Epidemiology of pulmonary hypertension: new data from the Swiss registry

BACKGROUND: since 1999 data from pulmonary hypertension (PH) patients from all PH centres in Switzerland were prospectively collected. We analyse the epidemiological aspects of these data. METHODS: PH was defined as a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise. Patients with pulmonary arterial hypertension (PAH), PH associated with lung diseases, PH due to chronic thrombotic and/or embolic disease (CTEPH), or PH due to miscellaneous disorders were registered. Data from adult patients included between January 1999 and December 2004 were analysed. RESULTS: 250 patients were registered (age 58 +/- 16 years, 104 (41%) males). 152 patients (61%) had PAH, 73 (29%) had CTEPH and 18 (7%) had PH associated with lung disease. Patients <50 years (32%) were more likely to have PAH than patients >50 years (76% vs. 53%, p <0.005). Twenty-four patients (10%) were lost to followup, 58 patients (26%) died and 150 (66%) survived without transplantation or thrombendarterectomy. Survivors differed from patients who died in the baseline six-minute walking distance (400 m [300-459] vs. 273 m [174-415]), the functional impairment (NYHA class III/IV 86% vs. 98%), mixed venous saturation (63% [57-68] vs. 56% [50-61]) and right atrial pressure (7 mm Hg [4-11] vs. 11 mm Hg [4-18]). DISCUSSION: PH is a disease affecting adults of all ages. The management of these patients in specialised centres guarantees a high quality of care. Analysis of the registry data could be an instrument for quality control and might help identify weak points in assessment and treatment of these patients.

INTERACTIVE CONTROLS OF WATER TABLE POSITION AND PLANT FUNCTIONAL TYPES ON PEAT POREWATER CHARACTER IN NORTHERN BOG ECOSYSTEMS: IMPLICATIONS FOR CARBON CYCLING DYNAMICS

Northern wetlands, and particularly peatlands, have been shown to store around 30% of the world's soil carbon and thus play a significant role in the carbon cycle of our planet. Changes in climate are altering peatland hydrology and vegetation communities. These changes are possibly resulting in declines in the ability of peatlands to sequester carbon because losses through carbon oxidation and mineralization are likely to increase relative to C inputs from net primary production in a warmer, drier climate. However, the consequences of interactive effects of altered hydrology and vegetation on carbon storage are not well understood. This research evaluated the importance of plant species, water table, and their interactive effects on porewater quality in a northern peatland with an average pH of 4.54, ranging from 4.15 to 4.8. We assessed the effects of plant functional group (ericaceous shrubs, sedges, and bryophytes) and water table position on biogeochemical processes. Specifically, we measured dissolved organic carbon (DOC), total dissolved nitrogen (TDN), potential enzyme activity, organic acids, anions and cations, spectral indexes of aromaticity, and phenolic content. Our results indicate that acetate and propionate concentrations in the sedge-dominated communities declined with depth and water table drawdown, relative to the control and ericaceous treatments. DOC increased in the lowered water table treatments in all vegetation community types, and the peat porewater C:N ratio declined in the sedge-dominated treatments when the water table was lowered. The relationship between DOC and ferrous iron showed significant responses to vegetation type; the exclusion of Ericaceae resulted in less ferrous iron per unit DOC compared to mixed species treatments and Ericaceae alone. This observation was corroborated with higher mean oxidation redox potential profiles (integrating 20, 40, and 70 cm) measured in the sedge treatments, compared with the mixed and Ericaceae species treatments over a growing season. Enzymatic activities did not show as strong of a response to treatments as expected; the oxidative enzyme peroxidase and the hydrolytic enzyme phosphatase were the only enzymes to respond to water table, where the potential activity of both enzymes increased with water table drawdown. Overall, there were significant interactive effects between changes in vegetation and water table position on peat porewater composition. These data suggest that vegetation effects on oxidation reduction potentials and peat porewater character can be as important as water table position in northern bog ecosystems.

