Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study

Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.     

Meta-analysis of the relationship between single nucleotide polymorphism rs72689236 of caspase-3 and Kawasaki disease

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology, for which a genetic influence is suspected. But whether single nucleotide polymorphism (SNP) of caspase-3 rs72689236 is associated with Kawasaki disease is controversial. The aim of our study is to assess the association between the SNP of caspase-3 and risk for Kawasaki disease. We searched PubMed, MEDLINE, EMBASE, Springer, Elsevier Science Direct, Cochrane Library Google scholar, CNKI (China National Knowledge Infrastructure, in Chinese) and Wanfang database (in Chinese) to identify studies investigating the association between rs72689236 polymorphism and Kawasaki disease occurrence. There were five eligible studies, which included 4,241 (case group 1,560; control group 2,681) participants in this meta-analysis. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model (the Mantel–Haenszel method) or a random-effects model (the DerSimonian and Laird method) when appropriate. Significant associations were found under the overall ORs for A-allele comparison (A vs. G, pooled OR 1.33, 95 % CI 1.21–1.46), AA versus GG comparison (pooled OR 1.64, 95 % CI 1.35–2.00), GA versus GG comparison (pooled OR 1.42, 95 % CI 1.24–1.63), recessive model (AA vs. GG + GA, pooled OR 1.37, 95 % CI 1.15–1.64) and dominant model (AA + GA vs. GG, pooled OR 1.47, 95 % CI 1.29–1.67). This meta-analysis suggested that SNP rs72689236 of caspase-3 might be associated with susceptibility of Kawasaki disease and the allele A might increase the risk of Kawasaki disease in Asian samples such as Japanese and Chinese. In addition, individual studies with large sample size are needed to further evaluate the associations in various ethnic populations.     

Thrombotic risk stratification using computational modeling in patients with coronary artery aneurysms following Kawasaki disease

Kawasaki disease (KD) is the leading cause of acquired heart disease in children and can result in life-threatening coronary artery aneurysms in up to 25 % of patients. These aneurysms put patients at risk of thrombus formation, myocardial infarction, and sudden death. Clinicians must therefore decide which patients should be treated with anticoagulant medication, and/or surgical or percutaneous intervention. Current recommendations regarding initiation of anticoagulant therapy are based on anatomy alone with historical data suggesting that patients with aneurysms \(\ge \) 8 mm are at greatest risk of thrombosis. Given the multitude of variables that influence thrombus formation, we postulated that hemodynamic data derived from patient-specific simulations would more accurately predict risk of thrombosis than maximum diameter alone. Patient-specific blood flow simulations were performed on five KD patients with aneurysms and one KD patient with normal coronary arteries. Key hemodynamic and geometric parameters, including wall shear stress, particle residence time, and shape indices, were extracted from the models and simulations and compared with clinical outcomes. Preliminary fluid structure interaction simulations with radial expansion were performed, revealing modest differences in wall shear stress compared to the rigid wall case. Simulations provide compelling evidence that hemodynamic parameters may be a more accurate predictor of thrombotic risk than aneurysm diameter alone and motivate the need for follow-up studies with a larger cohort. These results suggest that a clinical index incorporating hemodynamic information be used in the future to select patients for anticoagulant therapy.     

A public health approach to cholesterol. Confronting the 'TV-auto-supermarket society'.

Coronary heart disease has been proved to be associated with a "high-risk" diet and with elevated blood cholesterol levels. The National Cholesterol Education Program has embarked on a campaign based on intensive medical treatment of 60 million Americans with high blood cholesterol levels, but the degree of benefit of dietary change or pharmaceutical intervention or both to reduce blood cholesterol values remains a subject of disagreement within the scientific community. Evidence from comparative international studies suggests that to lower coronary heart disease mortality substantially, dietary alterations and general societal changes must be greater than those possible under the National Cholesterol Education Program''s approach of physician-centered patient counseling. The nation''s priority to prevent coronary heart disease should be a public policy approach, the goal of which is to reduce for the entire population all coronary disease risk factors. In the dietary area, three proposals to reduce the availability of atherogenic foods are the use of warning labels on atherogenic foods, the prohibition of advertising for such high-risk foods, and the imposition of an excise tax on the same foods. We must confront the "TV-auto-supermarket society" that underlies our nation''s high rate of coronary heart disease.     

