depeche Mode Compilation Albums.
- Software of the Mind #2: Adopting Natural Software
- Connection with Nature faded away as humanity removed itself physically and mentally from natural living. Thought replaced direct knowledge, (intuition) and ego replaced the mode of the natural mind. This is becoming increasingly the case not only at the...
Mystic Sciences >> Mind
- Software of the Mind #3: Implementing Natural Software
- " Logic " is a primary means for the refinement of the mental vehicle in particular. A common view of logic is that it is merely a system of reasoning that is in itself without direction. This view holds that logic is only a framework of...
Mystic Sciences >> Mind
- Elemental Associations
- The earliest of Greek natural philosophers, Thales, in considering which was the most basic element in the cosmos, from which the cosmos was made, supposed that the cosmos was made of Water. Later, Heraclitus decided that the most basic element in the cosmos...
Magick >> The Elements
- Dealing With World Mind Effects Through Greater Self Mastery (GM5)
- At one time or another, we have all experienced occasions where other people in the same room began to have a heated argument. The psychic dissonance created at that time, produced in us symptoms of shakiness, nervousness, a scattered thought pattern or other...
Mind >> World Mind
- Resurrection of the Higher Self
- In July of 1989, a controversial article crossed the managing editor's desk of an equally controversial magazine. This article was never actually published in the quarterly publication, then known as The Magical Blend , even though it was well documented by...
Body Mysteries >> Psychoactive Substances
- Survivalists' Guide for the New Millennium: Chapter 2
- WORKING TO LIVE RATHER THAN LIVING TO WORK Before the dawn of recorded history, a major period of transition occurred. Nomadic hunter-gatherer clans transformed themselves into larger communities who farmed the land. This they did by planting their own...
Philosophy >> Survivalists Guide for the New Millennium
- Survivalists' Guide for the New Millennium: Chapter 7
- MAKING FRIENDS WITH NATURE AND NATURAL LAW The fall of human society has not occurred overnight. It has taken many centuries, many millennia in fact, for the Divine potentials and inherent genius of the human being to degrade into the modern...
Philosophy >> Survivalists Guide for the New Millennium
Depeche Mode Compilation Albums is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Depeche Mode Compilation Albums books and related discussion.
Suggested Pdf Resources
- Tuesday, February 1, 2011
- THE 2011 JUNO AWARDS nominee compilation album is a non-profit "We are delighted and honoured to be releasing an album that showcases the . Beatles, Rosanne Cash, Terri Clark, Coldplay, Stompin' Tom Connors, Jesse Cook, Depeche.
- junoawards.ca
- 1~(~(~I~N1'llI(~.~
- DEPECHE MODE I II&WDepeche Mode's future as being limited. . Country did well in the U.
- www.eccentricsleevenotes.com
- latest album, released in January 2010, is the top seller of the year in the US. Our labels and .
- www.emimusic.com
- Harminder Singh Judge: The Inconsistency of Everything India is
- Cave and Depeche Mode.
- www.thenewartexchange.org.uk
- Depeche Mode: A band, its music, and the cult, Communications
- content.grin.com
Suggested Web Resources
- Category:Depeche Mode compilation albums - Wikipedia, the free
- Pages in category "Depeche Mode compilation albums". The following 8 pages are in this category, out of 8 total.
- en.wikipedia.org
- Catching Up with Depeche Mode - Wikipedia, the free encyclopedia
- Catching Up With Depeche Mode. Compilation album by Depeche Mode.
- en.wikipedia.org
- The Best of Depeche Mode Volume 1 - Wikipedia, the free
- en.wikipedia.org
- Depeche Mode Compilation Albums - ARTISTdirect Music
- Depeche Mode Compilation Albums on ARTISTdirect Music.
- www.artistdirect.com
- Amazon.com: The Singles 86>98: Depeche Mode: Music
- www.amazon.com
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text:
Korra's face is scaring me
ok WTF
friggin awesome custom!
jkljdkaljfdklsajf either the lighting is bad... or the color on Fluttershy is wrong! D:
is the trixie a custom? she's pretty well made!
Thank you! It was my first ever custom.
BWAHAHA I totally think "HIGH HO TRIXIE! AWAY!"
You've gotta be kidding me. The Bronies and Avatards of the world are gonna flip over this.
da heck
What pony is that? The blue one i mean? I can't see
thats the best
WOW!! I've never seen a Trixie doll before, Korra looks like Malcom's mom
who is the pony she is on
Trixie, I custom made her.
You do not recognise the Great and Powerful Trixie?! NEIGH-SAYER!
How did you get their hair like that? I'm not allowed to cut my ponies hair cuz I share a room with my sister and she might get my scissors.
The only one with a haircut is Twilight (and I have fixed it more with another hot wash and soap.) You need to dunk them in nearly boiling water and then fix their hair in the shape you want with rubber bands and things, so they dry that way.
Lol, looks like Luna, or Trixie doesn't seem impress of Korra riding on top.
They have action figures already? O_o Awesome!
No, I made her.
How exactly did you get Rarity's hair like that, if it's not too much to ask? : O
lol! Ponies ftw. On a related note, check out this picture of mine. Wonder if there's a "photographing stuff with ponies" group on here yet? X'D
MY LITTLE PONY!!!!! lol
I have Rarity
where did you get trixie!??!?!?!
This could be 20% cooler if Rainbow Dash was there
The Great and Powerful Trixie is not amused
Trixie doesn't seem amused...
Wow, how did you get their hair like that? OnO it looks so straight and stuff
and nice picture~! XD
and nice picture~! XD


