Harmful alcohol consumption in elite sports players in Ireland.

BACKGROUND: Sportspeople are more prone to binge drink than their peers. AIMS: We aimed to assess alcohol consumption, harms and behaviours in an elite Irish sporting population (Gaelic footballers and hurlers). METHODS: An anonymous web-based questionnaire (demographics, alcohol consumption, culture and related harms) was administered to all elite players. The AUDIT-C questionnaire (frequency, quantity of alcohol consumption and frequency of binge drinking) was used to assess for adverse alcohol use. Univariate and multivariate analyses assessed for predictors of adverse alcohol use. RESULTS: 717 players (mean age 24 years) were analysed. The majority of patients were male (75%), unmarried (93%) and had completed university (67%). 96% were current drinkers. Players consumed more alcohol during the off-season (median 20 versus 8 standard drinks in 28 days) compared to the elite season. Amongst current drinkers, 73% exhibit adverse alcohol use, 93% reported binge drinking and 65% an alcohol related harm in the past year. Most players would turn to family (36%) or friends (21%) for help. There were significant associations between monthly bingeing (OR 18.4), smoking (OR 3.3), generally drinking in public (OR 3.2), current gambling (OR 2.3), male gender (OR 2.1), an alcohol harm in the past year (OR 1.9) and adverse alcohol use. In contrast, co-habiting with a partner (OR 0.5) was protective. CONCLUSIONS: Excess alcohol consumption, alcohol related harms and binge drinking are prevalent in an elite sporting population, particularly during the off-season. Specific strategies are required to reduce alcohol related harms, particularly amongst high-risk groups during the off-season.

Covered self-expanding metal stents for the management of common bile duct stones.

BACKGROUND AND AIMS: Little medical literature exists for the use of fully covered self-expanding metal stents (CSEMSs) in the management of retained common bile duct (CBD) stones. Our aim was to assess the safety and efficacy of CSEMSs for the indication of retained "difficult" CBD stones. METHODS: This retrospective cases series included 44 patients (30 women; median age, 69 years [range, 24-88]) who underwent CSEMS insertion for the indication of retained "difficult" CBD stones in 2 tertiary referral centers. Patients underwent temporary placement of CSEMSs after incomplete stone clearance at ERCP. Follow-up ERCP was arranged for stent removal and subsequent attempt at duct clearance. Procedure-related adverse events were also recorded. RESULTS: Successful biliary drainage was achieved in all cases after CSEMS placement. Forty-two stents were removed with successful duct clearance achieved in 36 cases (82%) after a median in-stent duration of 8 weeks. There were 10 cases (22.7%) of stent migration, all noted incidentally during follow-up. One patient died of nonbiliary causes before attempted removal. CONCLUSION: This is the largest published retrospective case series for use of CSEMSs for management of retained CBD stone disease to date. We have shown high success rates for this indication. A well-designed, multicenter, randomized controlled trial might address the uncertainty of cost-to-benefit ratio and appropriate duration for CSEMSs to be left in situ. Specific stent modification for this indication, including wider distal flare and retrieval purse string loop, may also be useful.

The Inappropriate Prescription of Oral Proton Pump Inhibitors in the Hospital Setting: A Prospective Cross-Sectional Study.

UNLABELLED: Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal tract disorders. Their efficacy and perceived safety have led to widespread prescription. This is not without effect, in terms of adverse events and resource utilization. AIM: To prospectively assess oral PPI prescription in hospitalized patients. METHODS: PPI prescription in consecutive hospitalized patients was assessed. Indication and dose were assessed by patient interview and medical record review. Comparisons with current published prescribing guidelines were made. RESULTS: Four hundred and forty-seven patients were included. 57.5 % were prescribed PPIs. 26.8 % prescriptions were for inappropriate or unclear indications. 68.4 % were on higher doses than guidelines recommended, of which 41.6 % could have undergone dose reduction, and 26.5 % discontinued. In a multivariate analysis, age, gender, and length of stay had no association with PPI prescription. Although aspirin use was appropriately associated with PPI prescription (RR: 1.8, 95 % CI 1.127-3.69; p < 0.05), the PPI was often given at higher than recommended doses (p < 0.001). This may reflect older age and multiple risk factors in this subset. Surgical patients commenced more PPIs and at higher dosages (p < 0.001). Omeprazole and lansoprazole were most often inappropriately prescribed (p < 0.01, p < 0.001, respectively). CONCLUSION: Inappropriate PPI therapy is still a problem in hospitals, though it appears to be at a lower level compared with previous studies. Awareness of evidence-based guidelines and targeted medicine reconciliation strategies are essential for cost-effective and safe use of these medications.