HRV Biofeedback for Pediatric Irritable Bowel Syndrome and Functional Abdominal Pain: A Clinical Replication Series

Irritable bowel syndrome (IBS) and Functional Abdominal Pain (FAP) are among the most commonly reported Functional Gastrointestinal Disorders. Both have been associated with varying autonomic dysregulation. Heart Rate Variability Biofeedback (HRVB) has recently begun to show efficacy in the treatment of both IBS and FAP. The purpose of this multiple clinical replication series was to analyze the clinical outcomes of utilizing HRVB in a clinical setting. Archival data of twenty-seven consecutive pediatric outpatients diagnosed with IBS or FAP who received HRVB were analyzed. Clinical outcomes were self-report and categorized as full or remission with patient satisfaction, or no improvement. Qualitative reports of patient experiences were also noted. Full remission was achieved by 69.2 % and partial remission was achieved by 30.8 % of IBS patients. Full remission was achieved by 63.6 % and partial remission was achieved by 36.4 % of FAP patients. No patients in either group did not improve to a level of patient satisfaction or >50 %. Patient’s commonly reported feeling validated in their discomfort as a result of psychophysiological education. Results suggest that HRVB is a promising intervention for pediatric outpatients with IBS or FAP. Randomized controlled trials are necessary to accurately determine clinical efficacy of HRVB in the treatment of IBS and FAP.     

Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

Fabry disease is a monogenic X-linked lysosomal storage disease caused by α-galactosidase A (αGalA) deficiency. Enzyme replacement therapy through administration of the missing αGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction therapy for Fabry disease. Owing to the fact that αGalA-deficient humans and mice accumulate the same glycosphingolipids (i.e. globosides, galabiosylceramide and isoglobosides), αGalA-deficient mice were crossed with mice deficient in enzymes synthesizing these classes of glycosphingolipids (i.e. globotrihexosylceramide and isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of globosides was sufficient to fully abolish the storage of glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction therapy through inhibition of the synthesis of globosides and isoglobosides represents a valuable therapeutic option for Fabry disease, all the more as globosides and isoglobosides seem to be dispensable.     

Gender differences in the expression of genes involved during cardiac development in offspring from dams on high fat diet

Previously we have demonstrated that maternal high fat diet (HF) during pregnancy increase cardiovascular risk in the offspring, and pharmacological intervention using statins in late pregnancy reduced these risk factors. However the effects of maternal HF-feeding and statin treatment during pregnancy on development of heart remain unknown. Hence we measured expression of genes involved in cell cycle progression (cyclin G1), ventricular remodelling brain natriuretic peptide (BNP), and environmental stress response small proline-rich protein 1A (SPRR 1A) in the offspring left ventricle (LV) from dams on HF with or without statin treatment. Female C57 mice were fed a HF diet (45 % kcal fat) 4 weeks prior to conception, during pregnancy and lactation. From the second half of the pregnancy and throughout lactation, half of the pregnant females on HF diet were given a water-soluble statin (Pravastatin) in their drinking water (HF + S). At weaning offspring were fed HF diet to adulthood (generating dam/offspring dietary groups HF/HF and HF + S/HF). These groups were compared with offspring from dams fed standard chow (C 21 % kcal fat) and fed C diet from weaning (C/C). LV mRNA levels for cyclin G1, BNP and SPRR 1A were measured by RT-PCR. Heart weights and BP in HF/HF offspring were higher versus C/C group. Maternal Pravastatin treatment reduced BP and heart weights in HF + S/HF female offspring to levels found in C/C group. LV cyclin G1 mRNA levels were lower in HF/HF versus both C/C and HF + S/HF offspring. BNP mRNA levels were elevated in HF/HF females but lower in males versus C/C. BNP gene expression in HF + S/HF offspring was similar to HF/HF. SPRR 1A mRNA levels were similar in all treatment groups. Statins given to HF-fed pregnant dams reduced cardiovascular risk in adult offspring, and this is accompanied by changes in expression of genes involved in adaptive remodelling in the offspring LV and that there is a gender difference.     

