Figure Figure1 Research Articles

Should Cell Culture Platforms Move towards EV Therapy Requirements?

OPINION article Front. Immunol., 28 January 2015Sec. Inflammation Volume 6 - 2015 | https://doi.org/10.3389/fimmu.2015.00008

Creative Expression of Science through Poetry and Other Media can Enrich Medical and Science Education.

OPINION article Front. Neurol., 22 January 2015Sec. Neurology Education Volume 6 - 2015 | https://doi.org/10.3389/fneur.2015.00003

New techniques in the study of the brain development in newborn.

New techniques in the study of the brain development in newborn.

Structural Genomics Support for Infectious Disease Drug Design.

Structural Genomics Support for Infectious Disease Drug Design.

Calcium, a multitasking signaling actor in airway smooth muscle cells, as a target of novel strategies to limit airway disease?

Asthma, Chronic Obstructive Pulmonary Disease (COPD),… words that have entered our everyday vocabulary, but more especially diseases whose prevalence is growing steadily and which faithfully illustrate the continuous increase in respiratory diseases. The quantified estimations, suggesting that asthma affects 300,000 persons worldwide and that COPD will become the third cause of death in 2020, give a very clear vision of the future of these diseases. Thus, the investigation of the cellular mechanisms of the functioning of the respiratory system has led to the identification of signaling pathways in which modifications could be responsible for the appearance of pathophysiological situations. The ubiquitous nature of the role of calcium as a signaling actor in smooth muscle cells (SMC) associated with the fact that the SMC are major constituents of the airways, are two basic findings that clearly justify the importance of this book edited by Yong-Xiao Wang. Thus, the union of the 25 articles by almost 50 contributors that make up the 460 pages of this book clearly illustrates the variety and importance of the role of calcium in airway SMC (ASMC). However, more than a simple illustration, this book is a form of “state of the art” of the role of calcium in the physiology of ASMC and then, in its potential involvement in various pathophysiological conditions. However, it is first necessary to recognize the importance of Yong-Xiao Wang, who has gathered contributors recognized as experts in the field. The numerous works published by Yong-Xiao Wang on this subject therefore confer him the legitimacy to be the editor of such a book based on a simple observation: the number of scientific research is steadily increasing without a “comprehensive book compiling and detailing the (our) state-of-the-art advances” (preface p. v) is available. One reason for this increased interest in the role of calcium in ASCM directly comes from the involvement of alterations in regulating the calcium movements in pathophysiological situations. In this context, although the findings presented by Anderson in 1983 in one of the 1st review available on this subject seem very distant, he was clearly establishing the basis for all work presented here: “It cannot be excluded that changes in one or more of these mechanisms, induced by mediators, hormones, or other agents may be a contribution factor to airway hyperreactivity” (Anderson, 1983). Therefore, in the context of recent data collection on this theme, a book review on “calcium signaling in airway smooth muscle cells” should probably aim to try to offer an overview of this subject. As mention above, since this book is clearly a state of the art in the field, it seems to me that a figure summarizing the physiological pathways involving calcium in SMC could be the main asset that a short “book review” can provide (Figure ​(Figure1).1). It will enable readers to get an overview of the calcium-dependent pathways that are targets to consider in pathophysiological situations. Figure 1 Calcium-dependent pathways in airways smooth muscle cells. This figure summarizes the main effects of intracellular calcium dynamics (Ca2+-Sparks/Oscillations) from calcium entry into cell and local Calcium-Induced Calcium-Release (CICR) resulting from ... Figure ​Figure11 shows the intracellular mechanisms involving the calcium in the operation of the ASCM. The main roles presented here show the involvement of calcium in the control of the contraction and relaxation of ASCM but also its role in the control of cell proliferation. Although the main calcium-dependent pathways in ASMC are recalled in Figure ​Figure1,1, they can be modulated by sex hormones or maturation as well-described by Y.S. Prakash et al. in two chapters (pp. 322–332; 333–357). Moreover, since the respiratory pathologies are unanimously recognized as associated with inflammatory situations, the three chapters describing the influence of inflammatory mediators (H. Matsumoto pp. 359–379; Y. Amrani pp. 423–439; Y. Su pp. 441–457) on Ca-dependent pathways in ASMC perfectly complement this book. Finally this synthesis can be well-completed by the two chapters presenting an interesting approach based on mathematical simulation of calcium oscillation in the SMC. Therefore, the mathematical models of calcium dynamics proposed by Sneyd et al. (pp. 341–357) have to be related with the observations of E. Roux (pp. 147–175) on the kinetics of the mechanisms involved in calcium homeodynamics. In conclusion by drawing an updated synthesis of advanced knowledge of calcium-dependent intracellular pathways in the ASCM, this authoritative book can claim to be an important tool to the use not only for researchers but also for teachers and students.

