Genetic Variants Associated with Elevated Plasma Ceramides in Individuals with Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex condition of metabolic disorders and shows a steady onset globally. Ceramides are known as intracellular signaling molecules that influence key metabolism through various pathways such as MetS and insulin resistance. Therefore, it is important to identify novel genetic factors related to increased plasma ceramides in subjects with MetS. Here we first measured plasma ceramides levels in 37 subjects with MetS and in 38 healthy subjects by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, levels of C16 ceramide (Cer-16), C18 ceramide (Cer-18), C20 ceramide (Cer-20), C18 dihydroceramide (DhCer-18), C24 dihydroceramide (DhCer-24), and C24:1 dihydroceramide (DhCer-24:1) were significantly increased in MetS group (p < 5.0 × 10−2). We then performed single nucleotide polymorphism (SNP) genotyping to identify variants associated with elevated plasma ceramides in MetS group using Axiom® Korea Biobank Array v1.1 chip. We also performed linear regression analysis on genetic variants involved in ceramide synthesis and significantly elevated plasma ceramides and dihydroceramides. Ten variants (rs75397325, rs4246316, rs80165332, rs62106618, rs12358192, rs11006229, rs10826014, rs149162405, rs6109681, and rs3906631) across six genes (ACER1, CERS3, CERS6, SGMS1, SPTLC2, and SPTLC3) functionally involved in ceramide biosynthesis showed significant associations with the elevated levels of at least one of the ceramide species in MetS group at a statistically significant threshold of false discovery rate (FDR)-adjusted p < 5.0 × 10−2. Our findings suggest that the variants may be genetic determinants associated with increased plasma ceramides in individuals with MetS.

Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis.

Since several studies have inconsistently reported the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of stroke, we performed a meta-analysis on this issue. We identified studies by searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to August, 2013. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirteen relevant studies (three case-control, six nested case-control, and four cohort studies) were finally included in our study. In our meta-analyses, the use of SSRIs was associated with an increased risk of all types of stroke [adjusted odds ratio (aOR), 1.40; 95 % confidence interval (CI), 1.09-1.80], ischemic stroke (aOR 1.48; 95 % CI 1.08-2.02), and hemorrhagic stroke (aOR 1.32; 95 % CI 1.02-1.71). Between the two subtypes of hemorrhagic stroke, that is, intracerebral and subarachnoid, the increased risk of intracerebral hemorrhage was associated with the use of SSRIs (aOR 1.30; 95 % CI 1.02-1.67). When the analysis was restricted to the studies in which potential confounding by depression was considered, the risks were still higher in SSRI users than in non-users and the heterogeneities among studies were significantly decreased. Since there was heterogeneity among studies and a possible confounding effect from depression could not be fully excluded, further well-designed studies are needed to confirm this association.

Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies.

AIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer. METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H2RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached. RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I² = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H2RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I² = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I² = 0.0%, P = 0.377). CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.

Pre-existing diabetes mellitus increases the risk of gastric cancer: a meta-analysis.

AIM: To systematically assess the association between diabetes and incidence of gastric cancer. METHODS: We searched MedLine (PubMed), EMBASE, and the Cochrane Library without any limitations with respect to publication date or language, we also searched the references of qualifying articles. Case-control studies and cohort studies comparing the risk of gastric cancer between diabetic patients and control subjects were included. We excluded studies reporting only standardized incidence ratios without control groups and those that investigated only mortality but not incidence. Seventeen studies met our criteria, and the qualities of these studies were assessed using the Newcastle-Ottawa Quality Assessment Scale. We performed a meta-analysis of pre-existing diabetes and gastric cancer incidence using the DerSimonian-Laird method for random-effects. For subgroup analyses, we separated the studies by study type, region, sex and method to determine confounding factors and reliability. We also conducted subgroup analyses to examine the effects of smoking, Helicobacter pylori (H. pylori) infection, and cancer site. Publication bias was evaluated using Begg's test. RESULTS: A random-effects model meta-analysis showed an increased gastric cancer risk in diabetic patients [relative risk (RR) = 1.19; 95%CI: 1.08-1.31]. Subgroup analyses indicated that this result persisted in cohort studies (RR = 1.20; 95%CI: 1.08-1.34), in studies on populations of both Western (RR = 1.18; 95%CI: 1.03-1.36) and Eastern countries (RR = 1.19; 95%CI: 1.02-1.38), in a female subgroup (RR=1.24; 95%CI: 1.01-1.52), and in highly qualified studies (RR = 1.17; 95%CI: 1.05-1.31). Moreover, these results persisted when the analysis was confined to studies adjusted for well-known gastric cancer risk factors such as smoking (RR = 1.17; 95%CI: 1.01-1.34) and H. pylori infection (RR = 2.35; 95%CI: 1.24-4.46). CONCLUSION: Pre-existing diabetes mellitus may increase the risk of gastric cancer by approximately 19%. This effect seems to be unrelated to geographical region.