1-Stearoylglycerol is associated with risk of prostate cancer: results from a serum metabolomic profiling analysis

Although prostate cancer is the most commonly diagnosed cancer among men in developed populations, recent recommendations against routine prostate-specific antigen screening have cast doubt on its utility for early detection. We compared the metabolomic profiles of prospectively collected fasting serum from 74 prostate cancer cases and 74 controls selected from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers. Circulating 1-stearoylglycerol (1-SG, or 1-monostearin) was statistically significantly inversely associated with risk of prostate cancer after Bonferroni correction for multiple comparisons (i.e., 420 identified metabolites) (OR 0.34, 95 % CI 0.20–0.58, p 6.3 × 10^?5). The magnitude of this association did not differ by disease aggressiveness and was observed for cases diagnosed up to 23 years after blood collection. Similar but somewhat weaker prostate cancer risk signals were also evident for glycerol and alpha-ketoglutarate. In this population, men with higher serum 1-SG were less likely to develop prostate cancer, supporting a role for dysregulation of lipid metabolism in this malignancy. Additional studies are needed to retest the association and to examine 1-SG for its potential as a prostate cancer early detection marker.     

Associations of platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphisms with circulating PAF-AH levels and risk of coronary heart disease or blood stasis syndrome in the Chinese Han population

The circulating level of platelet-activating factor acetylhydrolase (PAF-AH) is a novel biomarker to predict the presence of coronary heart disease. PAF-AH gene polymorphisms may be responsible for the variance of circulating PAF-AH levels in individuals. However, the association of PAF-AH gene polymorphisms with circulating PAF-AH levels and the susceptibility to coronary heart disease (CHD) remains unsolved. Blood stasis syndrome (BSS) of CHD is the most common type of TCM syndromes, and a previous study discovered its relationship with the elevated circulating PAF-AH levels. However, the association of gene polymorphisms and CHD with BSS is unclear at present. In this study, four polymorphisms (R92H, I198T, A379V, V279F) of the PAF-AH gene were genotyped in 570 CHD patients, of which 299 had BSS. In addition, 317 unaffected individuals from the same hospitals served as controls. Plasma PAF-AH levels were measured in 155 controls and 271 CHD patients selected randomly, including 139 CHD patients with BSS. In the Chinese Han population, plasma PAF-AH levels in CHD patients with BSS or without BSS were significantly higher (12.9 ± 6.5 and 11.1 ± 5.0 μM, respectively) than in controls (9.3 ± 5.2 μM); this difference still remained significant after adjustment for traditional risk factors or the inflammatory factors. The R92H polymorphism was highly related to the plasma PAF-AH levels and the risk of CHD, especially among patients with BSS, even with the adjustment for the effects of traditional factors. The I198T polymorphism was highly associated with risk of CHD with BSS, but was associated with neither the risk of CHD with no BSS nor with elevated plasma PAF-AH levels.     

Selenium and Behçet's disease

Behçet's disease is an inflammatory disorder of unknown etiology, characterized by recurrent oral and genital aphthous ulcers, ocular inflammation, and skin lesions of erythema nodusum and acneiformeruptions. Selenium (Se) affects all components of the immune system, i.e., the development and expression of nonspecific, humoral, and cell-mediated responses. In general, a deficiency in Se appears to result in immunosuppression, whereas supplementation with low doses of Se appears to result in augmentation and/or restoration of immunoglogic functions. In this study, the distribution of Se and IgG, IgM in serum were compared in samples from healthy adult control and Behçet's disease patients. The serum Se levels were measured by AA-30-40 Varian Spectra, and immunoglobulins were measured by immunodiffusion technique. The mean (SD) serum Se level of 54.24 ± 8.06 ng/mL among Behçet's disease subjects was significantly different (P<0.01) from that in the control subjects (90.01 ± 9.94 ng/mL). We also measured IgG and IgM as 10.01 ± 2.74 mg/mL and 1.26 ± 0.29 mg/mL, respectively for patients, and 15.08 ± 4.73 mg/mL and 1.58 ± 0.43 mg/mL for controls. The mean values of IgG and IgM for patients were significantly (P<0.05) different from the values of controls. It seems, therefore, that a deficiency in selenium impedes the humoral immune response.     