Reassessing the Reassessment of suPAR in Glomerular Disease.

Soluble urokinase receptor (suPAR) is proposed as circulating factor in focal and segmental glomerulosclerosis (FSGS) (1). Spinale et al. attempt to validate the role of suPAR in glomerular disease (2). Their mouse overexpression experiments of physiological suPAR forms are distinct from the studies by Wei et al. that expressed either alternate suPAR forms or used different mouse models (1). Additional experiments will help to further clarify the distinct roles of suPAR variants. Spinale et al. extend previous clinical studies indicating that glomerular filtration rate (GFR) is an important determinant of suPAR (3). This, however, does not imply that suPAR is only bystander, as illustrated by epidemiological studies linking elevated suPAR – independent of the eGFR – to cardiovascular disease in patients with CKD (4). As for most large protein plasma components, the balance between generation and clearance determines suPAR accumulation, adding complexity when studying the direct renal effects of suPAR, especially when possibly also causing kidney disease. Biopsy proven FSGS patients with GFR >40 ml/min have in 50% elevated suPAR levels (5), suggesting also suPAR production. In addition, suPAR fragments (measured and unmeasured) may cause podocyte injury, potentially contributing to a reduced GFR. The strong effect of a low GFR on serum suPAR levels in observational studies could obfuscate the effects of suPAR-induced glomerular pathology. In conclusion, dependence of serum suPAR levels on GFR precludes using suPAR as a single value biomarker for FSGS in conditions of low GFR, but this correlation does not serve as an explanation for elevated suPAR under preserved GFR (Figure ​(Figure11). Figure 1 suPAR plasma levels above cut off of 3000 pg/ml in patients with eGFR >40 ml/min (blue line) as suggested by Li et al. applied to the patient cohort by Spinale et al. These values are likely not explained by reduced GFR alone. ...

Ion mobility-mass spectrometry: time-dispersive instrumentation.

The field of ion mobility-mass spectrometry (IM-MS) has grown with significant momentum in recent years in both fundamental advances and pioneering applications. A search of the terms “ion mobility” and “mass spectrometry” returns more than 2 000 papers, with over half of these being published in the past 4 years (Figure ​(Figure1,1, left). This increased interest has been motivated in large part by improved technologies which have enabled contemporary IM-MS to be amendable to a variety of samples in biology and medicine with high sensitivity, resolving power, and sample throughput. Figure 1 (Left) Histogram of the number of publications published per year in ion mobility and ion mobility-mass spectrometry. Note that the scale is truncated at 300 to highlight the number of publications specifically utilizing IM-MS. Further distinction is ... Highlights of the historical development of the field are presented in Figure ​Figure1,1, right. Ion mobility and mass spectrometry trace their foundations to the X-ray experiments of Thomson and Rutherford in the late 1800s,1 with Tyndall making significant improvements in the analytical capabilities of ion mobility around the 1930s.2,3 During this early era of discovery, a variety of ion mobility experimental parameters were explored, including differences in pressure,4,5 temperature,6,7 electric field,8 and the ion residence time (age) in the drift region.9 Hybrid IM-MS instruments of various configurations were developed by several groups in the 1960s to study gas-phase ion chemistry.10−12 Ion mobility measurements were used by Dole in the earliest development of electrospray ionization (ESI).13,14 Following commercialization,15 ion mobility instrumentation was used for structure-based characterization16 and differentiation of chemical isomers.17,18 In 1982, laser ionization was demonstrated with ion mobility as a means of generating simplified mobility spectra based on protonated species.19 The features which define modern IM-MS, namely, high resolution, high sensitivity, and broad sample compatibility, were developed in the 1990s and coincided with the rapid development of MS in response to the introduction of ESI and MALDI sample ionization.20−22 The last 2 decades saw significant improvements made in the coupling of IM to MS, notably the use of electrodynamic fields to confine, transfer, and focus ions across disparate pressure regions into high vacuum. An interesting observation to be made in this historical analysis is that many of the features we associate with contemporary ion mobility technology were key aspects of early ion mobility instrument design. Several noteworthy reviews of IM-MS have been published, which cover many aspects of the IM-MS technique and range of applications.23−28 A number of influential books covering various aspects of the ion mobility field are also available.29−34 Of particular relevance is Mason and McDaniel’s Transport Properties of Ions in Gases,35 which was recently republished by the American Society for Mass Spectrometry in their classic books series. Though last revised in 1988, this book is still widely considered the seminal treatment of the motion of ions in gases. The technologies and application areas which IM-MS now encompasses has expanded to such a breadth that new reviews covering IM-MS and related areas now appear every few years in the literature. A comprehensive and critical review of the field as a whole is no longer appropriate nor tractable, and as such it is the intent of this review to focus primarily on recent developments made with regard to temporally dispersive ion mobility techniques (drift tubes and traveling wave separators), with an emphasis on their use specifically in IM-MS instrumentation and methods. This focus is selected because of the recent commercial offerings in this regard that have become widely used in many research environments. The present review is not intended to be comprehensive of the ion mobility advances but rather focuses on time-dispersive IM-MS instrumentation over the past few years.

