Efficacy on resynchronization and longitudinal contractile function comparing His-bundle pacing with conventional biventricular pacing: a substudy to the His-alternative study.

AIMS: His-bundle pacing has emerged as a novel method to deliver cardiac resynchronization therapy (CRT). However, there are no data comparing conventional biventricular (BiV)-CRT with His-CRT with regard to effects on mechanical dyssynchrony and longitudinal contractile function. METHODS AND RESULTS: Patients with symptomatic heart failure, left ventricular ejection fraction ≤ 35%, and left bundle branch block (LBBB) by strict ECG criteria were randomized 1:1 to His-CRT or BiV-CRT. Two-dimensional strain echocardiography was performed prior to CRT implantation and at 6 months after implantation. Differences in changes in mechanical dyssynchrony (standard deviation of time-to-peak in 12 midventricular and basal segments) and regional longitudinal strain in the six left ventricular walls were compared between the BiV-CRT and His-CRT groups.In the on-treatment analysis, 31 received BiV-CRT and 19 His-CRT. In both groups, mechanical dyssynchrony was significantly reduced after 6 months [BiV group from 120 ms (±45) to 63 ms (±22), P < 0.001, and His group from 116 ms (±54) to 49 ms (±11), P < 0.001] but no significant differences in changes could be demonstrated between groups [-9.0 ms (-36; 18), P = 0.50]. Global longitudinal strain (GLS) improved in both groups [BiV group from -9.1% (±2.7) to -10.7% (±2.6), P = 0.02, and His group from -8.6% (±2.1) to -11.1% (±2.0), P < 0.001], but no significant differences in changes could be demonstrated from baseline to follow-up [-0.9% (-2.4; -0.6), P = 0.25] between groups. There were no regional differences between groups. CONCLUSION: In heart failure, patients with LBBB, BiV-CRT, and His-CRT have comparable effects with regard to improvements in mechanical dyssynchrony and longitudinal contractile function.

Duodenal lipid-induced symptom generation in gastroesophageal reflux disease: role of apolipoprotein A-IV and cholecystokinin.

BACKGROUND: Duodenal lipid intensifies the perception of esophageal acid perfusion. Recently, we showed that genes implicated in lipid absorption were upregulated in the duodenum of fasting gastro-esophageal reflux disease (GERD) patients. This suggests that chylomicron production and secretion may be enhanced and, consequently, the release of apolipoprotein A-IV (apoA-IV), a chylomicron-derived signaling protein. ApoA-IV may stimulate release of cholecystokinin (CCK), an activator of vagal afferents. This study evaluated putative involvement of abnormal apoA-IV and CCK responses to lipid in GERD. METHODS: Ten GERD patients and 10 healthy volunteers (HV) underwent duodenal perfusion with Intralipid 20%, 2 kcal min(-1) , for 60 min. Symptoms were scored, blood samples collected every 15 min during lipid perfusion and 15 min after discontinuation when duodenal biopsies were taken. Plasma and mucosal concentrations of apoA-IV and CCK and transcript levels of 21 genes implicated in lipid absorption, differentially expressed under fasting conditions, were quantified. KEY RESULTS: Heartburn (P = 0.003), abdominal discomfort (P = 0.037) and nausea (P = 0.008) only increased significantly during lipid infusion in GERD patients. Following lipid infusion mean mucosal apoA-IV concentration was lower in GERD patients compared with HV (P = 0.023), whereas plasma concentration tended to be elevated (P = 0.068). Mean mucosal CCK concentration was also lower in GERD patients (P = 0.009). Two genes, HIBADH and JTB, were upregulated in GERD patients (P = 0.008 and P = 0.038, respectively). CONCLUSIONS & INFERENCES: Our results suggest excessive duodenal lipid-induced release of apoA-IV and CCK in GERD. We postulate that the resulting heightened activation of duodenal vagal afferents may underlie central sensitization, thereby increasing the perception of reflux events.

Role of chemical stimulation of the duodenum in dyspeptic symptom generation.