The inhibitory effect of angiotensin II on BKCa channels in podocytes via oxidative stress

Angiotensin II (Ang II) is an important active substance of the renin-angiotensin system (RAS). The present study has confirmed that abnormalities of Ang II may be related with cerebrovascular diseases, endocrine diseases, cardiovascular diseases, liver diseases, such as: cerebral hypoxia, diabetes, obesity, atrial fibrillation, and liver cirrhosis. However, understanding effects of Ang II on podocytes is not enough. This study was to investigate the effects of oxidative stress on the large conductance, Ca²⁺-activated K⁺ channels (BK_Ca). Results from the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death in a concentration-dependent manner. The measurement of superoxide dismutase (SOD) generation demonstrated that Ang II decreased the total SOD of cellular levels. Meaningfully, pretreatment of a type of ROS scavenger formulations named N-(mercaptopropionyl)-glycine (N-MPG) could inhibit podocyte apoptosis induced by Ang II. Meanwhile, patch-clamp technique was used in this study to detect the effects of Ang II on currents of BK_Ca channel in podocytes. The results indicated that Ang II inhibited the current amplitude of BK_Ca channel and decreased the slope of I–V curve. Ang II also made the activation curves of BK_Ca channel shift to the left. These results may provide a theoretical basis for potential treatment of chronic glomerular disease in the future.     

Return to Work after Percutaneous Coronary Intervention: The Predictive Value of Self-Reported Health Compared to Clinical Measures

Aims

Coronary heart disease is prevalent in the working-age population. Traditional outcome measures like mortality and readmission are of importance to evaluate the prognosis but are hardly sufficient. Ability to work is an additional outcome of clinical and societal significance. We describe trends and predictors of Return To Work (RTW) after PCI and describe a possible benefit using patient-reported measures in risk stratification of RTW.

Methods

A total of 1585 patients aged less than 67 years treated with PCI in 2006–2008 at the Aarhus University Hospital were enrolled. Clinical information was provided through the West Denmark Heart Registry, and 4 weeks after PCI we mailed a questionnaire regarding self-rated health (response rate 83.5%). RTW was defined at weekly basis using extensive register data on transfer payments. Predictors of RTW were analysed as time to event. ROC curves constructed by logistic regression of predicting variables were evaluated by the c-statistic.

Results

Four weeks before PCI 50% of the patients were working; the corresponding figures were 25% after 4 weeks, 36% after 12 weeks, and 43% after one year. The patients’ self-rated health one month after the procedure was a significant better predictor of RTW compared to other variables including LVEF, both at short (12 weeks) and long (one year) term.

Conclusions

The patient''s self-rated health four weeks after the procedure was a stronger predictor than left ventricular ejection fraction (LVEF), and consequently useful when patients seek medical advice with respect to RWT.     

Genome-wide association study as a method to analyze the genome architecture in polygenic diseases,with the example of multiple sclerosis

Genome-wide association study (GWAS) provides a powerful tool for investigating the genetic architecture of human polygenic diseases and is generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. The differences in allele frequencies of single nucleotide polymorphisms (SNPs) distributed throughout the genome are analyzed with a microarray technique or other technologies that allow simultaneous genotyping at several tens of thousands to several millions of SNPs per sample. Owing to its power to find out highly reliable differences between patients and controls, GWAS became a common approach to identification of the genetic susceptibility factors in complex diseases of a polygenic nature. Using multiple sclerosis (MS) as a prototype complex disease, the review considers the main achievements and challenges of using GWAS to identify the genes involved in the disease and, therefore, to better understand the pathogenetic molecular mechanisms and genetic risk factors.     