CD39 is incorporated into plasma microparticles where it maintains functional properties and impacts endothelial activation

Plasma microparticles (MPs, <1.5 mum) originate from platelet and cell membrane lipid rafts and possibly regulate inflammatory responses and thrombogenesis. These actions are mediated through their phospholipid-rich surfaces and associated cell-derived surface molecules. The ectonucleotidase CD39/ecto-nucleoside triphosphate diphosphohydrolase1 (E-NTPDase1) modulates purinergic signalling through pericellular ATP and ADP phosphohydrolysis and is localized within lipid rafts in the membranes of endothelial- and immune cells. This study aimed to determine whether CD39 associates with circulating MPs and might further impact phenotype and function. Plasma MPs were found to express CD39 and exhibited classic E-NTPDase ecto-enzymatic activity. Entpd1 (Cd39) deletion in mice produced a pro-inflammatory phenotype associated with quantitative and qualitative differences in the MP populations, as determined by two dimensional-gel electrophoresis, western blot and flow cytometry. Entpd1-null MPs were also more abundant, had significantly higher proportions of platelet- and endothelial-derived elements and decreased levels of interleukin-10, tumour necrosis factor receptor 1 and matrix metalloproteinase 2. Consequently, Cd39-null MP augment endothelial activation, as determined by inflammatory cytokine release and upregulation of adhesion molecules in vitro. In conclusion, CD39 associates with circulating MP and may directly or indirectly confer functional properties. Our data also suggest a modulatory role for CD39 within MP in the exchange of regulatory signals between leucocytes and vascular cells.

Sphingosine kinase 1 is pivotal for Fc epsilon RI-mediated mast cell signaling and functional responses in vitro and in vivo

Mast cell degranulation is pivotal to allergic diseases; investigating novel pathways triggering mast cell degranulation would undoubtedly have important therapeutic potential. FcepsilonRI-mediated degranulation has contradictorily been shown to require SphK1 or SphK2, depending on the reports. We investigated the in vitro and in vivo specific role(s) of SphK1 and SphK2 in FcepsilonRI-mediated responses, using specific small interfering RNA-gene silencing. The small interfering RNA-knockdown of SphK1 in mast cells inhibited several signaling mechanisms and effector functions, triggered by FcepsilonRI stimulation including: Ca(2+) signals, NFkappaB activation, degranulation, cytokine/chemokine, and eicosanoid production, whereas silencing SphK2 had no effect at all. Moreover, silencing SPHK1 in vivo, in different strains of mice, strongly inhibited mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 had no effect and the mice developed anaphylaxis. Our data differ from a recent report using SPHK1(-/-) and SPHK2(-/-) mice, which showed that SphK2 was required for FcepsilonRI-mediated mast cell responses. We performed experiments in mast cells derived from SPHK1(-/-) and SPHK2(-/-) mice and show that the calcium response and degranulation, triggered by FcepsilonRI-cross-linking, is not different from that triggered in wild-type cells. Moreover, IgE-mediated anaphylaxis in the knockout mice showed similar levels in temperature changes and serum histamine to that from wild-type mice, indicating that there was no protection from anaphylaxis for either knockout mice. Thus, our data strongly suggest a previously unrecognized compensatory mechanism in the knockout mice, and establishes a role for SphK1 in IgE-mediated mast cell responses.

Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease

INTRODUCTION: Functional dyspepsia and non-erosive reflux disease (NERD) are prevalent gastrointestinal conditions with accumulating evidence regarding an overlap between the two. Still, patients with NERD represent a very heterogeneous group and limited data on dyspeptic symptoms in various subgroups of NERD are available. AIM: To evaluate the prevalence of dyspeptic symptoms in patients with NERD subclassified by using 24 h impedance-pH monitoring (MII-pH). METHODS: Patients with typical reflux symptoms and normal endoscopy underwent impedance-pH monitoring off proton pump inhibitor treatment. Oesophageal acid exposure time (AET), type of acid and non-acid reflux episodes, and symptom association probability (SAP) were calculated. A validated dyspepsia questionnaire was used to quantify dyspeptic symptoms prior to reflux monitoring. RESULTS: Of 200 patients with NERD (105 female; median age, 48 years), 81 (41%) had an abnormal oesophageal AET (NERD pH-POS), 65 (32%) had normal oesophageal AET and positive SAP for acid and/or non-acid reflux (hypersensitive oesophagus), and 54 (27%) had normal oesophageal AET and negative SAP (functional heartburn). Patients with functional heartburn had more frequent (p<0.01) postprandial fullness, bloating, early satiety and nausea compared to patients with NERD pH-POS and hypersensitive oesophagus. CONCLUSION: The increased prevalence of dyspeptic symptoms in patients with functional heartburn reinforces the concept that functional gastrointestinal disorders extend beyond the boundaries suggested by the anatomical location of symptoms. This should be regarded as a further argument to test patients with symptoms of gastro-oesophageal reflux disease in order to separate patients with functional heartburn from patients with NERD in whom symptoms are associated with gastro-oesophageal reflux.

