Search

Background Preventive health measures reduce treatment and disease-related complications including infections, osteoporosis, and malignancies in patients with inflammatory bowel disease (IBD). Although guidelines and quality measures for IBD care highlight the importance of preventive care, their uptake remains variable. This systematic review evaluates interventions aimed at improving the rates of provision and uptake of preventive health measures, including vaccinations, bone density assessment, skin cancer screening, cervical cancer screening, and smoking cessation counseling. Methods We searched PubMed, MEDLINE, EMBASE, and CENTRAL for full text articles published until March 2021. Studies were included if they evaluated interventions to improve the provision or uptake of 1 or more preventive health measures in adult IBD patients and if they reported pre- and postintervention outcomes. Results In all, 4655 studies were screened, and a total of 17 studies were included, including 1 randomized controlled trial, 1 cluster-controlled trial, and 15 prospective interventional studies. A variety of interventions were effective in improving the rates of adherence to preventive health measures. The most common interventions targeted gastroenterologists, including education, electronic medical records tools, and audit feedback. Other interventions targeted patients, such as education, questionnaires, and offering vaccine administration at clinic visits. Few interventions involved IBD nurses or primary care physicians. Conclusions A range of interventions—targeted at gastroenterologists, patients, or both—were effective in improving the provision and uptake of preventive care. Future studies should involve randomized controlled trials evaluating multifaceted interventions that target barriers to adherence and involve IBD nurses and primary care physicians.

The mucosa-associated microbiota is widely recognized as a potential trigger for Crohn’s disease pathophysiology but remains largely uncharacterised beyond its taxonomic composition. Unlike stool microbiota, the functional characterisation of these communities using current DNA/RNA sequencing approaches remains constrained by the relatively small microbial density on tissue, and the overwhelming amount of human DNA recovered during sample preparation. Here, we have used a novel ex vivo approach that combines microbe culture from anaerobically preserved tissue with metagenome sequencing (MC-MGS) to reveal patient-specific and strain-level differences among these communities in post-operative Crohn’s disease patients. The 16 S rRNA gene amplicon profiles showed these cultures provide a representative and holistic representation of the mucosa-associated microbiota, and MC-MGS produced both high quality metagenome-assembled genomes of recovered novel bacterial lineages. The MC-MGS approach also produced a strain-level resolution of key Enterobacteriacea and their associated virulence factors and revealed that urease activity underpins a key and diverse metabolic guild in these communities, which was confirmed by culture-based studies with axenic cultures. Collectively, these findings using MC-MGS show that the Crohn’s disease mucosa-associated microbiota possesses taxonomic and functional attributes that are highly individualistic, borne at least in part by novel bacterial lineages not readily isolated or characterised from stool samples using current sequencing approaches.

Inflammatory bowel disease (IBD) affects a growing cohort of elderly patients. Our aim was to compare the quality of care received by elderly patients with IBD with a nonelderly adult IBD population using clinical markers including steroid-free clinical remission.Retrospective audit of all consecutive patients attending a specialist IBD centre over a 1-year period aged60 (elderly cohort [EC]) and 50 consecutive patients aged 30-45 years (control cohort [CC]). A follow-up survey was completed assessing current symptoms and perceptions of care.One hundred thirty-nine patients were evaluated (89 EC, 50 CC). Steroid-free clinical remission was observed less commonly in the EC (58, 64%) compared with the CC (40, 80%) (P 0.05). Biologics such as infliximab (15% EC vs 36% CC; P 0.01) and adalimumab (14% EC vs 30% CC; P = 0.02) were used less frequently in the EC, whilst vedolizumab (6% EC vs 6% CC; P = 1) and ustekinumab (3% EC vs 2% CC; P = 1) were used at a similar frequency. Patients in the EC were less likely to have specialist IBD nursing contact (P 0.01), smoking screening (P 0.011) or influenza vaccinations (P 0.006). IBD nurse contact was associated with significantly greater provision of the preventative care measures.Elderly patients with IBD were less likely to experience steroid-free clinical remission or be prescribed biologics. Elderly patients were less likely to receive education with respect to preventative medicine. The models of care for the elderly need re-evaluation and greater incorporation with the multidisciplinary IBD team.