The response to chemical stimuli such as acid, nutrients, and capsaicin at the level of the duodenum is increasingly recognized as important in the etiology of dyspeptic symptoms. Increased duodenal acid exposure has been reported for patients with dyspeptic symptoms. Duodenal hypersensitivity to acid and the enhancing effect of duodenal acid on gastroduodenal mechanosensitivity may also contribute to dyspeptic symptom generation. Serotonergic signaling pathways may be involved in acid-induced dyspeptic symptoms. As for nutrients, lipid has been unequivocally shown to have a function in the pathogenesis of dyspeptic symptoms. Cholecystokinin (CCK) is an important mediator of the effects of duodenal lipid on gastroduodenal sensorimotor activities. It is unclear whether CCK hypersecretion or hypersensitivity to CCK is responsible for symptoms in dyspeptic patients. The presence of capsaicin in the duodenum evokes symptoms and affects gastric sensorimotor function. In patients with dyspepsia, capsaicin-induced symptoms appeared to occur earlier and to be more severe, however the effects of duodenal infusion and putative consequent gastric sensorimotor abnormalities have not been examined. Capsaicin activates transient receptor potential ion channel of the vanilloid type I, which can also be activated and sensitized by acid. The interaction between the different chemical stimuli is complex and has not yet been studied in patients with dyspeptic symptoms. In conclusion, the mechanisms underlying an enhanced response to duodenal chemical stimulation in patients with dyspeptic symptoms are partially understood. At the level of the duodenum, abnormalities may exist in stimulus intensity, mucosal mRNA expression, biosynthesis, release, or inactivation of mucosal mediators, or receptor expression on afferent nerve endings. Elucidation of the abnormalities involved will provide a basis for rational treatment of dyspeptic symptoms.

Potential future increase in extreme one-hour precipitation events over Europe due to climate change.

In this study the potential increase of extreme precipitation in a future warmer European climate has been examined. Output from the regional climate model (RCM) HIRHAM4 covering Europe has been analysed for two periods, a control period 1961-1990 and a scenario 2071-2100, the latter following the IPCC scenario A2. The model has a resolution of about 12 km, which is unique compared with existing RCM studies that typically operate at 25-50 km scale, and make the results relevant to hydrological phenomena occurring at the spatial scale of the infrastructure designed to drain off rainfall in large urban areas. Extreme events with one- and 24-hour duration were extracted using the Partial Duration Series approach, a Generalized Pareto Distribution was fitted to the data and T-year events for return periods from 2 to 100 years were calculated for the control and scenario period in model cells across Europe. The analysis shows that there will be an increase of the intensity of extreme events generally in Europe; Scandinavia will experience the highest increase and southern Europe the lowest. A 20 year 1-hour precipitation event will for example become a 4 year event in Sweden and a 10 year event in Spain. Intensities for short durations and high return periods will increase the most, which implies that European urban drainage systems will be challenged in the future.

In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epithelium.

Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6-12% and SAP > or = 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P-value < 1(E)- 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell-cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function.

Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3).

OBJECTIVES: Visceral hypersensitivity is involved in the etiology of reflux symptoms. Familial clustering and twin studies demonstrated a genetic predisposition to gastroesophageal reflux disease (GERD). G-protein-coupled receptors (GPCRs) mediate the response to acid, neurotransmitters and humoral factors modulating esophageal sensory function. Thus, polymorphisms in G-proteins are putative genetic factors contributing to GERD manifestation. A functional polymorphism in the G-protein beta3 subunit gene (GNB3) is associated with functional dyspepsia (FD), in which visceral hypersensitivity is implicated in symptom generation. We evaluated the association of the GNB3 C825T polymorphism with GERD and GERD subgroups classified according to esophageal acid exposure time, symptom-reflux correlation, or coexistence of FD and/or irritable bowel syndrome (IBS) symptoms. METHODS: In total, 363 GERD patients, defined as having esophageal pH < 4 > or = 6% of time and/or symptom index (SI) > or = 50% or symptom association probability (SAP) > or = 95%, participated. In addition, 373 healthy controls free of gastrointestinal symptoms were studied. Genotyping was performed by molecular beacon assay. RESULTS: The CT genotype was more prevalent in GERD patients relative to healthy controls (adjusted odds ratio (OR)=1.43, 95% CI 1.04-1.98). GERD patients sensitive to physiological amounts of reflux displayed a higher OR (1.59), as did GERD patients with a positive symptom association score (1.50). The strongest association was detected in patients without concomitant FD and/or IBS symptoms (OR=1.66). CONCLUSIONS: GERD is associated with GNB3 C825T. The results for GERD subgroups support the hypothesis that enhanced perception of reflux events, as a consequence of the increased signal transduction upon GPCR activation associated with the 825T allele, underlies this association.