Integration of electrical neuroimaging with other functional imaging methods

Integrating evidence from different imaging modalities is important to overcome specific limitations of any given imaging method, such as insensitivity of the EEG to unsynchronized neural events, or the lack of fMRI sensitivity to events of low metabolic demand. Processes that are visible in one modality may be related in a nontrivial way to other processes visible in another modality and insight may only be obtained by integrating both methods through a common analysis. For example, brain activity at rest seems to be at least partly determined by an interaction of cortical rhythms (visible to EEG but not to fMRI) with sub-cortical activity (visible to fMRI, but usually not to EEG without averaging). A combination of EEG and fMRI data during rest may thus be more informative than the sum of two separate analyses in both modalities. Integration is also an important source of converging evidence about specific aspects and general principles of neural functions and their dysfunctions in certain pathologies. This is because not only electrical, but also energetic, biochemical, hemodynamic and metabolic processes characterize neural states and functions, and because brain structure provides crucial constraints upon neural functions. Focusing on multimodal integration of functional data should not distract from the privileged status of the electric field as the primary direct, noninvasive real-time measure of neural transmission. The preceding chapters illustrate how electrical neuroimaging has turned scalp EEG into an imaging modality which directly captures the full temporal dynamics of neural activity in the brain.

Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures

Rationale: Focal onset epileptic seizures are due to abnormal interactions between distributed brain areas. By estimating the cross-correlation matrix of multi-site intra-cerebral EEG recordings (iEEG), one can quantify these interactions. To assess the topology of the underlying functional network, the binary connectivity matrix has to be derived from the cross-correlation matrix by use of a threshold. Classically, a unique threshold is used that constrains the topology [1]. Our method aims to set the threshold in a data-driven way by separating genuine from random cross-correlation. We compare our approach to the fixed threshold method and study the dynamics of the functional topology. Methods: We investigate the iEEG of patients suffering from focal onset seizures who underwent evaluation for the possibility of surgery. The equal-time cross-correlation matrices are evaluated using a sliding time window. We then compare 3 approaches assessing the corresponding binary networks. For each time window: * Our parameter-free method derives from the cross-correlation strength matrix (CCS)[2]. It aims at disentangling genuine from random correlations (due to finite length and varying frequency content of the signals). In practice, a threshold is evaluated for each pair of channels independently, in a data-driven way. * The fixed mean degree (FMD) uses a unique threshold on the whole connectivity matrix so as to ensure a user defined mean degree. * The varying mean degree (VMD) uses the mean degree of the CCS network to set a unique threshold for the entire connectivity matrix. * Finally, the connectivity (c), connectedness (given by k, the number of disconnected sub-networks), mean global and local efficiencies (Eg, El, resp.) are computed from FMD, CCS, VMD, and their corresponding random and lattice networks. Results: Compared to FMD and VMD, CCS networks present: *topologies that are different in terms of c, k, Eg and El. *from the pre-ictal to the ictal and then post-ictal period, topological features time courses that are more stable within a period, and more contrasted from one period to the next. For CCS, pre-ictal connectivity is low, increases to a high level during the seizure, then decreases at offset. k shows a ‘‘U-curve’’ underlining the synchronization of all electrodes during the seizure. Eg and El time courses fluctuate between the corresponding random and lattice networks values in a reproducible manner. Conclusions: The definition of a data-driven threshold provides new insights into the topology of the epileptic functional networks.

Automatic Data Normalization and Parameterization for Optical Motion Tracking

Methods for optical motion capture often require timeconsuming manual processing before the data can be used for subsequent tasks such as retargeting or character animation. These processing steps restrict the applicability of motion capturing especially for dynamic VR-environments with real time requirements. To solve these problems, we present two additional, fast and automatic processing stages based on our motion capture pipeline presented in [HSK05]. A normalization step aligns the recorded coordinate systems with the skeleton structure to yield a common and intuitive data basis across different recording sessions. A second step computes a parameterization based on automatically extracted main movement axes to generate a compact motion description. Our method does not restrict the placement of marker bodies nor the recording setup, and only requires a short calibration phase.