Background and aim Fecal incontinence and/or evacuation difficulty are common after ileoanal pouch surgery. This study aimed to determine whether the development of these symptoms can be predicted so that preventive measures might be instituted. Methods A consecutive series of 46 patients with ulcerative colitis (median age at surgery, 41 years; 50% female) and a functioning pouch for a duration ≥12 months was included. Assessment utilized medical record review and questionnaires on pre‐ and postoperative bowel function, quality of life, and psychological well‐being. Pouch function was assessed by the Colorectal Functional Outcome score (0 = no impairment, 100 = worst impairment). Good pouch function was defined as a score ≤24. Results Fecal incontinence occurred in 67% preoperatively and 54% postoperatively; evacuation difficulty occurred in 65% and preoperatively and 85% postoperatively. The postoperative median Colorectal Functional Outcome score was 20 (range 2–74), with 44% of patients >24 (poor pouch function). Preoperative nocturnal fecal incontinence (odds ratio [OR] 4.92, 95% confidence interval [CI] 1.2–19.4, P = 0.02) and pouchitis (OR 5.41, 95% CI 1.2–23.7, P = 0.02) were associated with poor pouch function after multivariable regression analysis. Postoperative satisfaction, psychological well‐being, and quality of life were significantly better in those with good pouch function, while poor sleep, impaired work, and sexual dysfunction were independently associated with poor pouch function. Conclusions Functional bowel symptoms are common before and after pouch surgery and are associated with the impairment of patient‐reported outcomes. Preoperative nocturnal fecal incontinence predicts poor pouch function. Therapeutic focus on continence, bowel evacuation, psychological well‐being, and quality of life should begin before surgery., In this consecutive series of 46 patients, with a functioning pouch for ulcerative colitis, high rates of fecal incontinence and evacuation difficulty were reported by patients preoperatively. After pouch creation, the rate of fecal incontinence decreased, and evacuation difficulty increased. Postoperative satisfaction, psychological well‐being, and quality of life were significantly better in those with good pouch function, highlighting the importance of recognizing symptoms early and providing appropriate treatment.

Refractory bowel symptoms in quiescent inflammatory bowel disease (IBD) are common but evidence for effective management is limited. We aimed to determine whether behavioral treatment, including pelvic floor muscle training, decreases the severity of functional bowel symptoms in patients with quiescent IBD. Secondary aims were to evaluate the treatment effect on quality of life, psychological well-being and pelvic floor muscle function. This prospective study included IBD patients in remission with persistent symptoms of fecal incontinence or constipation who received up to six sessions of behavioral treatment at monthly intervals. The primary outcome was patient-rated symptom improvement on a 7-point Likert scale (1 = substantially worse, 7 = substantially better). Secondary outcomes included validated symptom scores, quality-of-life, psychological measures, and transperineal ultrasound assessment of pelvic floor muscle activity. Thirty-four patients (median age 38 years; 24 females; 18 ulcerative colitis, 13 Crohn’s disease, 3 ileo-anal pouch) were included. Twenty-one of the 29 (72%) patients who completed treatment, or 21 of all 34 (62%) patients, reported moderate or substantial improvement (patient rating of 6 or 7). Symptom scores (p < .001), IBD-specific quality of life (p = .008) and illness perception scores (p = .003) significantly improved. General quality of life, and anxiety and depression scores, did not change significantly. Transperineal ultrasound pelvic floor measures did not correlate with patient-rating of symptom improvement. Significant symptomatic improvement occurred in a majority of patients with quiescent IBD. Behavioral treatment should be considered for patients with quiescent IBD and ongoing functional bowel symptoms of fecal incontinence, fecal urgency, or constipation.