Trypsinogen IV, serotonin transporter transcript levels and serotonin content are increased in small intestine of irritable bowel syndrome patients.

Colorectal and small intestinal visceral hypersensitivity has been demonstrated in irritable bowel syndrome (IBS). Serine protease signalling via protease-activated receptor (PAR)-2 promotes hyperalgesia to mechanical distension. Furthermore, serotonergic pathways are involved in gastrointestinal visceral sensitivity. Abnormalities of serine protease and serotonergic signalling components have been identified in IBS colorectal mucosal biopsies. We determined the role of altered mucosal serine protease and serotonergic signalling in small intestine of IBS patients. Duodenal mucosal biopsies of 34 IBS patients (10 constipation-,11 diarrhoea-predominant and 13 alternating) and 20 healthy subjects (HS) were collected. Gene transcripts of PAR-2, trypsinogen IV, TPH-1, SERT (serotonin transport protein) and serotonin (5-HT(3)) subunits were quantified using real-time PCR and 5-HT content was measured by ELISA. Irritable bowel syndrome patients showed 1.5-fold higher trypsinogen IV mRNA level compared to HS (P = 0.016). SERT expression was 1.8-fold higher in IBS compared to HS (P = 0.007). Mucosal 5-HT content was 1.7-fold higher in IBS compared to HS (P = 0.015). The increase was 2.1-fold in IBS-C relative to HS (P = 0.018). Transcript levels of PAR-2, TPH-1 and 5-HT(3) receptor subunits did not differ between IBS and HS. In conclusion enhanced trypsinogen IV expression in IBS may cause increased PAR-2 activation. Increased SERT expression and mucosal 5-HT content in IBS suggest higher 5-HT availability. Both may contribute to small intestinal visceral hypersensitivity in IBS patients.

The effect of climate change on urban drainage: an evaluation based on regional climate model simulation.

That we are in a period of extraordinary rates of climate change is today evident. These climate changes are likely to impact local weather conditions with direct impacts on precipitation patterns and urban drainage. In recent years several studies have focused on revealing the nature, extent and consequences of climate change on urban drainage and urban runoff pollution issues. This study uses predictions from a regional climate model to look at the effects of climate change on extreme precipitation events. Results are presented in terms of point rainfall extremes. The analysis involves three steps: Firstly, hourly rainfall intensities from 16 point rain gauges are averaged to create a rain gauge equivalent intensity for a 25 x 25 km square corresponding to one grid cell in the climate model. Secondly, the differences between present and future in the climate model is used to project the hourly extreme statistics of the rain gauge surface into the future. Thirdly, the future extremes of the square surface area are downscaled to give point rainfall extremes of the future. The results and conclusions rely heavily on the regional model's suitability in describing extremes at timescales relevant to urban drainage. However, in spite of these uncertainties, and others raised in the discussion, the tendency is clear: extreme precipitation events effecting urban drainage and causing flooding will become more frequent as a result of climate change.

Potential of genetic translational research in gastroenterology.

The concept that genetic variation underlies inter-individual differences in drug response and contributes to the risk of developing common, complex disorders is expanding rapidly. Consequently the interest in genetic translational research has increased. Polymorphic DNA markers, either microsatellites or single nucleotide polymorphisms (SNPs), are used to assess genetic identities and track genetic differences between individuals. Given their abundance and stability, SNPs hold great promise as markers for mapping disease susceptibility loci for common, complex disorders by association studies. For this purpose the development of inexpensive, accurate, high-throughput methods for scoring large numbers of SNPs from hundreds of patients and controls is critical. Furthermore, gene expression profiling using DNA microarrays is likely to become a useful diagnostic tool enabling classification of disease phenotype based on molecular basis of disease pathogenesis, revealing information that cannot be obtained by histological assessment. Moreover, identification of differentially expressed genes in affected versus control tissue or over time in affected tissue will lead to better understanding of the mechanisms underlying disease and ultimately to the development of more effective drug therapies. To illustrate the potential of genetic translational research, several examples in the field of gastroenterology are described.