Epidermal growth factor receptor signaling and the progression of diabetic nephropathy.

Epidermal growth factor receptor signaling and the progression of diabetic nephropathy.

Effects of script similarity on bilingual advantages in executive control are likely to be negligible or null.

Effects of script similarity on bilingual advantages in executive control are likely to be negligible or null.

Central Integration of Canal and Otolith Signals is Abnormal in Vestibular Migraine: A Commentary.

Central Integration of Canal and Otolith Signals is Abnormal in Vestibular Migraine: A Commentary.

Ultrasound and cytological diagnostics of thyroid - its proper application in case of coexisting disturbing clinical signs and symptoms, suggestive of active proliferative lesion

Ultrasound and cytological diagnostics of thyroid - its proper application in case of coexisting disturbing clinical signs and symptoms, suggestive of active proliferative lesion

Coagulation support algorithm with rapid TEG and functional fibrinogen TEG in critical bleeding: more results and less time

Early coagulation support is essential in massively bleeding patients. A Coagulation Support Algorithm (CSA), integrating rapid TEG (r-TEG) and functional fibrinogen TEG (ff-TEG) could shorten the time to a tailored treatment (Figure ​(Figure11). Figure 1 Coagulation Support Algorithm. Methods A retrospective comparison of the time to available TEG and Standard Coagulation Tests (SCT: INR, aPTTr, fibrinogen level) results in two groups of bleeding and coagulopathic patients using citrate kaolin-TEG (k-TEG) or the CSA protocol (r-TEG/ff-TEG). Statistical analysis was performed with Student's t test for unpaired samples.

Validation of an electronic early warning score using decision tree analysis: proposal

Decision tree analysis uses an algorithm to classify data items by recursively posing a series of questions about items within a dataset. Each question leads to another node and potentially more questions until a predefined end condition is reached or no more questions can be asked (Figure ​(Figure1).1). We hypothesize that scores generated using the decision tree method will improve upon our existing Hamilton Early Warning Score (HEWS) for a composite endpoint of cardiac arrest, unplanned ICU admission or death. Figure 1 Sample heart rate decision tree. Methods A database of 156,642 electronically captured vital signs from 6,757 consecutively admitted patients to eight medical and surgical wards will be used to train and test the decision tree early warning score. One-third of the data will be withheld from the algorithm for use as a testing set. The algorithm will look for significant changes in vitals 72 hours prior to an outcome and develop the score based upon the resulting relative risk of the composite endpoint happening given a certain vital sign. The scores and predictions generated by the decision tree analysis will then be compared with that of the inception HEWS cohort.