The composition and function of the dynamic microbial community that constitutes the gut microbiome is continuously shaped by the host genome, mode of birth delivery, geography, life stage, antibiotic consumption, and diet. Diet is one of the most potent factors in determining microbiome integrity. Dietary factors in early life appear to substantially determine the risk of later health or disease; for example, exposure to ultra-processed foods in childhood or adolescence may increase the risk of the later development of inflammatory bowel disease or colorectal cancer, thought to be mediated by modulation of the gut microbiota. Dietary factors when gut diseases are established influence symptoms and disease activity, can form a risk factor for ongoing disease, or can be used as therapy to decrease disease activity. The characterization of dietary content is currently complex and imperfect, but tools are emerging to define precisely the nature of dietary composition. Similarly, the revolution in microbial analysis allows greater understanding of how diet influences microbial composition and function. Defining the interaction between diet, the gut microbiome, and gastrointestinal disease is leading to radical changes in our clinical approach to these disorders.

Functional gastrointestinal disorders are common and costly to the healthcare system. In the Multidisciplinary Treatment of Functional Gastrointestinal Disorders study, we demonstrated that multidisciplinary care resulted in superior clinical and cost outcomes, when compared with standard gastroenterologist-only care at end of treatment. In this study we evaluate the longer-term outcomes.In a single-center, pragmatic trial patients with Rome IV criteria-defined functional gastrointestinal disorders were randomized 1:2 to a gastroenterologist-only standard care vs a multidisciplinary clinic comprising gastroenterologists, dietitians, gut hypnotherapists, psychiatrists, and biofeedback physiotherapists. Outcomes in this study were assessed 12 months after the end of treatment. Global symptom improvement was assessed by using a 5-point Likert scale. Symptoms, specific disorder status, psychological state, quality of life, and cost were additional outcomes. A modified intention-to-treat analysis was performed.Of 188 randomized patients, 143 (46 standard care, 97 multidisciplinary) formed the longer-term modified intention-to-treat analysis. Sixty-two percent of multidisciplinary clinic patients saw allied clinicians. Sixty-five percent (30/46) standard care versus 76% (74/97) multidisciplinary clinic patients achieved global symptom improvement 12 months after end of treatment (P = .17), whereas 20% (9/46) versus 37% (36/97) rated their symptoms as "5/5 much better" (P = .04). A ≥50-point reduction in Irritable Bowel Syndrome Severity Scoring System occurred in 38% versus 66% (P = .02), respectively, for irritable bowel syndrome patients. Anxiety and depression were greater in the standard care than multidisciplinary clinic (12 vs 10, P = .19), and quality of life was lower in standard care than the multidisciplinary clinic (0.75 vs 0.77, P =·.03). An incremental cost-effectivness ratio found that for every additional 3555AUD spent in the multidisciplinary clinic, a further quality-adjusted life year was gained.Twelve months after the completion of treatment, integrated multidisciplinary clinical care achieved a greater proportion of patients with improvement of symptoms, psychological state, quality of life, and cost, compared with gastroenterologist-only care.gov: number NCT03078634.

Background A diverse range of treatments are available for the treatment of functional gastrointestinal disorders (FGIDs). Individual treatments, including drug therapies, behavioral therapy ("biofeedback"), psychological therapies, and dietary therapies, have been well validated in controlled, randomized trials and real-life case series. However, few studies have evaluated models of delivery of care for the whole population of referred patients with an FGID. This review evaluates models of specialist outpatient care for the management of FGIDs. Methods A systematic review was performed of full-text articles published until October 2018 in Pubmed/Medline and Embase. Studies were included if they evaluated a model of outpatient care in a specialist setting for the treatment of adult patients with an FGID and included patient-reported outcomes comprising symptoms, quality of life, or psychological well-being. Results Few studies have evaluated the delivery of care for the whole population of referred patients with an FGID, and there was one randomized comparison of different models of care. Two studies that evaluated the outcome of gastroenterologist-only clinics suggested poor long-term results. Two non-comparative case series reported the outcome of multidisciplinary care, including gastroenterologists and psychological therapists, suggesting improved patient quality of life and psychological well-being. Conclusions Despite the high prevalence and cost of treating FGIDs, and the availability of effective treatments, there are few data and limited randomized comparisons reporting the outcome of different types of specialist care. The few data available suggest that multidisciplinary care is superior to gastroenterologist-only care, but this needs to be validated in prospective comparative studies.