Transcriptional regulation of YML083c under aerobic and anaerobic conditions.

YML083c and DAN1 were among the Saccharomyces cerevisiae ORFs that displayed the strongest increase in transcript abundance during anaerobic growth compared to aerobic growth, as determined by oligonucleotide microarrays. We here report that transcription of YML083c is regulated by at least three different factors. First, repression under aerobic conditions depends on the presence of heme. Second, deletion analysis of the 5'-flanking region of YML083c and DAN1 revealed two regions responsible for anaerobic induction. Each of these regions conferred anoxia-regulated expression to the heterologous, minimal, CYC1-lacZ reporter. Mutations in the AAACGA subelement, common to the positive acting regions of YML083c and DAN1, almost completely abolished the ability to drive anaerobic expression of the reporter gene. This subelement is similar to the AR1 site, which is involved in anaerobic induction of the DAN/TIR genes. Activation through the AR1 site depends on Upc2. Indeed, transcription from the YML083c promoter was decreased in an upc2 null mutant. Third, expression of Sut1 under aerobic conditions enhanced transcription of YML083c, suggesting that aerobic repression of YML083c is promoted by the general Tup1-Ssn6 co-repressor complex. However, despite the presence of a sequence that matches the consensus for binding of Rox1, YML083c is not controlled by Rox1, since deletion or replacement of the putative binding site did not cause aerobic derepression. Moreover, YML083c expression was undetectable in aerobically grown cells of a rox1 null mutant.

Cost benefit risk--a concept for management of integrated urban wastewater systems?

Urban wastewater systems should be evaluated and analysed from an integrated point of view, taking all parts of the system, that is sewer system, wastewater treatment plant and receiving waters into consideration. Risk and parameter uncertainties are aspects that hardly ever have been addressed in the evaluation and design of urban wastewater systems. In this paper we present and discuss a probabilistic approach for evaluation of the performance of urban wastewater systems. Risk analysis together with the traditional cost-benefit analysis is a special variant of multi-criteria analysis that seeks to find the most feasible improvement alternative for an urban wastewater system. The most feasible alternative in this context is the alternative that has the best performance, meaning that the alternative has the lowest sum of costs, benefits and risks. The sum is expressed as the Net Present Cost (NPC). To use NPC as a decision variable has the problematic effect, that two alternatives performing completely differently when focusing on environmental cost can have the same NPC. The extreme example is one alternative with high risk and low cost and another with low risk and high cost. In this example it is up to the decision-maker to decide whether she wants to spend the budget on preventive installations or cleaning up after failures in the environment.

Plasmids with the Cre-recombinase and the dominant nat marker, suitable for use in prototrophic strains of Saccharomyces cerevisiae and Kluyveromyces lactis.

Two plasmids are described which can be used to remove the "loxP-markerMX-loxP" cassettes in strains lacking the ura3 mutation. Both contain the Cre-recombinase under control of the GAL1 promoter and the natMX cassette with the dominant marker nat, which gives yeasts resistance to the antibiotic ClonNat. pNatCre contains ARSH and CEN6 for maintenance in Saccharomyces cerevisiae. pKlNatCre has a Kluyveromyces lactis replication origin and centromere in addition.

Genome-wide transcriptional analysis of aerobic and anaerobic chemostat cultures of Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae is unique among eukaryotes in exhibiting fast growth in both the presence and the complete absence of oxygen. Genome-wide transcriptional adaptation to aerobiosis and anaerobiosis was studied in assays using DNA microarrays. This technique was combined with chemostat cultivation, which allows controlled variation of a single growth parameter under defined conditions and at a fixed specific growth rate. Of the 6,171 open reading frames investigated, 5,738 (93%) yielded detectable transcript levels under either aerobic or anaerobic conditions; 140 genes showed a >3-fold-higher transcription level under anaerobic conditions. Under aerobic conditions, transcript levels of 219 genes were >3-fold higher than under anaerobic conditions.