De novo expression of fetal ED-A+ fibronectin and B+ tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection

Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re-expression could be demonstrated for ED-A⁺ Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A⁺ Fn, B⁺ Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A⁺ Fn and B⁺ Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A⁺ Fn (r = 0.442, p = 0.000) and B⁺ Tn-C (r = 0.408, p = 0.001) as well as between both proteins (r = 0.663, p = 0.000). A spatial association of ED-A⁺ Fn and B⁺ Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED-A⁺ Fn and B⁺ Tn-C following human heart transplantation could be demonstrated with spatial association to signs of rejection and a significant correlation to tissue inflammation. These data might contribute to the identification of novel biomarkers reflecting the rejection process and to the development of promising strategies to image, prevent or treat cardiac rejection.     

Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families

Wolfram syndrome also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare neurodegenerative autosomal recessive disorder. There is evidence of variable expressivity both in patients and heterozygous carriers. In this study, we describe three Persian Wolfram syndrome families with differences in the age of onset, signs and symptoms of the disease. We clinically evaluated affected families for verifying WS clinical diagnosis. After linkage analysis via 5 STR markers, molecular analysis for WFS1 was performed by direct sequencing for patients and available family members. Three homozygous mutations were identified including c.1885 C>T, c.2205C>A both in exon 8 and c.460+1G>A in intron 4. The mutation c.2205C>A was found to be novel. We report interesting phenotype-genotype correlations: homozygous c.1885C>T and c.2205C>A variants were correlated with quite different disease severity and onset in the siblings. We report a rare case of WS with homozygous c.1885C>T who is married and has a healthy child. c.460+1G>A showed a possible partial dominant inheritance put forth by a heterozygous parent showing partial WS symptoms while her daughter displayed typical WS symptoms. Due to variable expressivity, detailed clinical examination and molecular diagnostics should be used to confirm WS and a more exact recurrence risk data.     

Neurotrophic Factors,Clinical Features and Gender Differences in Depression

Recent studies have evaluated the role of brain-derived neurotrophic factor (BDNF) in mood disorders; however, little is known about alterations in nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF). The aim of this study was to evaluate differences among serum neurotrophic factors (BDNF, NGF and GDNF) in depressed patients and healthy controls and to verify the association between serum neurotrophic levels and clinical characteristics in a young, depressed population stratified by gender. This is a cross-sectional study with depressed patients and population controls 18–29 years of age. The concentrations of neurotrophic factors were determined by the ELISA method. The diagnosis of depression and the duration of the disease were assessed by the Structured Clinical Interview according to the diagnostic and statistical manual of mental disorders. Depression severity was measured with the 17-item Hamilton Rating Scale for Depression, and the severity of anxiety symptoms was measured using the Hamilton Anxiety Rating Scale. Serum BDNF and GDNF were lower in major depressive disorder (MDD) patients compared to controls (p ≤ 0.001). Serum NGF levels were higher in MDD patients versus controls (p ≤ 0.001). BDNF was associated with the duration of disease only in women (p = 0.005). GDNF was not associated with clinical characteristics in either gender. In women, NGF was associated with the severity of depressive symptoms (p = 0.009), anxiety (p = 0.011) and disease duration (p = 0.005). NGF was associated with disease duration in men (p = 0.026). Our results demonstrated that significant neurochemical differences in NGF and BDNF, but not in GDNF, were associated with the clinical features of MDD when patients were stratified by gender.     

Association between the MMP-9−1562 C>T polymorphism and the risk of stroke: a meta-analysis

