Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data

In questionable cystic fibrosis (CF), mild or monosymptomatic phenotypes frequently cause diagnostic difficulties despite detailed algorithms. CF transmembrane conductance regulator (CFTR)-mediated ion transport can be studied ex vivo in rectal biopsies by intestinal current measurement (ICM).

Retention force measurement of telescopic crowns

This study deals with the determination of the retentive force between primary and secondary telescopic crowns under clinical conditions. Forty-three combined fixed-removable prostheses with a total of 140 double crowns were used for retention force measurement of the telescopic crowns prior to cementation. The crowns had a preparation of 1-2°. A specifically designed measuring device was used. The retentive forces were measured with and without lubrication by a saliva substitute. The measured values were analyzed according to the type of tooth (incisors, canines, premolars, and molars). Additionally, a comparison between lubricated and unlubricated telescopic crowns was done. As maximum retention force value 29.98 N was recorded with a telescopic crown on a molar, while the minimum of 0.08 N was found with a specimen on a canine. The median value of retention force of all telescopic crowns reached 1.93 N with an interquartile distance of 4.35 N. No statistically significant difference between lubricated and unlubricated specimens was found. The results indicate that retention force values of telescopic crowns, measured in clinical practice, are often much lower than those cited in the literature. The measurements also show a wide range. Whether this proves to be a problem for the patient's quality of life or not can however only be established by a comparison of the presented results with a follow-up study involving measurement of intraoral retention and determination by e.g. oral health impact profile.

Current status of drug-eluting stents

First-generation drug-eluting stents (DES) with controlled release of sirolimus or paclitaxel from durable polymers compared with bare-metal stents have been consistently shown to reduce the risk of repeat revascularization procedures due to restenosis. The superior efficacy was found across a wide range of patients and lesion subsets and persisted up to 5 years whereas similar outcomes have been observed in terms of death and myocardial infarction. Newer generation DES have been developed with the goal to further improve upon the safety profile of first-generation DES while maintaining efficacy. These platforms include DES with improved and more biocompatible durable polymers, DES using bioabsorbable polymers for drug release, DES with polymer-free drug release, and fully bioabsorbable DES. Newer generation DES with durable polymers such as zotarolimus-eluting or everolimus-eluting XIENCE V stents have been directly compared with first-generation DES. Most recent results of large scale clinical trials are encouraging in terms of similar or increased efficacy while improving safety by reducing the rates of myocardial infarctions and stent thrombosis. DES using biodegradable polymers for drug release represent the next technological modification and preliminary results are favorable and demonstrate similar angiographic and clinical efficacy as first-generation DES, but only longer term follow-up and investigation in larger patient cohorts will determine whether their use is associated with improved long-term safety. Fully bioabsorbable stents represent another innovative approach. Whether this innovative concept will enter into clinical routine remains yet to be determined.

Coupling of eastern and western subpolar North Atlantic: salt transport in the Irminger Current

Salt transport in the Irminger Current and thus the coupling between eastern and western subpolar North Atlantic plays an important role for climate variability across a wide range of time scales. High-resolution ocean modeling and observations indicate that 5 salinities in the eastern subpolar North Atlantic decrease with enhanced circulation of the North Atlantic subpolar gyre (SPG). This has led to the perception that a stronger SPG also transports less salt westward. In this study, we analyze a regional ocean model and a comprehensive global coupled climate model, and show that a stronger SPG transports more salt in the Irminger Current irrespective of lower salinities in its 10 source region. The additional salt converges in the Labrador Sea and the Irminger Basin by eddy transports, increases surface salinity in the western SPG, and favors more intense deep convection. This is part of a positive feedback mechanism with potentially large implications for climate variability and predictability.

Arthroplasty - current strategies for the management of knee osteoarthritis.

Osteoarthritis of the knee is a major clinical burden. Recent decades have witnessed an improved understanding of knee physiology and kinematics, which has led to the introduction of a wide range of enhanced prosthetic implant designs for a variety of indications. However, the increase in the number of procedures performed annually has led to complications being encountered at higher rates than ever before, requiring the development of optimised therapeutic strategies. The future holds several promising options, primarily in the treatment of early osteoarthritis, biological therapy, surgical navigation and patient-specific implants. This review provides an insight into the current options of knee arthroplasty, with emphasis on available designs, and examines the complications that may be encountered.