Band ligation of gastric antral vascular ectasia is a safe and effective endoscopic treatment.

BACKGROUND AND AIM: Gastric antral vascular ectasia (GAVE) or 'watermelon stomach' is a rare and often misdiagnosed cause of occult upper gastrointestinal bleeding. Treatment includes conservative measures such as transfusion and endoscopic therapy. A recent report suggests that endoscopic band ligation (EBL) offers an effective alternative treatment. The aim of the present study is to demonstrate our experiences with this novel technique, and to compare argon plasma coagulation (APC) with EBL in terms of safety and efficacy. METHODS: A retrospective analysis of all endoscopies with a diagnosis of GAVE was carried out between 2004 and 2010. Case records were examined for information pertaining to the number of procedures carried out, mean blood transfusions, mean hemoglobin, and complications. RESULTS: A total of 23 cases of GAVE were treated. The mean age was 73.9 (55-89) years. Female to male ratio was 17:6 and mean follow up was 26 months. Eight patients were treated with EBL with a mean number of treatments of 2.5 (1-5). This resulted in a statistically significant improvement in the endoscopic appearance and a trend towards fewer transfusions. Of the eight patients treated with EBL, six (75%) patients had previously failed APC treatment despite having a mean of 4.7 sessions. Band ligation was not associated with any short- or medium-term complications. The 15 patients who had APC alone had a mean of four (1-11) treatments. Only seven (46.7%) of these patients had any endoscopic improvement with a mean of four sessions. CONCLUSIONS: EBL represents a safe and effective treatment for GAVE.

Ursodeoxycholic acid attenuates colonic epithelial secretory function.

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 µm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

Re-infection following sustained virological response with a different hepatitis C virus genotype: implications for infection control policy.

We report the case of a 45-year-old haemodialysis patient who achieved a sustained virological response (SVR) following pegylated interferon therapy for hepatitis C virus (HCV) genotype 2 infection. He was subsequently cohorted with other HCV-infected dialysis patients and became re-infected with HCV genotype 3a. Epidemiological and molecular investigations identified a highly viraemic HCV genotype 3a-infected dialysis patient as the likely source of this infection. This critical incident informed a revision to local and national infection control policy regarding the dialysis management of patients who achieve an SVR following anti-viral treatment.

Inter-endoscopist agreement in diagnosis of Barrett's oesophagus.

OBJECTIVE: To assess how interpretation of abnormalities at the oesophago-gastric junction (OGJ) when making a diagnosis of Barrett's oesophagus (BO) varies between endoscopists and to examine the impact of the endoscopy experience on these decisions. DESIGN/SETTING: Members of the Irish Society of Gastroenterology who regularly perform gastroscopy were invited to participate in a web based image assessment study. INTERVENTIONS: Questions were posed to ascertain level of endoscopy experience, and participants were asked to indicate the presence or absence of BO in 12 endoscopic images of the OGJ. OUTCOME MEASURES: Primary outcome was overall level of agreement in responses and relationship to endoscopy experience. RESULTS: The responses of 65 clinicians regularly performing gastroscopy were analysed. In 3/12 images, showing typical long segment BO, there was a strong consensus on the endoscopic diagnosis (>95% agreement). However, agreement was fair to poor (κ for multiple raters, 0.31) on the presence or absence of short BO segments at endoscopy. Minimal differences were observed between experienced endoscopists (individuals with >10 years' endoscopy experience) and less experienced counterparts in the threshold for BO diagnosis. Inter-endoscopist agreement overall was not significantly better within the more experienced group. CONCLUSION: The study demonstrates low interobserver agreement in endoscopic diagnosis of (short segment) BO, even among experienced endoscopists. Given the costs associated with endoscopic surveillance of BO, prompt efforts to promote consensus diagnosis and improve agreement are required as an important quality improvement measure in this area.