Background Functional gastrointestinal disorders (FGID) are the commonest conditions observed in gastrointestinal (GI) practice, yet the outcomes of their outpatient care are not known. Aim To evaluate the outcome for patients with FGID attending a specialist GI clinic. Methods Consecutive, newly referred patients with a FGID attending a specialist GI clinic in a tertiary hospital, over a 1-year period were reviewed and then completed a phone survey to assess current symptoms. Results Of 102 patients, 57% had irritable bowel syndrome, 28% functional dyspepsia and 15% other functional disorders. At interview, a median of 402 days after the last consultation 38% expressed symptom improvement, but 64% remained concerned about their condition despite 62% having been reassured. After treatment, 50% of employed patients took time off work because of gut symptoms. Functional dyspepsia patients were less likely to be symptomatically improved than other FGID (21% vs 45%, P = 0.02). Patients given a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols were more likely than others to achieve symptom improvement (53% vs 31%, P = 0.03); PPI-treated patients were less likely to experience improvement (22% vs 44%, P = 0.05); other treatments did not predict outcome. Number of visits, seniority of clinician, duration of care and comorbidities did not predict outcome. Conclusion One year after attending a specialist GI clinic a minority of patients with FGID were symptomatically improved. Failure to benefit by many patients may relate to the nature of patients and conditions being treated or the limited nature and range of treatments offered. Different models of care, including more diverse multidisciplinary models, should be explored.

Summary Background Functional gastrointestinal disorders are common and costly to the health-care system. Most specialist care is provided by a gastroenterologist, but only a minority of patients have improvement in symptoms. Although they have proven to be effective, psychological, behavioural, and dietary therapies are not provided routinely. We aimed to compare the outcome of gastroenterologist-only standard care with multidisciplinary care. Methods In an open-label, single-centre, pragmatic trial, consecutive new referrals of eligible patients aged 18–80 years with Rome IV criteria-defined functional gastrointestinal disorders were randomly assigned (1:2) to receive gastroenterologist-only standard care or multidisciplinary clinic care. The multidisciplinary clinic included gastroenterologists, dietitians, gut-focused hypnotherapists, psychiatrists, and behavioural (biofeedback) physiotherapists. Randomisation was stratified by Rome IV disorder and whether referred from gastroenterology or colorectal clinic. Outcomes were assessed at clinic discharge or 9 months after the initial visit. The primary outcome was a score of 4 (slightly better) or 5 (much better) on a 5-point Likert scale assessing global symptom improvement. Modified intention-to-treat analysis included all patients who attended at least one clinic visit and who had answered the primary outcome question. This study is registered with ClinicalTrials.gov, NCT03078634. Findings Between March 16, 2017, and May 10, 2018, 1632 patients referred to the hospital gastrointestinal clinics were screened, of whom 442 were eligible for a screening telephone call and 188 were randomly assigned to receive either standard care (n=65) or multidisciplinary care (n=123). 144 patients formed the modified intention-to-treat analysis (n=46 in the standard-care group and n=98 in the multidisciplinary-care group), 90 (63%) of whom were women. 61 (62%) of 98 patients in the multidisciplinary-care group patients saw allied clinicians. 26 (57%) patients in the standard-care group and 82 (84%) patients in the multidisciplinary-care group had global symptom improvement (risk ratio 1·50 [95% CI 1·13–1·93]; p=0·00045). 29 (63%) patients in the standard-care group and 81 (83%) patients in the multidisciplinary-care group had adequate relief of symptoms in the past 7 days (p=0·010). Patients in the multidisciplinary-care group were more likely to experience a 50% or higher reduction in all Gastrointestinal Symptom Severity Index symptom clusters than were patients in the standard-care group. Of the patients with irritable bowel syndrome, a 50-point or higher reduction in IBS-SSS occurred in 10 (38%) of 26 patients in the standard care group compared with 39 (66%) of 59 patients in the multidisciplinary-care group (p=0·017). Of the patients with functional dyspepsia, a 50% reduction in the Nepean Dyspepsia Index was noted in three (11%) of 11 patients in the standard-care group and in 13 (46%) of 28 in the multidisciplinary-care group (p=0·47). After treatment, the median HADS scores were higher in the standard-care group than in the multidisciplinary-care group (13 [8–20] vs 10 [6–16]; p=0·096) and the median EQ-5D-5L quality of life visual analogue scale was lower in the standard-care group compared with the multidisciplinary-care group (70 [IQR 50–80] vs 75 [65–85]; p=0·0087). The eight SF-36 scales did not differ between the groups at discharge. After treatment, median Somatic Symptom Scale-8 score was higher in the standard-care group than in the multidisciplinary-care group (10 [IQR 7–7] vs 9 [5–13]; p=0·082). Cost per successful outcome was higher in the standard-care group than the multidisciplinary-care group. Interpretation Integrated multidisciplinary clinical care appears to be superior to gastroenterologist-only care in relation to symptoms, specific functional disorders, psychological state, quality of life, and cost of care for the treatment of functional gastrointestinal disorders. Consideration should be given to providing multidisciplinary care for patients with a functional gastrointestinal disorder. Funding None.