Current concepts: host-pathogen interactions in cystic fibrosis airways disease.

Chronic infection and inflammation are defining characteristics of cystic fibrosis (CF) airway disease. Conditions within the airways of patients living with CF are conducive to colonisation by a variety of opportunistic bacterial, viral and fungal pathogens. Improved molecular identification of microorganisms has begun to emphasise the polymicrobial nature of infections in the CF airway microenvironment. Changes to CF airway physiology through loss of cystic fibrosis transmembrane conductance regulator functionality result in a wide range of immune dysfunctions, which permit pathogen colonisation and persistence. This review will summarise the current understanding of how CF pathogens infect, interact with and evade the CF host.

Phenotypes of childhood asthma: are they real?

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

Cardiac patients after an acute event and/or with chronic heart disease deserve special attention to restore their quality of life and to maintain or improve functional capacity. They require counselling to avoid recurrence through a combination of adherence to a medication plan and adoption of a healthy lifestyle. These secondary prevention targets are included in the overall goal of cardiac rehabilitation (CR). Cardiac rehabilitation can be viewed as the clinical application of preventive care by means of a professional multi-disciplinary integrated approach for comprehensive risk reduction and global long-term care of cardiac patients. The CR approach is delivered in tandem with a flexible follow-up strategy and easy access to a specialized team. To promote implementation of cardiac prevention and rehabilitation, the CR Section of the EACPR (European Association of Cardiovascular Prevention and Rehabilitation) has recently completed a Position Paper, entitled 'Secondary prevention through cardiac rehabilitation: A condition-oriented approach'. Components of multidisciplinary CR for seven clinical presentations have been addressed. Components include patient assessment, physical activity counselling, exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise training as central components in all rehabilitation and preventive interventions. Many of the risk factor improvements occurring in CR can be mediated through exercise training programmes. This call-for-action paper presents the key components of a CR programme: physical activity counselling and exercise training. It summarizes current evidence-based best practice for the wide range of patient presentations of interest to the general cardiology community.

Phosphatidylinositol 3-kinase isoforms as novel drug targets

Phosphatidylinositol 3-kinases (PI3Ks) are key molecules in the signal transduction pathways initiated by the binding of extracellular signals to their cell surface receptors. The PI3K family of enzymes comprises eight catalytic isoforms subdivided into three classes and control a variety of cellular processes including proliferation, growth, apoptosis, migration and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer, but is also involved in other commonly occurring diseases such as chronic inflammation, autoimmunity, allergy, atherosclerosis, cardiovascular and metabolic diseases. The fact that the PI3K pathway is deregulated in a large number of human diseases, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. However, due to the complexity of PI3K signaling pathways, developing an effective anti-cancer therapy may be difficult. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments. In this article we will give an overview of the complex role of PI3K isoforms in human diseases and discuss their potential as drug targets. In addition, we will describe the drugs currently used in clinical trials, as well as promising emerging candidates.

Quassinoids: From traditional drugs to new cancer therapeutics

Quassinoids are a group of compounds extracted from plants of the Simaroubaceae family, which have been used for many years in folk medicine. These molecules gained notoriety after the initial discovery of the anti-leukemic activity of one member, bruceantin, in 1975. Currently over 150 quassinoids have been isolated and classified based on their chemical structures and biological properties investigated in vitro and in vivo. Many molecules display a wide range of inhibitory effects, including anti-inflammatory, anti-viral, anti-malarial and anti-proliferative effects on various tumor cell types. Although often the exact mechanism of action of the single agents remains unclear, some agents have been shown to affect protein synthesis in general, or specifically HIF-1α and MYC, membrane polarization and the apoptotic machinery. Considering that future research into chemical modifications is likely to generate more active and less toxic derivatives of natural quassinoids, this family represents a powerful source of promising small molecules targeting key prosurvival signaling pathways relevant for diverse pathologies. Here, we review available knowledge of functionality and possible applications of quassinoids and quassinoid derivatives, spanning traditional use to the potential impact on modern medicine as cancer therapeutics.

