Smart modification of the single conical nanochannel to fabricate dual-responsive ion gate by self-initiated photografting and photopolymerization

Publication date: 1 March 2016
Source:Talanta, Volume 149
Author(s): Qingfeng Zhai, Hong Jiang, Xiaowei Zhang, Jing Li, Erkang Wang
A simple, rapid and general method of self-initiated photografting and photopolymerization (SIPGP) was first introduced to fabricate dual-responsive nanochannel with a solid-state conical nanopore for the first time. The high density of carboxyl and hydroxyl groups on the internal surface of the etched poly(ethylene terephthalate) (PET) nanochannel acted as photo-active sites to provide further growth and amplification of polymer brushes via SIPGP. Poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) was chosen as a prototypical polymer which can be grafted on the surface of the nanochannel with high efficiency. SIPGP provided a smart and simple strategy to graft polymer brush on the surface of the nanochannel without the need of a surface bonded initiator. Series of characterizations including current–voltage curves, scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) indicated the successful construction of the polymer. The functionalized nanochannel was finally used for the construction of smart gate with perfect responsibility, reversibility and stability towards CO2 and temperature. This modification strategy combined with unique character of the polymer may hold a great potential in building various smart responsive systems.

Graphical abstract

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Bioluminescent bioreporter pad biosensor for monitoring water toxicity

Publication date: 1 March 2016
Source:Talanta, Volume 149
Author(s): Tim Axelrod, Evgeni Eltzov, Robert S. Marks
Toxicants in water sources are of concern. We developed a tool that is affordable and easy-to-use for monitoring toxicity in water. It is a biosensor composed of disposable bioreporter pads (calcium alginate matrix with immobilized bacteria) and a non-disposable CMOS photodetector. Various parameters to enhance the sensor's signal have been tested, including the effect of alginate and bacterium concentrations. The effect of various toxicants, as well as, environmental samples were tested by evaluating their effect on bacterial luminescence. This is the first step in the creation of a sensitive and simple operative tool that may be used in different environments.

Graphical abstract

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Exploring the Link between the Components of Metabolic Syndrome and the Risk of Depression

Background. Metabolic syndrome (MetS) has been reported with an increased risk of depression. MetS was also associated with insulin resistance. This study aimed to evaluate whether MetS components might contribute to depression in participants with insulin resistance (IR) or not. Methods. This study included 3,331 participants ≥18 years in the NHANES 2009-2010. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). MetS components were measured using blood chemistry and body measurements. IR was identified using the homeostasis model assessment method. Results. Predicted PHQ-9 scores significantly increased as the number of MetS components increased in patients with IR. The adjusted β coefficients of the predicted PHQ-9 score with 2, 4, and 5 MetS components were 1.803, 2.081, and 3.048, respectively ( for trend

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IJMS, Vol. 16, Pages 29148-29160: Primary Phenomenon in the Network Formation of Endothelial Cells: Effect of Charge

Blood vessels are essential organs that are involved in the supply of nutrients and oxygen and play an important role in regulating the body's internal environment, including pH, body temperature, and water homeostasis. Many studies have examined the formation of networks of endothelial cells. The results of these studies have revealed that vascular endothelial growth factor (VEGF) affects the interactions of these cells and modulates the network structure. Though almost all previous simulation studies have assumed that the chemoattractant VEGF is present before network formation, vascular endothelial cells secrete VEGF only after the cells bind to the substrate. This suggests VEGF is not essential for vasculogenesis especially at the early stage. Using a simple experiment, we find chain-like structures which last quite longer than it is expected, unless the energetically stable cluster should be compact. Using a purely physical model and simulation, we find that the hydrodynamic interaction retard the compaction of clusters and that the chains are stabilized through the effects of charge. The charge at the surface of the cells affect the interparticle potential, and the resulting repulsive forces prevent the chains from folding. The ions surrounding the cells may also be involved in this process.