Objective An elevated total serum bilirubin level has been demonstrated to be protective against cardiovascular disease with the majority of evidence limited to males. We assessed the hypothesis th...

(1) Background: The Food Agricultural Organization/World Health Organization (FAO/WHO) International Food Standards Codex Alimentarius CXS 192e International Food Standards (hereafter, CODEX) declares additives non-toxic, but they have been associated with changes to the microbiota changes and thinning of the mucus layer of the gut. Their widespread use has occurred in parallel with increased inflammatory bowel disease (IBD) incidence. This paper reports on the development and validation of surveys to estimate additive intake. (2) Methods: Dietitians created a food-additive database, with a focus on additives that have been associated with IBD. For each additive, information on the CODEX food-category they are permitted in and the associated maximum permissible levels (mg/kg) was recorded. Based on the database, questions to assess early life (part 1) and recent (part 2) additive intake were written. Forward&ndash, backward translation from English to Chinese was undertaken. Thirty-one individuals were evaluated to assess understandability. A further fifty-seven individuals completed the tool on two occasions, a fortnight apart, agreement was assessed using Cohen&rsquo, s kappa coefficient or the intra-class correlation coefficient (ICC). (3) Results: The participants reported that it was difficult to remember food intake and estimate portion sizes. The participants also noted confusion around the term &lsquo, home-grown&rsquo, Instructions and definitions were added, after this, respondents judged the questionnaires as clear. The average kappa coefficient for part 1 and part 2 questions were 0.61 and 0.67, respectively. The average ICC ranged from 0.30 to 0.94, three food lists were removed due to low reliability. (4) Conclusions: Two tools have been created and validated, in two languages, that reliably assess remote and recent food additive intake.

Functional gastrointestinal disorders (FGID) are the commonest conditions observed in gastrointestinal (GI) practice, yet the outcomes of their outpatient care are not known.To evaluate the outcome for patients with FGID attending a specialist GI clinic.Consecutive, newly referred patients with a FGID attending a specialist GI clinic in a tertiary hospital, over a 1-year period were reviewed and then completed a phone survey to assess current symptoms.Of 102 patients, 57% had irritable bowel syndrome, 28% functional dyspepsia and 15% other functional disorders. At interview, a median of 402 days after the last consultation 38% expressed symptom improvement, but 64% remained concerned about their condition despite 62% having been reassured. After treatment, 50% of employed patients took time off work because of gut symptoms. Functional dyspepsia patients were less likely to be symptomatically improved than other FGID (21% vs 45%, P = 0.02). Patients given a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols were more likely than others to achieve symptom improvement (53% vs 31%, P = 0.03); PPI-treated patients were less likely to experience improvement (22% vs 44%, P = 0.05); other treatments did not predict outcome. Number of visits, seniority of clinician, duration of care and comorbidities did not predict outcome.One year after attending a specialist GI clinic a minority of patients with FGID were symptomatically improved. Failure to benefit by many patients may relate to the nature of patients and conditions being treated or the limited nature and range of treatments offered. Different models of care, including more diverse multidisciplinary models, should be explored.