Developing European conservation and mitigation tools for pollination services: approaches of the STEP (Status and Trends of European Pollinators) project

Pollinating insects form a key component of European biodiversity, and provide a vital ecosystem service to crops and wild plants. There is growing evidence of declines in both wild and domesticated pollinators, and parallel declines in plants relying upon them. The STEP project (Status and Trends of European Pollinators, 2010-2015, www.step-project.net) is documenting critical elements in the nature and extent of these declines, examining key functional traits associated with pollination deficits, and developing a Red List for some European pollinator groups. Together these activities are laying the groundwork for future pollinator monitoring programmes. STEP is also assessing the relative importance of potential drivers of pollinator declines, including climate change, habitat loss and fragmentation, agrochemicals, pathogens, alien species, light pollution, and their interactions. We are measuring the ecological and economic impacts of declining pollinator services and floral resources, including effects on wild plant populations, crop production and human nutrition. STEP is reviewing existing and potential mitigation options, and providing novel tests of their effectiveness across Europe. Our work is building upon existing and newly developed datasets and models, complemented by spatially-replicated campaigns of field research to fill gaps in current knowledge. Findings are being integrated into a policy-relevant framework to create evidence-based decision support tools. STEP is establishing communication links to a wide range of stakeholders across Europe and beyond, including policy makers, beekeepers, farmers, academics and the general public. Taken together, the STEP research programme aims to improve our understanding of the nature, causes, consequences and potential mitigation of declines in pollination services at local, national, continental and global scales.

First middle-atmospheric zonal wind profile measurements with a new ground-based microwave Doppler-spectro-radiometer

We report on the wind radiometer WIRA, a new ground-based microwave Doppler-spectro-radiometer specifically designed for the measurement of middle-atmospheric horizontal wind by observing ozone emission spectra at 142.17504 GHz. Currently, wind speeds in five levels between 30 and 79 km can be retrieved which makes WIRA the first instrument able to continuously measure horizontal wind in this altitude range. For an integration time of one day the measurement error on each level lies at around 25 m s−1. With a planned upgrade this value is expected to be reduced by a factor of 2 in the near future. On the altitude levels where our measurement can be compared to wind data from the European Centre for Medium-Range Weather Forecasts (ECMWF) very good agreement in the long-term statistics as well as in short time structures with a duration of a few days has been found. WIRA uses a passive double sideband heterodyne receiver together with a digital Fourier transform spectrometer for the data acquisition. A big advantage of the radiometric approach is that such instruments can also operate under adverse weather conditions and thus provide a continuous time series for the given location. The optics enables the instrument to scan a wide range of azimuth angles including the directions east, west, north, and south for zonal and meridional wind measurements. The design of the radiometer is fairly compact and its calibration does not rely on liquid nitrogen which makes it transportable and suitable for campaign use. WIRA is conceived in a way that it can be operated remotely and does hardly require any maintenance. In the present paper, a description of the instrument is given, and the techniques used for the wind retrieval based on the determination of the Doppler shift of the measured atmospheric ozone emission spectra are outlined. Their reliability was tested using Monte Carlo simulations. Finally, a time series of 11 months of zonal wind measurements over Bern (46°57′ N, 7°26′ E) is presented and compared to ECMWF wind data.

Multiple time scales of temporal response in pyramidal and fast spiking cortical neurons

Neural dynamic processes correlated over several time scales are found in vivo, in stimulus-evoked as well as spontaneous activity, and are thought to affect the way sensory stimulation is processed. Despite their potential computational consequences, a systematic description of the presence of multiple time scales in single cortical neurons is lacking. In this study, we injected fast spiking and pyramidal (PYR) neurons in vitro with long-lasting episodes of step-like and noisy, in-vivo-like current. Several processes shaped the time course of the instantaneous spike frequency, which could be reduced to a small number (1-4) of phenomenological mechanisms, either reducing (adapting) or increasing (facilitating) the neuron's firing rate over time. The different adaptation/facilitation processes cover a wide range of time scales, ranging from initial adaptation (<10 ms, PYR neurons only), to fast adaptation (<300 ms), early facilitation (0.5-1 s, PYR only), and slow (or late) adaptation (order of seconds). These processes are characterized by broad distributions of their magnitudes and time constants across cells, showing that multiple time scales are at play in cortical neurons, even in response to stationary stimuli and in the presence of input fluctuations. These processes might be part of a cascade of processes responsible for the power-law behavior of adaptation observed in several preparations, and may have far-reaching computational consequences that have been recently described.