Perceptions of medication safety among patients with inflammatory bowel disease.

OBJECTIVE: The aim of this study was to assess attitudes towards and knowledge of medication safety in inflammatory bowel disease (IBD). IBD patients frequently require long-term treatment with potentially toxic medications. Techniques are employed to improve patient awareness of medication safety, but there are sparse data on their effectiveness. MATERIAL AND METHODS: Questionnaires relating to the safety and efficacy of commonly used IBD treatments (aminosalicylates, corticosteroids, immunomodulators, biologics) were completed by IBD patients attending the gastroenterology clinics at a teaching hospital. RESULTS: One hundred patients (51 male) with a median (interquartile range) age of 37 (29-49) years were included: 56 Crohn's disease, 44 ulcerative colitis. Aminosalicylates (median 0.8 (IQR 0.1-1.9)) were ranked as the safest medication; corticosteroids (4.6 (1.1-8.2)), immunomodulators (4.2 (1.1-8.4) and biologics (4.4 (1.1-6.8)) were ranked equally. 36%, 53% and 79% reported no knowledge regarding safety of corticosteroids, immunomodulators and biologics, respectively. Most patients wish to be informed of all medication side-effects, no matter how rare, and ranked their gastroenterologist as their primary information source. CONCLUSIONS: IBD patients want to be informed of all potential adverse events and identify their gastroenterologist as their principal information source. The majority have no knowledge regarding or underestimate the toxicity of common IBD medications. This places a responsibility on gastroenterologists to manage and meet patients' expectations in the area of medication safety.

Economic impact of prescreening on gastroenterology outpatient clinic practice.

BACKGROUND: Outpatient clinic activity represents a major workload for clinicians. Unnecessary outpatient visits place a strain on service provision, resulting in unnecessary delays for more urgent cases. GOALS: We sought to determine both the impact and economic benefit of employing phone follow-up and physician assistant (PA) triage systems on attendances at a gastroenterology outpatient department. STUDY: We performed a retrospective chart review of all patients attending a gastroenterology outpatient clinic over a 2-week period. Patients were categorized into new or follow-up attendees and the follow-up patients were further subcategorized into 1 of 4 groups: (1) those attending to receive results of investigations requiring no further treatment (group A); (2) those attending to receive results of investigations requiring further treatment (group B); (3) those attending with a chronic gastrointestinal disease requiring no active change in management (group C); (4) those attending with a chronic gastrointestinal disease requiring active change in management (group D). It was assumed that patients in group A could be managed by phone follow-up in place of clinic attendance and patients in group C could be triaged to see a PA. RESULTS: Out of a total of 329 outpatient attendees, 40 (12%) required no active intervention (group A) and would have been suitable for phone follow-up. A further 58 (18%) had stable disease, requiring no change in management and hence, could have been triaged to see a PA. Implementation of phone follow-up and patient review by PA could reduce salary expenses of outpatient practice by 17%. CONCLUSIONS: Our findings support routine prescreening of outpatient attendees to enhance the efficiency of gastroenterology outpatient practice.

Efficacy and safety of colonic stenting for malignant disease in the elderly.