Background The burden of cardiovascular disease is higher in rural populations. Existing data on rural cardiovascular health is mainly based on community surveys. Regional differences are not well addressed. This study aims to identify regional inequalities in cardiovascular risk factors (CVRFs) in Australian patients with suspected coronary artery disease. Methods and results 538 subjects (72% male; mean age 63years) were recruited from a single cardiac catheter laboratory over a 24-month period. Subjects were stratified into Remoteness Areas (RAs) according to the Australian Standard Geographical Classification (RA1 corresponds to Major Cities, RA2 to Inner Regional Areas, RA3 to Outer Regional Areas). Body-mass index, blood pressure, hypertension, dyslipidaemia, diabetes and smoking history were recorded. A blood sample taken before the angiogram was analysed for lipids and fasting blood glucose (FBG). Distribution of the study population across RA1, RA2 and RA3 was 34.8%, 46.1% and 19.1%. Only FBG (p=0.019) and diagnosed diabetes (p=0.009) were significantly different i.e. higher in RA1. Of those without known diabetes, RA3 had the highest prevalence of dysglycaemia (p=0.023) with two-thirds having either pre-diabetes or undiagnosed diabetes. Logistic regression showed that age and RA3 were the only statistically significant predictors of elevated FBG. Conclusion CAD patients from remote Australia had higher rates of pre-diabetes, undiagnosed diabetes and poorer glycaemic control. Analysis of the main CVRFs revealed a regional inequality in the recognition and management of diabetes alone. Attention to this gap in rural and urban healthcare is crucial to future cardiovascular health outcomes in Australia.

Background Functional gastrointestinal disorders (FGIDs) are the commonest reason for gastroenterological consultation, with patients usually seen by a specialist working in isolation. There is a wealth of evidence testifying to the benefit provided by dieticians, behavioral therapists, hypnotherapists and psychotherapists in treating these conditions, yet they rarely form a part of the therapeutic team, and these treatment modalities are rarely offered as part of the therapeutic management. There has been little examination of different models of care for FGIDs. We hypothesize that multi-disciplinary integrated care is superior to standard specialist-based care in the treatment of functional gut disorders. Methods The “MANTRA” (Multidisciplinary Treatment for Functional Gut Disorders) study compares comprehensive multi-disciplinary outpatient care with standard hospital outpatient care. Consecutive new referrals to the gastroenterology and colorectal outpatient clinics of a single secondary and tertiary care hospital of patients with an FGID, defined by the Rome IV criteria, will be included. Patients will be prospectively randomized 2:1 to multi-disciplinary (gastroenterologist, gut-hypnotherapist, psychiatrist, behavioral therapist (‘biofeedback’) and dietician) or standard care (gastroenterologist or colorectal surgeon). Patients are assessed up to 12 months after completing treatment. The primary outcome is an improvement on a global assessment scale at the end of treatment. Symptoms, quality of life, psychological well-being, and healthcare costs are secondary outcome measures. Discussion There have been few studies examining how best to deliver care for functional gut disorders. The MANTRA study will define the clinical and cost benefits of two different models of care for these highly prevalent disorders. TRIAL REGISTRATION Number: Clinicaltrials.gov NCT03078634 Registered on Clinicaltrials.gov , completed recruitment, registered on March 13th 2017. Ethics and Dissemination: Ethical approval has been received by the St Vincent's Hospital Melbourne human research ethics committee (HREC-A 138/16). The results will be disseminated in peer-reviewed journals and presented at international conferences. Protocol version 1.2