Impact of perceived social support on the mental health and health-related quality of life in cancer patients: results from a nationwide, multicenter survey in South Korea.

OBJECTIVE: We investigated whether and how perceived social support is associated with depression and quality of life among patients with various cancer diagnoses. METHODS: Data were collected from 1930 cancer patients treated at the National Cancer Center and nine regional cancer centers across Korea. The Duke-UNC functional social support scale was used to measure the perceived social support, and the PHQ-9 and the EORTC QLQ-C30 were used to measure the cancer patients' depression levels and quality of life, respectively. RESULTS: Subjects with low perceived social support reported significantly higher levels of depression, lower scores on all functional scales, higher scores on all three symptom scales, lower global health/quality of life scale scores, and higher scores on most single items than subjects with high perceived social support. There was no interaction between potential stressors and perceived social support, supporting the main effect model as the mechanism that the perceived social support reduce the adverse psychological outcomes. CONCLUSION: Perceived social support was associated with mental health and quality of life in cancer patients, through direct effect rather than stress-buffering effect. Interventions to enhance perceived social support might be helpful for improving mental health and QOL in cancer patients.

The association between perceived social support and continued smoking in cancer survivors.

OBJECTIVE: With the increased survival rate of cancer patients, positive changes in health behaviors, including smoking cessation, are becoming progressively more important. While studies in the general population have demonstrated the beneficial effects of high perceived support of smoking cessation and continuing abstinence, few studies have addressed such issues in cancer survivors. We examined the factors related to continued smoking among cancer survivors with specific attention given to the role of perceived social support. METHODS: A nationwide, multicenter survey was conducted with 1956 cancer patients. Smoking status at the time of diagnosis and at the time of survey, and perceived social support, as measured by the Duke-UNC Functional Social Support Questionnaire, were collected by self-reported questionnaire. RESULTS: Among 493 participants who were smoking at the time of cancer diagnosis, 131 (26.6%) were continued smokers at the time of survey. In a multivariate logistic regression analysis, current alcohol consumption (odds ratio, 3.29; 95% confidence interval, 1.91-5.65), early cancer stage (P(for trend)< 0.01), lung cancer diagnosis (odds ratio, 0.41; 95% confidence interval, 0.19-0.88), and high perceived social support (odds ratio, 0.59; 95% confidence interval, 0.37-0.96) showed significant associations with continued smoking. CONCLUSIONS: Cancer survivors with low perceived social support were more likely to continue smoking. Our study suggests that perceived social support may be an important factor for smoking cessation and maintenance of smoking cessation in this population.

Use of antidepressants and the risk of breast cancer: a meta-analysis.

The goal of this study was to perform a meta-analysis to examine the association between the use of antidepressants (AD) and the risk of breast cancer. We searched the EMBASE and MEDLINE databases from inception through February 25, 2012, using search terms related to ADs and breast cancer. Two evaluators independently reviewed and selected articles and extracted data based on predetermined selection criteria. Pooled effect estimates were obtained by using random- and fixed effects meta-analyses. Of the 3,209 titles identified, 18 articles met the inclusion criteria. The overall risk of breast cancer did not increase among AD users [adjusted odds ratio (aOR) 1.02; 95 % CI 0.96-1.08]. Those who took tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) were not at increased risks of breast cancer. In subgroup meta-analyses, null associations were consistent across the type of AD, funding sources, the number of adjusted variables, medication dose, the ascertainment of exposure, and methodological quality. In subgroup analyses based on exposure duration, a marginal association was observed for the use of SSRIs < 1-2 years (aOR 1.10; 95 % CI 1.02-1.19). However, this effect was attenuated over time and those using SSRIs for more than 1-2 years had no elevated breast cancer risk. These results support the lack of a clinically meaningful association between AD use and the development of breast cancer and provide considerable reassurance. Given that the data collected to date do not support changing the current prescribing patterns for ADs, the important benefits of AD therapy must be considered.

Use of Proton Pump Inhibitor and Risk of Colorectal Cancer: A Meta-analysis of Observational Studies.