text:
How long does zara take to process orders?(27 Posts)
Beaverfeaver Fri 04-Jan-13 17:07:52
CashewNuts Fri 04-Jan-13 17:12:53
rubytutu Fri 04-Jan-13 18:59:25
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CointreauVersial Fri 04-Jan-13 20:31:26
CashewNuts Fri 04-Jan-13 22:46:03
Beaverfeaver Sat 05-Jan-13 02:11:15
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text: We were looking for a cheap comfortable clean place to stay. It definitely was that. The place was clean, the beds were comfortable and the price was right. Mr Patel was very accommodating and even offered free use of the lobby telephone if we needed to call home. No it does not have a complete breakfast, but what do you... More


text:
Dating the King of Pentacles
"Carnal love: a practical man's love. A love you can see, touch, and taste if you're kinky. If you can't hear it, you're probably better suited to its more abstract form." ― Benson Bruno The King of Pentacles is the King of Practicality. He's a no-nonsense family provider and businessman. He doesn't waste time on dreams that can't be turned into (profitable) reality. He can be intelligent but is usually not too imaginative. He prefers the tried and trusted to novel ideas…. Unless, of course, there is a large sum of money attached to the end of it. He's intuitive when it comes to making a buck but doesn't usually extend his gut instincts to serve him in other areas. Because the material realm is his domain, he can also be quite health conscious. Traditionally a Virgo male, he can even be fastidious to the point of OCD. Being male, he tends to not air his worries but tucks them in the gut where they can wreak havoc with his digestive system. His shady (reversed) aspects can be seen over at 8 Types of W*ankers. Pros: He's responsible. Stuff matters to this guy and he takes a lot of pride in his work. This is one man you won't have to teach how to floss. It's more likely that he's the one who'll remind you daily about how flossing adds six years to your life. If you like the idea of a big garden but aren't too keen on doing the actual gardening, he's your man! Being quite conventional, he's one of the safest bets if you're looking to start a family. He takes his role as breadwinner very seriously which allows you to focus on raising the children should you so wish. Cons: Can take the whole 'cleanliness is next to godliness' thingy a tad too far. You shouldn't have to worry about having a shower before sex every time on your honeymoon, should you? Nor should you have the man of the house walk behind you and check your dusting with his index finger. And god help you if you put his carefully arranged kitchen knives in the wrong order! Very careful about spending and expects the same of you, especially after the initial courtship period has ended. Be prepared to justify any purchase as useful. Not very subtle when it comes to using words in the game of seduction. The King or Knight of Wands can be blunt too but are usually better at carrying it off because they somehow manage to make you laugh at the same time. Out of all his mates, you can count on him to be the first to reach the pipe and slippers stage. Type of date he prefers: He'll worry about how it 'should' be done. Traditional wining and dining is on the menu in other words. He might also try to impress...Read More »