Background/objectives We performed a prospective study to investigate markers of percutaneous coronary intervention (PCI) related microvascular injury. Methods Consecutive patients undergoing PCI for stable angina were studied. The index of microvascular resistance (IMR) was measured using a temperature and pressure sensing guidewire (TPSG) before and after single vessel PCI. Basal transit-time (TmnBase), that reflected non-hyperemic blood flow was also measured. Fasting bloods were taken to measure blood sugar, HbA1c and lipids. Asymmetric dimethylarginine (ADMA) was also measured as a marker of systemic endothelial function. Results 55 patients were included in the study. Mean age was 59.9 ± 11.2, 74.1% male. There was no significant difference in IMR post PCI compared with pre PCI values (IMR pre PCI = 16.96 [11.5,25.38] vs. IMR post PCI 14.2 [10.37,26.25] p = 0.96). IMR post PCI was higher in diabetic (DM) patients compared with non-diabetics [IMR post DM = 22.72 (13.35,42.91) vs. no DM = 13.9 (10.18,21.45), p = 0.02]. Fasting blood sugar, HbA1c and IMR pre PCI were correlated with post PCI IMR. IMR pre PCI, HbA1C and fasting glucose were higher in patients who developed PCI related microvascular dysfunction. The strongest independent predictor of post PCI IMR was the pre PCI IMR. Conclusion The baseline status of the microcirculation is an important determinant of post PCI microvascular function. Diabetics appear to have higher post PCI IMR.

Introduction: Nitric Oxide (NO) is a crucial molecule in cardiovascular biology. Abnormalities in NO are critical in atherosclerosis and impairment of the NO pathway increases risk of cardiovascular disease (CVD). A possible cause of endothelial dysfunction is an elevation (in plasma) of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA). ADMA was initially described in renal failure. 80% of ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the liver. DDAH-1 is widely distributed and felt to be the major determinant of circulating ADMA levels. Very little data is available regarding the cause and effects of DDAH dysregulation in the liver. Understanding the biology of DDAH represents a target for better understanding of CVD and for novel therapy. Hypothesis: Diabetes and related factors will alter DDAH expression/activity potentially modulating the amount of ADMA. Methods: Liver tissues from control and db/db mice were archival. Human skeletal muscle tissue was obtained from cardiovascular surgical patients. HepG2 cells were used for low/high glucose treatment studies (5mM/25mM). DDAH-1 expression was determined using Western immunoblotting. DDAH activity measurement used a colourimetric assay. Intra/extracellular ADMA were measured in HepG2 cells using an HPLC-MS/MS technique. Results: In skeletal muscle from diabetic cardiac surgery patients DDAH-1 protein expression is increased ( P < 0.05). Further to this, db/db mice livers versus control had a significant increase in DDAH expression and activity. Using HepG2 cells we specifically examined the effect of 25mM glucose on DDAH-1. Treatment increased expression and activity of DDAH-1 ( P Conclusion: These novel results report an alteration of DDAH-1 expression and activity in hepatic tissues and cells in response to elevated glucose - a result which has not been reported previously. This suggests a possible link between the DDAH/ADMA/NOS pathway, diabetes, and glycaemic dysregulation - key risk factors in CVD.

Background: Within the endothelium, Nitric Oxide Synthase (NOS) activity through the conversion of Arginine to Citrulline and Nitric Oxide (NO) is largely seen as beneficial. NO is a powerful bioactive molecule which elicits an antithrombotic and antioxidant effect preventing platelet aggregation and atherosclerosis. In immune cells NOS however is largely thought to be beneficial as a microbicidal agent involved in inflammatory responses. Systemic inflammation is also a common outcome in patients undergoing cardiac surgery and those receiving Cardiopulmonary Bypass (CPB) due to contact with foreign surfaces and surgical trauma. Through the Urea Cycle, Citrulline is converted back to Arginine via intermediate Ornithine. Asymmetric Dimethylmethylarginine (ADMA) is an inhibitor of all NOS isoforms, with circulating ADMA being an independent risk factor for mortality within ICU patients and is associated with an increased cardiovascular disease risk profile. Relatively recent studies have demonstrated the beneficial role of ADMA within diseases where iNOS production is overactive such as pulmonary fibrosis. Hypothesis: Cardiac surgery and CPB will alter NOS inhibitor ADMA and other metabolites . Results: Cardiac surgery patients (n=44) had arterial blood sampled over 4 time points: Morning of surgery (A), Pre (B) and post cardiac injury (C), and post-operative morning (D). Dimethylarginines (ADMA and SDMA) and Urea Cycle intermediates (Arginine, Citrulline and Ornithine) were measured via HPLC-MS/MS. Both Dimethylarginines are released as a function of proteolysis, ADMA remained unchanged over surgery (0.48±0.09μM Vs 0.46±0.08μM Vs 0.50±0.09μM Vs 0.43±0.07μM, p< 0.05) whilst SDMA increased during surgery (B) from morning of the surgery (A) (0.73±0.21μM Vs 0.89±0.25μM; p ) then decreasing post-surgery (D) (0.77±0.33μM) and Arginine (A; 111.83±53.74μM Vs B; 67.91±48.96μM; p D; 60.41±34.26μM, A Vs D; p< 0.001) and other metabolites steadily decreased. Conclusions: These findings indicate that the regulation of circulating ADMA compared to SDMA is homeostatic even within cardiac surgery. NOS substrate Arginine and Urea Cycle intermediates are consumed which may be predictive of post-operative morbidity.