Survey on ICP, target CPP and MAP measurement level in patients with severe acute brain injury in different ICUs

Since most patients with acute brain injury are treated head-up at 30 to 45°, there can be a height difference of up to 15 cm between the heart and the ear canal. This causes a difference between mathematical CPP and true CPP of up to 11 mmHg depending on the zero reference level used and the body length of the patient (Figure ​(Figure1).1). We conducted a survey to analyze the current practice on CPP targets and zero reference levels in different ICUs. Figure 1 Methods Neuro-ICU physicians were invited to participate in a survey on ICP and CPP targets and the level of measurement.

Cardiac involvement in laminopathies

Lamin A/C gene mutations can be associated with myocardial diseases, usually characterized by dilated cardiomyopathy and/or arrhythmic disorders. Phenotypic penetrance is age-related but expression is extremely heterogeneous, so that muscular and arrhythmic disease can be present in combination in the same patient, or one phenotypic manifestation can appear earlier than the other or even not become overt for a long time period[1]. From a cardiological point of view, aetiological diagnosis in dilated cardiomyopathy, and specifically the diagnosis of cardiolaminopathy, is relevant, since clinical and prognostic implications as well as specific management strategies can be different, particularly with regard to prevention of sudden cardiac death. Patients can be diagnosed as being affected by a cardiolaminopathy as a result of a cardiological workup performed for symptoms of heart failure or for arrhythmic events or can be diagnosed incidentally or during family screening. Family history, physical examination, laboratory findings (specifically serum creatine kinase values) and ECG findings are important “red flags” to diagnose a cardiolaminopathy. Patients with cardiolaminopathies may present a wide range of arrhythmic disturbances, which include either bradyarrhythmias (conduction disturbances and ario-ventricular blocks, sinus node dysfunction, atrial standstill) or tachyarrhyhmias (atrial fibrillation, ventricular tachycardia and ventricular fibrillation), in variable combinations, and with frequent association with left ventricular dysfunction and heart failure (Figure ​(Figure1).1). The presence and severity of arrhythmic disturbances is usually not related to the presence and degree of neuromuscular impairment[2-4]. The most common clinical manifestations are lightheadedness, syncope, palpitations, or even ischemic stroke due to cardioembolism (in case of atrial fibrillation or atrial standstill) or sudden death[2-5]. Implantation of a pacemaker protects form the consequences of bradyarrhythmias, while an implantable cardioverter defibrillator (ICD) is able to interrupt malignant ventricular tachyarrhythmias, thus preventing sudden cardiac death[6]. Biventricular pacing is a form of cardiac stimulation, referred as cardiac resynchronization therapy (CRT) that may improve cardiac function in case of heart failure, low ejection fraction and ventricular dyssynchrony[7]. Clinical decision making has to consider the risk and benefit of brady- and tachyarrhythmias, taking into account presence/absence of ventricular dysfunction, and the decision to implant a cardiac electrical device (pacemaker, ICD, with/without CRT) should consider potential risks and benefits (brignole EP). In a multicenter study a series of risk factors emerged as predictors of the occurrence of ventricular tachyarrhythmias (male gender, non-sustained ventricular tachycardia, left ventricular ejection fraction < 45% and non-missense mutation) and their presence or combination and should help for the decision to implant an ICD[8]. Figure 1 Spectrum of cardiac involvement in cardiolaminopathies, with regard to arrhythmic disturbances and heart failure. Legend: AV: atrio-ventricular, LV: left ventricular.

Molecular impact of graphene oxide with different shape dimension on human immune cells