The MIRELA framework: modeling and analyzing mixed reality applications using timed automata

Mixed Reality (MR) aims to link virtual entities with the real world and has many applications such as military and medical domains [JBL+00, NFB07]. In many MR systems and more precisely in augmented scenes, one needs the application to render the virtual part accurately at the right time. To achieve this, such systems acquire data related to the real world from a set of sensors before rendering virtual entities. A suitable system architecture should minimize the delays to keep the overall system delay (also called end-to-end latency) within the requirements for real-time performance. In this context, we propose a compositional modeling framework for MR software architectures in order to specify, simulate and validate formally the time constraints of such systems. Our approach is first based on a functional decomposition of such systems into generic components. The obtained elements as well as their typical interactions give rise to generic representations in terms of timed automata. A whole system is then obtained as a composition of such defined components. To write specifications, a textual language named MIRELA (MIxed REality LAnguage) is proposed along with the corresponding compilation tools. The generated output contains timed automata in UPPAAL format for simulation and verification of time constraints. These automata may also be used to generate source code skeletons for an implementation on a MR platform. The approach is illustrated first on a small example. A realistic case study is also developed. It is modeled by several timed automata synchronizing through channels and including a large number of time constraints. Both systems have been simulated in UPPAAL and checked against the required behavioral properties.

Fulfilled and missed requirements for online reservation systems: an empirical investigation of Austrian and Swiss hotels

Temporal data are a core element of a reservation. In this paper we formulate 10 requirements and 14 sub-requirements for handling temporal data in online hotel reservation systems (OHRS) from a usability viewpoint. We test the fulfillment of these requirements for city and resort hotels in Austria and Switzerland. Some of the requirements are widely met; however, many requirements are fulfilled only by a surprisingly small number of hotels. In particular, numerous systems offer options for selecting data which lead to error messages in the next step. A few screenshots illustrate flaws of the systems. We also draw conclusions on the state of applying software engineering principles in the development of Web pages.

Subclinical thyroid dysfunction and functional capacity among elderly

Background: Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. Methods: We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. Results: At baseline, compared to euthyroid participants (BI 19.73±SE 0.06; IADL 13.52±0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60±0.09; IADL 13.51±0.12, p>0.05) or subclinical hypothyroidism (BI 19.82±0.06; IADL 13.55±0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. Conclusion: Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.

Different Prognostic Value of Functional Right Ventricular Parameters in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

BACKGROUND -The value of standard two-dimensional transthoracic echocardiographic (TTE) parameters for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is controversial. METHODS AND RESULTS -We investigated the impact of right ventricular fractional area change (FAC) and tricuspid annulus plane systolic excursion (TAPSE) for prediction of major adverse cardiovascular events (MACE) defined as the occurrence of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia or arrhythmogenic syncope. Among 70 patients who fulfilled the 2010 ARVC/D Task Force Criteria and underwent baseline TTE, 37 (53%) patients experienced a MACE during a median follow-up period of 5.3 (IQR 1.8-9.8) years. Average values for FAC, TAPSE, and TAPSE indexed to body surface area (BSA) decreased over time (p=0.03 for FAC, p=0.03 for TAPSE and p=0.01 for TAPSE/BSA, each vs. baseline). In contrast, median right ventricular end-diastolic area (RVEDA) increased (p=0.001 vs. baseline). Based on the results of Kaplan-Meier estimates, the time between baseline TTE and experiencing MACE was significantly shorter for patients with FAC <23% (p<0.001), TAPSE <17mm (p=0.02) or right atrial (RA) short axis/BSA ≥25mm/m(2) (p=0.04) at baseline. A reduced FAC constituted the strongest predictor of MACE (hazard ratio 1.08 per 1% decrease; 95% confidence interval 1.04-1.12; p<0.001) on bivariable analysis. CONCLUSIONS -This long-term observational study indicates that TAPSE and dilation of right-sided cardiac chambers are associated with an increased risk for MACE in ARVC/D patients with advanced disease and a high risk for adverse events. However, FAC is the strongest echocardiographic predictor of adverse outcome in these patients. Our data advocate a role for TTE in risk stratification in patients with ARVC/D, although our results may not be generalizable to lower risk ARVC/D cohorts.

Expression, purification, and projection structure by single particle electron microscopy of functional human TRPM4 heterologously expressed in Xenopus laevis oocytes

Despite efforts implicating the cationic channel transient receptor potential melastatin member 4 (TRPM4) to cardiac, nervous, and immunological pathologies, little is known about its structure and function. In this study, we optimized the requirements for purification and extraction of functional human TRPM4 protein and investigated its supra-molecular assembly. We selected the Xenopus laevis oocyte expression system because it lacks endogenous TRPM4 expression, it is known to overexpress functional human membrane channels, can be used for structure-function analysis within the same system, and is easily scaled to improve yield and develop moderate throughput capabilities through the use of robotics. Negative-stain electron microscopy (EM) revealed various sized low-resolution particles. Single particle analysis identified the majority of the projections represented the monomeric form with additional oligomeric structures potentially characterized as tetramers. Two-electrode voltage clamp electrophysiology demonstrated that human TRPM4 is functionally expressed at the oocyte plasma membrane. This study opens the door for medium-throughput screening and structure-function determination of this important therapeutically relevant target.