BACKGROUND: Previous case-control studies have reported inconsistent findings regarding the association between proton pump inhibitor (PPI) use and colorectal cancer (CRC) risk. We investigated these associations using meta-analysis. METHODS: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library in April 2011. Two evaluators independently reviewed and selected articles, based on pre-determined selection criteria. RESULTS: Out of 737 articles meeting our initial criteria, 5 case-control studies, which involved 120,091 participants (9,514 cases and 110,577 controls), were included in the final analyses. The overall use of PPI (used vs. never or rarely used) was not significantly associated with the risk of CRC in a fixed-effects model meta-analysis of all 5 case-control studies (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.96 to 1.20; I(2) = 3.5%). Also, in sensitivity meta-analysis by cumulative duration of PPI use, there was no association between PPI use of 1 year or longer and the risk of colorectal cancer in a fixed-effects meta-analysis (OR, 1.09; 95% CI, 0.98 to 1.22; I(2) = 0%). CONCLUSION: Although hypergastrinemia could be an important factor in the pathogenesis of some colorectal cancers, our study suggests that this does not lead to significant clinical risk for most PPI users. Further prospective studies or randomized controlled trials related to PPI use and colorectal cancer risk are needed to investigate this association.

Meta-analysis: selective serotonin reuptake inhibitors and colon cancer.

OBJECTIVE: To perform meta-analyses using observational studies to assess the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of colorectal cancer. METHODS: A systematic search of relevant studies published through February 2012 was carried out using the Medline (PubMed), Embase, and Cochrane Library databases. We reviewed the observational studies that were associated with our subject and carried out a meta-analysis. RESULTS: Out of 324 screened articles, six observational studies were included in the final analyses. According to this meta-analysis, the use of SSRIs was not associated with an increased risk of colorectal cancer in pooled analyses (adjusted odds ratio 0.89, 95% confidence interval 0.79-1.01). This finding was consistently observed in subgroup analyses of study area, location of colorectal cancer, duration of SSRI use, study quality, adjustment for NSAID use, and the prevalence of overweight. CONCLUSION: Our research shows that the use of SSRIs does not increase the risk of colorectal cancer. Further studies are needed to confirm the association between SSRIs and colorectal cancer.

Alcohol consumption shows a J-shaped association with lower urinary tract symptoms in the general screening population.

PURPOSE: Controversial and contradictory data on the association between alcohol consumption and lower urinary tract symptoms are currently available in the literature. In this study we determined the association between alcohol consumption and lower urinary tract symptoms, including voiding and storage symptoms, in a large general screening population. MATERIALS AND METHODS: This cross-sectional study included 30,196 men 30 years old or older participating in a comprehensive health evaluation at the Seoul National University Hospital Healthcare System Gangnam Center. Men with a history of prostate related medical problems such as prostate cancer, prostate surgery or prostatitis were excluded from study. Using the International Prostate Symptom Score, lower urinary tract symptoms were defined as a score of 8 or greater, indicating moderate to severe symptoms. We used logistic regression analysis to determine the association between alcohol consumption and lower urinary tract symptoms. RESULTS: After adjustment for eligible covariates, graphing of the association between alcohol consumption and the risk of moderate to severe lower urinary tract symptoms showed a J-shaped curve. Compared with nondrinkers, the odds ratios of moderate to severe lower urinary tract symptoms were 0.91 (95% CI 0.84-0.98) in men who drank 0 to 10 gm daily and 1.19 (95% CI 1.07-1.33) in those who drank 40 or more gm daily. This is a cross-sectional study with data from self-reported alcohol consumption and, therefore, the reported amounts of alcohol consumption might be underestimated. CONCLUSIONS: To the best of our knowledge this is the largest population based study to evaluate the relationship between alcohol consumption and moderate to severe lower urinary tract symptoms, including voiding and storage symptoms. In men alcohol consumption shows a J-shaped curve relationship with the risk of moderate to severe lower urinary tract symptoms.

Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis.

Previous studies have reported inconsistent findings regarding the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of fracture. We identified relevant studies by searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to October 20, 2010. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. We identified 12 studies: seven case-control studies and five cohort studies. A meta-analysis of these 12 observational studies showed that the overall risk of fracture was higher among people using SSRIs (adjusted odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.51-1.90, I(2 ) = 89.9%). Subgroup analysis by adjusted number of key risk factors for osteoporotic fracture showed a greater increased fracture risk in those adjusted for fewer than four variables (adjusted OR = 1.83, 95% CI 1.57-2.13, I(2) = 88.0%) than those adjusted for four or more variables (adjusted OR = 1.38, 95% CI 1.27-1.49, I(2) = 46.1%). The pooled ORs anatomical site of fracture in the hip/femur, spine, and wrist/forearm were 2.06 (95% CI 1.84-2.30, I(2 ) = 62.3%), 1.34 (95% CI 1.13-1.59, I(2 ) = 48.5%), and 1.51 (95% CI 1.26-1.82, I(2 ) = 76.6%), respectively. Subgroup analysis by exposure duration revealed that the strength of the association decreased with a longer window of SSRI administration before the index date. The risk of fracture was greater within 6 weeks before the index date (adjusted OR = 3.83, 95% CI 1.96-7.49, I(2 ) = 41.5%) than 6 weeks or more (adjusted OR = 1.60, 95% CI 0.93-2.76, I(2 ) = 63.1%). Fracture risk associated with SSRI use may have a significant clinical impact. Clinicians should carefully consider bone mineral density screening before prescribing SSRIs and proper management for high-risk populations.