In the last few years, there has been enormous interest in graphene oxide (GO) for its wide variety of applications[1]. However, for any medical application, the immune system-impact of GO still remain to be fully understood. Moreover, the modulation of immune cells mediated by nanomaterials could be interesting also in immunotheraphy applications[2]. Indeed, nanomaterials and more in general nanotechnology can enhance the efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics[3]. Following these aims we focused on the molecular effects of two GOs, different for lateral size dimensions, on human peripheral blood mononuclear cells (PBMCs). GOs were fully characterized then, we performed a wide range of standard assays looking at cell viability, cell activation and multiple cytokines secretion. We characterized the molecular impact of GOs on 84 genes immune-response-related. Additionally, a whole genome analysis was conducted on T cells and monocytes as representative of the innate and adaptive immune responses. In Figure ​Figure11 TEM and AFM characterization of GO-Small (140 nm) and GO-Large (4mm). We did not detect any toxicity in GO PBMCs treated samples. The 84 gene expression analysis evidenced a clear dimension-dependent impact of GOs on cell activation (Figure ​(Figure2).2). In particular, the GO-Small modulated 16 genes (Fold Regulation >4) compared to only 5 of GO-Large (in red in Figure ​Figure22 C). Action confirmed also by cytokine analysis (Figure ​(Figure22 D). These evidences were also confirmed by microarray analysis on T and monocytes cell lines. GO-Small impact the immune cell activation, underlined by the over expression of many pathways such as leukocyte chemotaxis pathway (Figure ​(Figure3),3), genes such as CXCL10 ligand pathway and CXCR3 receptor (Figure ​(Figure3,3, red box). Moreover, we found a strong action on cell metabolism with a down-regulation on energetic pathways such as oxidative-phosphorylation pathway in both cell types (data not shown). Our work represents a comprehensive molecular-characterization of different sized GOs on immune cells giving crucial information for the chemical and physical design of graphene for biomedical applications i.e. as a new possible drug delivery systems and nanoimmunotherapy tools. Figure 1 Figure 2 Figure 3

When too much of a novel thing may be what's "bad": commentary on Fisher, Godwin, and Seltman (2014).

When too much of a novel thing may be what's "bad": commentary on Fisher, Godwin, and Seltman (2014).

Electrochemical sensors and biosensors based on nanomaterials and nanostructures.

Taking advantage of exceptional attributes, such as being easy-to-operate, economical, sensitive, portable, and simple-to-construct, in recent decades, considerable attention has been devoted to the integration of recognition elements with electronic elements to develop electrochemical sensors and biosensors.Various electrochemical devices, such as amperometric sensors, electrochemical impedance sensors, and electrochemical luminescence sensors as well as photoelectrochemical sensors, provide wide applications in the detection of chemical and biological targets in terms of electrochemical change of electrode interfaces. With remarkable achievements in nanotechnology and nanoscience, nanomaterial-based electrochemical signal amplifications have great potential of improving both sensitivity and selectivity for electrochemical sensors and biosensors. First of all, it is well-known that the electrode materials play a critical role in the construction of high-performance electrochemical sensing platforms for detecting target molecules through various analytical principles. Furthermore, in addition to electrode materials, functional nanomaterials can not only produce a synergic effect among catalytic activity, conductivity, and biocompatibility to accelerate the signal transduction but also amplify biorecognition events with specifically designed signal tags, leading to highly sensitive biosensing. Significantly, extensive research on the construction of functional electrode materials, coupled with numerous electrochemical methods, is advancing the wide application of electrochemical devices. For example, Walcarius et al. highlighted the recent advances of nano-objects and nanoengineered and/or nanostructured materials for the rational design of biofunctionalized electrodes and related (bio)sensing systems.1 The attractiveness of such nanomaterials relies on their ability to act as effective immobilization matrices and their intrinsic and unique features as described above. These features combined with the functioning of biomolecules contribute to the improvement of bioelectrode performance in terms of sensitivity and specificity. Our group recently presented a general overview of nanomaterial-enhanced paper-based biosensors including lateral-flow test-strip and paper microfluidic devices.2 With different kinds of nanoparticles (NPs), paper-based biosensor devices have shown a great potential in the enhancement of sensitivity and specificity of disease diagnosis in developing countries. This Review focuses on recent advances in electrochemical sensors and biosensors based on nanomaterials and nanostructures during 2013 to 2014. The aim of this effort is to provide the reader with a clear and concise view of new advances in areas ranging from electrode engineering, strategies for electrochemical signal amplification, and novel electroanalytical techniques used in the miniaturization and integration of the sensors. Moreover, the authors have attempted to highlight areas of the latest and significant development of enhanced electrochemical nanosensors and nanobiosensors that inspire broader interests across various disciplines. Electrochemical sensors for small molecules, enzyme-based biosensors, genosensors, immunosensors, and cytosensors are reviewed herein (Figure ​(Figure1).1). Such novel advances are important for the development of electrochemical sensors that open up new avenues and methods for future research. We recommend readers interested in the general principles of electrochemical sensors and electrochemical methods to refer to other excellent literature for a broad scope in this area.3,4 However, due to the explosion of publications in this active field, we do not claim that this Review includes all of the published works in the past two years and we apologize to the authors of excellent work, which is unintentionally left out. Figure 1 Schematic illustration of electrochemical sensors and biosensors based on nanomaterials and nanostructures, in which electrochemical sensors for small molecular, enzyme-based biosensors, genosensors, immunosensors, and cytosensors are demonstrated.