Matrix metalloproteinase (MMP)-9 so far is identified as extremely large and complicated MMP family member. Recently, dozens of studies have explored the association between a promoter polymorphism (?1562 C>T) in MMP-9 and stroke susceptibility. However, the conclusions of these studies still remain equivocal. Therefore, our current meta-analysis was conducted to investigate whether or not the MMP-9 promoter polymorphism is related to the risk of stroke. Electronic databases (PubMed, EMBASE, Web of Science, Cochrane Library and the Chinese Biomedical Literature Database) were searched to obtain all the available studies investigating this polymorphism and stroke from inception to October 2013. Overall and subgroup analyses were rigorously conducted after data extraction. Pooled odds ratio (OR) corresponding to 95 % confidence interval (CI) were estimated. The statistical analysis was performed using Review Manager 5.2. Totally, seven studies involving 1,624 cases and 1,525 controls were identified. The overall results suggested that there was no association of the C?1562T variant on stroke risk under the T allele versus C allele [OR _{T vs. C} 0.98, 95 % CI (0.84, 1.15), P = 0.84], the dominant model [OR _{TT+TC vs. CC} 0.95, 95 % CI (0.81, 1.13), P = 0.59], the recessive model [OR _{TT vs. TC+CC} 1.55, 95 % CI (0.86, 2.81), P = 0.15], the homozygote comparison [OR _{TT vs. CC} 1.48, 95 % CI (0.82, 2.68), P = 0.20] and the heterozygote comparison [OR _{TC vs. CC} 0.93, 95 % CI (0.78, 1.10), P = 0.38]. In the subgroup analyses by ethnicity, age, stroke type and source of controls, no significant relations were observed in any genetic models. Our results indicated that MMP-9?1562 C>T polymorphism was not a risk factor for stroke. Further studies should focus on gene–gene and gene–environment interactions, and provide a more convincing explanation for this association.     

Predictive modelling to aid the regional-scale management of a vertebrate pest

Extensive resources are allocated to managing vertebrate pests, yet spatial understanding of pest threats, and how they respond to management, is limited at the regional scale where much decision-making is undertaken. We provide regional-scale spatial models and management guidance for European rabbits (Oryctolagus cuniculus) in a 260,791 km² region in Australia by determining habitat suitability, habitat susceptibility and the effects of the primary rabbit management options (barrier fence, shooting and baiting and warren ripping) or changing predation or disease control levels. A participatory modelling approach was used to develop a Bayesian network which captured the main drivers of suitability and spread, which in turn was linked spatially to develop high resolution risk maps. Policy-makers, rabbit managers and technical experts were responsible for defining the questions the model needed to address, and for subsequently developing and parameterising the model. Habitat suitability was determined by conditions required for warren-building and by above-ground requirements, such as food and harbour, and habitat susceptibility by the distance from current distributions, habitat suitability, and the costs of traversing habitats of different quality. At least one-third of the region had a high probability of being highly suitable (support high rabbit densities), with the model supported by validation. Habitat susceptibility was largely restricted by the current known rabbit distribution. Warren ripping was the most effective control option as warrens were considered essential for rabbit persistence. The anticipated increase in disease resistance was predicted to increase the probability of moderately suitable habitat becoming highly suitable, but not increase the at-risk area. We demonstrate that it is possible to build spatial models to guide regional-level management of vertebrate pests which use the best available knowledge and capture fine spatial-scale processes.     

Trophic state evaluation after urban loads diversion in a eutrophic coastal lagoon (Óbidos Lagoon,Portugal): a modeling approach

Óbidos Lagoon is classified as a sensible system according to the eutrophication criteria in the Portuguese Decree-Law 149/2004, which transpose the standards of Urban Waste Water Treatment Directive (Council Directive 91/271/EEC) concerning urban waste water treatment. From September 2005 onwards, the urban loads of five Waste Water Treatment Plant (WWTP) were deviated to a submarine outfall to prevent water degradation and improve the lagoon trophic state (LTS). This paper evaluated the LTS after urban loads diversion, testing the hypothesis behind the management decision. First, the loads reaching the lagoon were determined with the Harp-Nut guidelines and watershed modeling. Then, the water quality in the lagoon was simulated with a hydro-ecological model and compared with measured data. Finally, management scenarios corresponding to nutrient loads reduction were tested to determine hypothesis-driven LTS. Results showed that the loads from pig farms should be diverted instead of the WWTP, to improve the LTS and achieve a “Good/Bad” status. The proposed method stresses the importance of integrated modeling tools in the Water Framework Directive, given their skill in testing various hypothesis, and ultimately ruling out inadequate management decisions before implementation.