Metabolic syndrome and accompanying hyperinsulinemia have favorable effects on lower urinary tract symptoms in a generally healthy screened population.

PURPOSE: We assessed the association of metabolic syndrome, insulin resistance and lower urinary tract symptoms in a large, screened adult population. MATERIALS AND METHODS: We analyzed 33,841 Korean men 30 years old or older who underwent routine health assessments from October 2003 to February 2010. Metabolic syndrome was defined according to the modified Adult Treatment Panel III guidelines. Lower urinary tract symptoms were assessed using the International Prostate Symptom Score. Blood samples were drawn in the morning after patients had fasted at least 12 hours. RESULTS: Lower urinary tract symptoms had a marginally negative association with metabolic syndrome after adjusting for age (p = 0.045). This negative association became more significant as the number of metabolic syndrome components increased (p trend <0.01), especially voiding symptoms (p trend <0.01). Increasing the level of fasting insulin and the severity of insulin resistance were associated with a lower age adjusted OR for lower urinary tract symptoms (p <0.01 and 0.03, respectively). However, the diabetes group with high HbA1c (8.0% or greater) had a higher age adjusted OR for lower urinary tract symptoms, especially storage symptoms. The group with metabolic syndrome plus insulin resistance had lower total International Prostate Symptom Score, voiding symptoms, storage symptoms and quality of life scores than those without metabolic syndrome and/or insulin resistance (p <0.01, 0.01, 0.047 and 0.03, respectively). CONCLUSIONS: Metabolic syndrome, insulin resistance and the accompanying hyperinsulinemia may have favorable effects on lower urinary tract symptoms in the early compensatory stage, especially voiding symptoms. However, advanced diabetes may have unfavorable effects on lower urinary tract symptoms, especially storage symptoms. Hyperinsulinemia in patients with metabolic syndrome or insulin resistance may be a key factor in this phenomenon.

Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies.

PURPOSE: Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis. METHODS: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity. RESULTS: Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk. CONCLUSIONS: We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.

Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis.

BACKGROUND: Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association. METHODS: We searched three electronic databases (MEDLINE [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. RESULTS: We identified 31 studies: five case-control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11-1.46, I(2) 90.5%) and histamine(2) receptor antagonists (adjusted OR 1.22, 95% CI 1.09-1.36, I(2) 0.0%). In the randomized controlled trials, use of histamine(2) receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01-1.48, I(2) 30.6%). INTERPRETATION: Use of a proton pump inhibitor or histamine(2) receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.

Risk of fracture and pneumonia from acid suppressive drugs.

A recently published systematic review and meta-analysis, incorporating all relevant studies on the association of acid suppressive medications and pneumonia identified up to August 2009, revealed that for every 200 patients, treated with acid suppressive medication, one will develop pneumonia. They showed the overall risk of pneumonia was higher among people using proton pump inhibitors (PPIs) [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I(2) = 90.5%] and Histamine-2 receptor antagonists (H2RAs) (adjusted OR = 1.22, 95% CI: 1.09-1.36, I(2) = 0.0%). In the randomized controlled trials, use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI: 1.01-1.48, I(2) = 30.6%). Another meta-analysis of 11 studies published between 1997 and 2011 found that PPIs, which reduce stomach acid production, were associated with increased risk of fracture. The pooled OR for fracture was 1.29 (95% CI: 1.18-1.41) with use of PPIs and 1.10 (95% CI: 0.99-1.23) with use of H2RAs, when compared with non-use of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and of hip fracture risk (adjusted OR = 1.34, 95% CI: 1.09-1.66), whereas long-term H2RA use was not significantly associated with fracture risk. Clinicians should carefully consider when deciding to prescribe acid-suppressive drugs, especially for patients who are already at risk for pneumonia and fracture. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using the only minimum effective dose of drug required to achieve the desired therapeutic goals.