Response: Influence of sleep disorders on television viewing time, diabetes and obesity

We thank Gandolphi and colleagues 1 for raising important issues about diabetes-related comorbidities, such as sleep disorders as possible confounding factors in relation to our recently published work 2. In addition they emphasize the importance of our study, which evaluated television (TV) viewing time as a risk factor for diabetes mellitus, a global health issue. Gandolphi et al. 1 have stated that TV exerts great influence on individuals’ behaviors, including biological and psychological mechanisms, and in particular suggested that sleep disorders are highly associated with TV viewing. The association between TV viewing and sleep remains relatively unexplored in older adults. In a small sample of 711 adults, TV viewing was associated with later bed time but was not associated with sleep duration (the interval between bedtime and rise time) or tiredness 3. Previous data from a controlled trial designed to reduce TV viewing did not observe any effects on sleep duration or awakenings 4 although this was perhaps not unexpected given that all participants demonstrated normal sleeping patterns at study entry. We agree that verifying the presence of sleep disorders in the present sample may provide additional insights. Thus we have explored the association between TV and sleep in the current cohort of older adults from the English Longitudinal Study of Ageing, previously described (2). Sleep duration was measured by an open-ended question asking participants how many hours they slept on an average week night. Responses were coded into ‘‘ 8 h’’. Sleep disturbance was assessed with three questions enquiring about difficulties falling sleep, staying asleep, and feeling tired upon waking up. These items were rated on a 4-point scale (ranging from 1 = ‘‘not during the last month’’ to 4 = ‘‘three or more times a week’’). Sleep disturbance (three or more times a week) was commonly reported; 15.1% reported difficulty falling asleep, 49.0% reported problems with waking up in the night, 19.5% reported being tired when waking up. TV viewing was associated with sleep disturbances in a dose-response manner, particularly with difficulties in falling asleep (Table​(Table1).1). We observed a ‘U-shaped’ association between sleep duration and TV viewing, suggesting that both short ( 8 hrs) was associated with more TV time (Figure​(Figure1).1). In fully adjusted models, participants that reported 6 – 7 hrs sleep per night displayed the lowest TV time (−0.57, 95% CI, −0.89, −0.25 hrs/d) in relation to those reporting < 5 hrs sleep. In summary, our results do demonstrate an association between TV viewing and sleep disturbance in older adults. Table 1 The association between TV viewing and sleep disturbance in men and women (N = 7,190; aged 65.1 ± 9.3 yrs) from the English Longitudinal study of Ageing. Figure 1 Association between sleep duration and TV viewing. Data are displayed as means ± SEM, adjusted for age, sex, cigarette smoking, alcohol intake, physical activity, self-reported chronic illness, disability, depressive symptoms, ... As our data are cross-sectional it is difficult to interpret the direction of the association, that is, if TV viewing displaces and disrupts sleep or if people watch TV if they cannot sleep. Indeed, the association between TV/sitting and obesity may also be explained by reverse causation 5. We agree that TV viewing is associated with numerous risk factors, including poor diet, lower socio economic status, obesity, smoking, depressive symptoms, and comorbidity. However, it remains unknown if excessive TV viewing is a causal factor in explaining disease risk or whether it simply reflects a cluster of unhealthy behaviors. Sleep disturbance might be important in explaining the association between TV viewing and adverse health, although the temporal sequence cannot be established using the present study design. Numerous health behaviours, such as physical activity, sleep, and diet, are often imprecisely measured in large scale epidemiological studies, thus the inclusion of objective measures such as polysomnography examinations in the near future may greatly improve our understanding in this area.

Molecular approaches to chromatography using single molecule spectroscopy.

Molecular approaches to chromatography using single molecule spectroscopy.