Functional Multiparametric Magnetic Resonance Imaging of the Kidneys Using Blood Oxygen Level-Dependent and Diffusion-Weighted Sequences: a Reliable Tool for Monitoring Acute Upper Urinary Tract Obstruction.

PURPOSE Little data is available on noninvasive MRI-based assessment of renal function during upper urinary tract (UUT) obstruction. In this study, we determined whether functional multiparametric kidney MRI is able to monitor treatment response in acute unilateral UUT obstruction. MATERIAL AND METHODS Between 01/2008 and 01/2010, 18 patients with acute unilateral UUT obstruction due to calculi were prospectively enrolled to undergo kidney MRI with conventional, blood oxygen level-dependent (BOLD) and diffusion-weighted (DW) sequences on emergency admission and after release of obstruction. Functional imaging parameters of the obstructed and contralateral unobstructed kidneys derived from BOLD (apparent spin relaxation rate [R2*]) and DW (total apparent diffusion coefficient [ADCT], pure diffusion coefficient [ADCD] and perfusion fraction [FP]) sequences were assessed during acute UUT obstruction and after its release. RESULTS During acute obstruction, R2* and FP values were lower in the cortex (p=0.020 and p=0.031, respectively) and medulla (p=0.012 and p=0.190, respectively) of the obstructed compared to the contralateral unobstructed kidneys. After release of obstruction, R2* and FP values increased both in the cortex (p=0.016 and p=0.004, respectively) and medulla (p=0.071 and p=0.044, respectively) of the formerly obstructed kidneys to values similar to those found in the contralateral kidneys. ADCT and ADCD values did not significantly differ between obstructed and contralateral unobstructed kidneys during or after obstruction. CONCLUSIONS In our patients with acute unilateral UUT obstruction due to calculi, functional kidney MRI using BOLD and DW sequences allowed for the monitoring of pathophysiologic changes of obstructed kidneys during obstruction and after its release.

ELUCIDATING FUNCTIONAL ROLES FOR MYOGENIN IN ADULT SKELETAL MUSCLE METABOLISM, EXERCISE CAPACITY, AND REGENERATION

The four basic helix-loop-helix myogenic transcription factors, myogenin, Myf5, MRF4, and MyoD are critical for embryonic skeletal muscle development. Myogenin is necessary for the terminal differentiation of myoblasts into myofibers during embryogenesis, but little is known about the roles played by myogenin in adult skeletal muscle function and metabolism. Furthermore, while metabolism is a well-studied physiological process, how it is regulated at the transcriptional level remains poorly understood. In this study, my aim was to determine the function of myogenin in adult skeletal muscle metabolism, exercise capacity, and regeneration. To investigate this, I utilized a mouse strain harboring the Myogflox allele and a Cre recombinase transgene, enabling the efficient deletion of myogenin in the adult mouse. Myogflox/flox mice were stressed physically through involuntary treadmill running and by breeding them with a strain harboring the Duchenne’s muscular dystrophy (DMDmdx) allele. Surprisingly, Myog-deleted animals exhibited an enhanced capacity for exercise, running farther and faster than their wild-type counterparts. Increased lactate production and utilization of glucose as a fuel source indicated that Myog-deleted animals exhibited an increased glycolytic flux. Hypoglycemic Myog-deleted mice no longer possessed the ability to outrun their wild-type counterparts, implying the ability of these animals to further deplete their glucose reserves confers their enhanced exercise capacity. Moreover, Myog-deleted mice exhibited an enhanced response to long-term exercise training. The mice developed a greater proportion of type 1 oxidative muscle fibers, and displayed increased levels of succinate dehydrogenase activity, indicative of increased oxidative metabolism. Mdx:Myog-deleted mice exhibited a similar phenotype, outperforming their mdx counterparts, although lagging behind wild-type animals. The morphology of muscle tissue from mdx:Myog-deleted mice appears to mimic that of mdx animals, indicating that myogenin is dispensable for adult skeletal muscle regeneration. Through global gene expression profiling and quantitative (q)RT-PCR, I identified a unique set of putative myogenin-dependent genes involved in regulating metabolic processes. These data suggest myogenin’s functions during adulthood are distinctly different than those during embryogenesis, and myogenin acts as a high-level transcription factor regulating metabolic activity in adult skeletal muscle.