text:
"2011 looks like this at the moment:
The Light is the Darkness Bloodletting Press
"Blackwood's Baby" Ghosts by Gaslight
"The Siphon" Blood and Other Cravings
"The Carrion Gods in Their Heaven" Supernatural Noir
"The Hard and the Soft Kiss, in the Dark Room" mystery antho
"Blood & Stardust," mystery antho"
"Two other stories, "Gula de Saturnus" and "The Men from Porlock" have either found homes or will soon.
"The Forest" will appear in a mega anthology of a 100 years of weird by the VanderMeers. Will also appear in Cuásar, a magazine out of Argentina.
"Proboscis" Creatures
Mysterium Tremendum Wilde Stories
"--30--" Datlow's The Best New Horror of the Year 3
"The Broadsword" Guran's Best Dark Fantasy & Horror of the Year 2011"
5 out of 5
Sunday, April 17, 2011
Twenty-nine - Laird Barron
Posted by Blue Tyson at 1:03 PM
Labels: 5.0, bibliography, z non fiction
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text:
On June 13, funeral services were held in Nashville, Tennessee for U.S. Marine Sgt. Kevin Balduf who was killed in action on May 12 while serving in Afghanistan.The friends and family of Sgt. Balduf were faced not only with the task of mourning someone they cared for, but with the unwelcome attention of the controversial Westboro Baptist Church, who announced their plans to protest at his funeral services.Westboro Baptist is a church headed by Fred Phelps, which is primarily comprised of a … [Read more...]
Wyrd Designs – Heathens Support Fallen Soldier At Anti-Westboro Baptist Protest
Wyrd Designs – Radical Protesters at Veteran Funerals…
I think in all the recent attention to politician Christine O'donnell, we've overlooked another equally important news story, one that hasn't just appeared out of nowhere but that has been an on-going plague of religious fundamentalists protesting at the funerals of U.S. veterans for years. At the moment the Supreme Court is reviewing a case concerning free speech as it applies to a lawsuit filed by Arthur Snyder, father of a deceased soldier against one of those groups: the infamous Westboro Bap … [Read more...]


text:
- Is it OK to have Secure(SSL) equal to No
- Is port 26 OK (25 is more common)
CNET's Forum on Windows legacy operating systems, (XP, 2000/NT, ME, & Windows 95/98) is the best source for finding help or getting troubleshooting advice from a community of experts. Discussions cover Windows 2003 Server, Windows installation, adding and removing programs, driver problems, crashes, upgrading, and other OS-related questions.
I suddenly cannot send email in outlook, but I can rcv email. I've already scanned my laptop for viruses and ran malware and it all checks out OK. When I send an email it stays stuck in the outbox and never sends. The error I rcv is this:
"The connection to the server has failed. Account: 'mail.blankblank.com', Server: 'mail.blankblank.com', Protocol: SMTP, Port: 26, Secure(SSL): No, Socket Error: 10060, Error Number: 0x800CCC0E"
Has anyone had this problem or know what I can try next? Thanks
Big screens for the big game
Still looking for the best TV deals ahead of Sunday's game? Here are our top three big screen picks.


text:
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Tag Archives: quilt
a tale of twin quilts.
Here's another old one that I finally finished up! I've been trying my best to alternate new quilts with older quilts, and it's been working well so far. After working on something new, I decided it was time for this … Continue reading
Posted in [search] Other Quilts, Fabric, Finished Quilts, Posts about Quilts, Quilts Tagged churn dash, churn dash quilt, handmade, liberty of london, quilt, quilting, vintage quilt 14 Comments
shimmering strings
This quilt was mostly finished the day I found out that Lake Champlain had completely frozen over, and I decided that mostly finished would have to be good enough. If you've been following along, you'll know that I love it … Continue reading
Macaroni twist quilt
Don't mind me while I gaze at these photos and dream about green grass, leaves, and warm temperatures! In the midst of the arctic temperatures we're experiencing now, it's kind of nice to post these sunny summer photos. I made … Continue reading


text:
BELLAWOOD Engineered 1/2" x 5" Red Oak Engineered
BELLAWOOD- 1/2" x 5" Red Oak Prefinished Engineered Flooring- 100 Year Warranty!
Length: 1'-7'
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Red Oak is America's most popular choice for wood floors and serves as the industry benchmark when rating hardness among species. It features a reddish tan color and has a distinctive glow that creates an inviting atmosphere in rooms near and far. Better yet, changes due to sunlight exposure are minimal with Red Oak, ensuring a bright and beautiful floor for years to come.
Bellawood Engineered Hardwood Floors feature a multi-ply cross-layered wood core and a solid 3 mm thick veneer(dry-sawn top layer). This construction design offers more dimensional stability for wide planks, making them less susceptible to the climatic effects of moisture or dryness.
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A:Full refinishing will take slightly under a 1/32" off the veneer of the wood flooring. The thickness of the veneer and how much wear and dents a floor has will determine how many times it can be refinished. This flooring has a 3mm veneer layer.
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A:Bellawood engineered has a 3 mm wear layer a superior finish. It is factory pre-finished with a solvent-free aluminum oxide-based finish. During the multi-step application process, each coat is cured using Ultraviolet (UV) light.