BACKGROUND: Self-expandable metal stents (SEMS) are an accepted palliation for malignant colorectal obstruction. Outcomes of stent insertion solely in older patients are unknown. OBJECTIVE: To compare outcomes of SEMS insertion for malignant colorectal disease, in older versus younger patients. METHODS: Forty-three patients were retrospectively identified as having undergone SEMS insertion for obstructing colorectal cancer. Of these, 24 were > or = 70 years of age (older patient group) and 19 were <70 years of age (younger patient group). RESULTS: There was no significant difference in successful SEMS insertion between the groups (88% in older versus 100% in younger patients, p > 0.05). Furthermore, the complication rate was similar in both groups (12.5% versus 26%, p > 0.10). There was no difference in median survival (113 days versus 135 days, p > 0.09). CONCLUSION: Colorectal stenting for malignant disease in older patients is both safe and effective with comparative success and complication rates to a younger population.

JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.

Co-prescription of gastro-protectants in hospitalized patients: an analysis of what we do and what we think we do.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the risk of upper gastrointestinal hemorrhage (UGIH) associated with the use of many medications. GOALS: To examine how clinicians perceive such risk and whether PPI co-prescribing is based on an accurate assessment. STUDY METHODS: Clinicians in a single teaching hospital were asked to estimate risk of UGIH and comment on PPI co-prescription in hypothetical patients. Records of 160 hospital in-patients (median age; 74 y) were then reviewed to examine PPI prescribing and risk factors for UGIH. RESULTS: In general, clinicians estimated UGIH risk accurately and reported low thresholds for PPI co-prescription. Prescribing records showed regular PPI use increased between admission and discharge of patients from 61/160 (38%) to 93/160 (58%). Ten percent had a prior history of peptic ulcer disease. Proton pump inhibitor prescription was significantly associated with the use of aspirin and clopidogrel. Half of the patients with multiple risk factors for UGIH on admission and almost a third at discharge were not co-prescribed a PPI. CONCLUSIONS: Clinicians generally estimate correctly the risk of UGIH and report a low threshold for prescribing gastro-protection. Despite this, prescribing practice does not consistently take account of relative risk of UGIH. Targeted PPI co-prescribing on the basis of risk factors would lead to more rational PPI use.

Bid and calpains cooperate to trigger oxaliplatin-induced apoptosis of cervical carcinoma HeLa cells.

The Bcl-2 homology 3-only protein Bid is an important mediator of death receptor-induced apoptosis. Recent reports and this study suggest that Bid may also mediate genotoxic drug-induced apoptosis of various human cancer cells. Here, we characterized the role of Bid and the mechanism of Bid activation during oxaliplatin-induced apoptosis of HeLa cervical cancer cells. Small hairpin RNA-mediated silencing of Bid protected HeLa cells against both death receptor- and oxaliplatin-induced apoptosis. Expression of a Bid mutant in which caspase-8 cleavage site was mutated (D59A) reactivated oxaliplatin-induced apoptosis in Bid-deficient cells but failed to reactivate death receptor-induced apoptosis, suggesting that caspase-8-mediated Bid cleavage did not contribute to oxaliplatin-induced apoptosis. Overexpression of bcl-2 or treatment with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone abolished caspase-2, -8, -9, and -3 activation as well as Bid cleavage in response to oxaliplatin, suggesting that Bid cleavage occurred downstream of mitochondrial permeabilization and was predominantly mediated by caspases. We also detected an early activation of calpains in response to oxaliplatin. Calpain inhibition reduced Bid cleavage, mitochondrial depolarization, and activation of caspase-9, -3, -2, and -8 in response to oxaliplatin. Further experiments, however, suggested that Bid cleavage by calpains was not a prerequisite for oxaliplatin-induced apoptosis: single-cell imaging experiments using a yellow fluorescent protein-Bid-cyan fluorescent protein probe demonstrated translocation of full-length Bid to mitochondria that was insensitive to calpain or caspase inhibition. Moreover, calpain inhibition showed a potent protective effect in Bid-silenced cells. In conclusion, our data suggest that calpains and Bid act in a cooperative, but mutually independent, manner to mediate oxaliplatin-induced apoptosis of HeLa cells.

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer.