We hypothesized that glucose transporter 12 (GLUT12) is involved in regulation of glucose flux in distal renal tubules in response to elevated glucose. We used the Madin-Darby canine kidney polarized epithelial cell model and neutralizing antibodies to analyze GLUT12 targeting and directional GLUT12-mediated glucose transport. At physiological glucose concentrations, GLUT12 was localized to a perinuclear position. High glucose and serum treatment resulted in GLUT12 localization to the apical membrane. This mitogen-stimulated targeting of GLUT12 was inhibited by rapamycin, the specific inhibitor of mammalian target of rapamycin (mTOR). The functional role of GLUT12 was also examined. We constructed a GLUT12 cDNA containing a c-Myc epitope tag in the fifth exofacial loop. Assays of glucose transport at the apical membrane were performed using Transwell filters. By comparing transport assays in the presence of neutralizing anti-c-Myc monoclonal antibody, we specifically measured GLUT12-mediated glucose transport at the apical surface. GLUT12-mediated glucose transport was mitogen dependent and rapamycin sensitive. Our results implicate mTOR signaling in a novel pathway of glucose transporter protein targeting and glucose transport. Activity of the mTOR pathway has been associated with diabetic kidney disease. Our results provide evidence for a link between GLUT12 protein trafficking, glucose transport and signaling molecules central to the control of metabolic disease processes.

Background In general, sugar porters function by proton-coupled symport or facilitative transport modes. Symporters, coupled to electrochemical energy, transport nutrients against a substrate gradient. Facilitative carriers transport sugars along a concentration gradient, thus transport is dependent upon extracellular nutrient levels. Across bacteria, fungi, unicellular non-vertebrates and plants, proton-coupled hexose symport is a crucial process supplying energy under conditions of nutrient flux. In mammals it has been assumed that evolution of whole body regulatory mechanisms would eliminate this need. To determine whether any isoforms bearing this function might be conserved in mammals, we investigated the relationship between the transporters of animals and the proton-coupled hexose symporters found in other species. Results We took a comparative genomic approach and have performed the first comprehensive and statistically supported phylogenetic analysis of all mammalian glucose transporter (GLUT) isoforms. Our data reveals the mammalian GLUT proteins segregate into five distinct classes. This evolutionary ancestry gives insight to structure, function and transport mechanisms within the groups. Combined with biological assays, we present novel evidence that, in response to changing nutrient availability and environmental pH, proton-coupled, active glucose symport function is maintained in mammalian cells. Conclusions The analyses show the ancestry, evolutionary conservation and biological importance of the GLUT classes. These findings significantly extend our understanding of the evolution of mammalian glucose transport systems. They also reveal that mammals may have conserved an adaptive response to nutrient demand that would have important physiological implications to cell survival and growth.

up and echo. Diagnosis ofMFS byGhent criteria. Bicuspid aortic valve (BAV) diagnosed by echo.Mean follow-upwas 10± 8 years. Results: Patients with non-MFS TAAD presented later but had similar severity of aortic dilation. Major adverse cardiac events (MACE=dissection, surgery or death)were similar in MFS and non-MFS TAAD but first MACE occurred at younger age in MFS. Death rates and age of death were comparable between MFS and non-MFS TAAD. MFS +ve BAV +ve MFS/BAV −ve p