BACKGROUND: Prostaglandin E2 (PGE2) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE2 cell surface receptors (EP 1-4) to examine the mechanisms by which PGE2 regulates tumour progression. METHODS: Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue. RESULTS: EP4 was the most abundant subtype of PGE2 receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE2 generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 microM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE2 (1 microM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21WAF1/CIP1 expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21WAF1/CIP1 was also seen with PD153025 (1 microM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted. CONCLUSION: COX-2 regulates cell cycle transition via EP4 receptor and altered p21WAF1/CIP1 expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.

Cyclooxygenase as a target for chemoprevention in colorectal cancer: lost cause or a concept coming of age?

COX-2 is upregulated at an early stage in colorectal carcinogenesis and generates prostaglandins, which promote cancer cell proliferation, impair apoptosis and enhance angiogenesis, promoting tumour growth and metastasis. There are ample data from animal models and human studies to demonstrate enhanced tumour progression associated with COX-2 activity in cancer cells. Conversely, NSAIDs including aspirin inhibit COX-2 and, therefore, have anti-neoplastic properties. There has been sustained interest in COX-2 as a chemopreventive target in colorectal cancer (CRC) and although both aspirin and COX-2 selective NSAIDs have demonstrated efficacy, adverse effects have limited their widespread adoption. In particular, evidence of the cardiovascular effects of COX-2 selective inhibitors has led to questioning of the suitability of COX-2 as a target for chemoprevention. This review examines the basis for targeting COX-2 in CRC chemoprevention, evaluates the efficacy and safety of the approach and examines future strategies in this area.

Cyclooxygenase-2 expression in chronic hepatitis C and the effect of interferon alpha treatment.

BACKGROUND AND AIM: Cyclooxygenase-2 (COX-2), a target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), is upregulated in chronic hepatitis B and may have a role in hepatocellular carcinoma. Little is known about the expression of COX-2 in chronic hepatitis C (HCV) infection. The aim the present study was to evaluate the extent of COX-2 expression in liver biopsies in patients with HCV infection and to determine the effect of treatment with interferon alpha (IFN). METHODS: Percutaneous liver biopsy specimens were retrieved. Following formalin fixation and paraffin embedding, the biopsies were histologically evaluated for inflammation and fibrosis. The extent of COX-2 expression was measured by the avidin biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to the number of hepatocytes expressing COX-2. Data were analyzed using Student's t-test. RESULTS: Liver biopsies from 10 patients before and after treatment with IFN were obtained and compared with nine normal liver biopsies. All of the liver biopsies showed some COX-2 expression. COX-2 expression was confined to hepatocytes and bile duct epithelium and was not detected in vascular endothelium or inflammatory cells. The extent of COX-2 expression was greater in hepatitis C infected liver biopsies than in normal biopsies. Following treatment with IFN, there was a greater than threefold reduction in COX-2 expression (P < 0.01). This result was independent of the sustained virological response. CONCLUSION: In this small pilot study we have shown that COX-2 is overexpressed in liver biopsies infected with HCV and COX-2 expression is reduced following treatment with IFN.

The effect of different strains of Helicobacter pylori on platelet aggregation.

BACKGROUND AND AIMS: Helicobacter pylori is the major causative agent in peptic ulcer disease and is strongly implicated in the development of gastric cancer. It has also been linked, less strongly, to cardiovascular disease. The mechanisms by which certain strains of H pylori induce platelet aggregation through interactions with platelet glycoprotein Ib have been previously described. METHODS: In the present study, 21 different strains of H pylori, varying in their vacuolating toxin gene, cytotoxic-associated gene A status and other pathogenicity factors, were tested for their ability to induce platelet aggregation. RESULTS: Ten of the 21 strains induced platelet aggregation, a response that appeared to be independent of their vacuolating toxin gene and cytotoxic-associated gene A status. CONCLUSIONS: Platelet aggregation has been suggested to be one of the possible mechanisms involved in the effects on the cardiovascular system induced by H pylori. Our results suggest that any putative role H pylori plays in cardiovascular disease may be strain dependent. Further work to identify the H pylori factors involved in induction of platelet aggregation may allow for identification of 'higher risk' strains for cardiovascular disease.