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Photonics, Vol. 2, Pages 1152-1163: InP-Based Waveguide Triple Transit Region Photodiodes for Hybrid Integration with Passive Optical Silica Waveguides

We report on a novel InP-based 1.55 μm waveguide triple transit region photodiode (TTR-PD) structure for hybrid integration with passive optical silica waveguides. Using the beam propagation method, numerical analyses reveal that, for evanescent optical coupling between a passive silica waveguide and the InP-based waveguide TTR-PD, a coupling efficiency of about 90% can be obtained. In addition to that, an absorption of about 50% is simulated within a TTR-PD length of 30 µm. For fabricated TTR-PD chips, a polarization dependent loss (PDL) of less than 0.9 dB is achieved within the complete optical C-band. At the operational wavelength of 1.55 µm, a reasonable PDL of 0.73 dB is measured. The DC responsivity and the RF responsivity are achieved on the order of 0.52 A/W and 0.24 A/W, respectively. Further, a 3 dB bandwidth of 132 GHz is experimentally demonstrated and high output-power levels exceeding 0 dBm are obtained. Even at the 3 dB cut-off frequency, no saturation effects occur at a photocurrent of 15.5 mA and an RF output power of −4.6 dBm is achieved. In addition to the numerical and experimental achievements, we propose a scheme for a hybrid-integrated InP/silicon-based photonic millimeter wave transmitter.

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IJMS, Vol. 16, Pages 29120-29133: Phenolic Phytoalexins in Rice: Biological Functions and Biosynthesis

Phytoalexins are inducible secondary metabolites possessing antimicrobial activity against phytopathogens. Rice produces a wide array of phytoalexins in response to pathogen attacks and environmental stresses. With few exceptions, most phytoalexins identified in rice are diterpenoid compounds. Until very recently, flavonoid sakuranetin was the only known phenolic phytoalexin in rice. However, recent studies have shown that phenylamides are involved in defense against pathogen attacks in rice. Phenylamides are amine-conjugated phenolic acids that are induced by pathogen infections and abiotic stresses including ultra violet (UV) radiation in rice. Stress-induced phenylamides, such as N-trans-cinnamoyltryptamine, N-p-coumaroylserotonin and N-cinnamoyltyramine, have been reported to possess antimicrobial activities against rice bacterial and fungal pathogens, an indication of their direct inhibitory roles against invading pathogens. This finding suggests that phenylamides act as phytoalexins in rice and belong to phenolic phytoalexins along with sakuranetin. Phenylamides also have been implicated in cell wall reinforcement for disease resistance and allelopathy of rice. Synthesis of phenolic phytoalexins is stimulated by phytopathogen attacks and abiotic challenges including UV radiation. Accumulating evidence has demonstrated that biosynthetic pathways including the shikimate, phenylpropanoid and arylmonoamine pathways are coordinately activated for phenolic phytoalexin synthesis, and related genes are induced by biotic and abiotic stresses in rice.

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IJMS, Vol. 16, Pages 29161-29178: Antioxidant and ACE Inhibitory Bioactive Peptides Purified from Egg Yolk Proteins

Protein by-products from the extraction of lecithin from egg yolk can be converted into value-added products, such as bioactive hydrolysates and peptides that have potential health enhancing antioxidant, and antihypertensive properties. In this study, the antioxidant and angiotensin converting enzyme (ACE) inhibitory activities of peptides isolated and purified from egg yolk protein were investigated. Defatted egg yolk was hydrolyzed using pepsin and pancreatin and sequentially fractionated by ultrafiltration, followed by gel filtration to produce egg yolk gel filtration fractions (EYGF). Of these, two fractions, EYGF-23 and EYGF-33, effectively inhibited the peroxides and thiobarbituric acid reactive substance (TBARS) in an oxidizing linoleic acid model system. The antioxidant mechanism involved superoxide anion and hydroxyl radicals scavenging and ferrous chelation. The presence of hydrophobic amino acids such as tyrosine (Y) and tryptophan (W), in sequences identified by LC-MS as WYGPD (EYGF-23) and KLSDW (EYGF-33), contributed to the antioxidant activity and were not significantly different from the synthetic BHA antioxidant. A third fraction (EYGF-56) was also purified from egg yolk protein by gel filtration and exhibited high ACE inhibitory activity (69%) and IC50 value (3.35 mg/mL). The SDNRNQGY peptide (10 mg/mL) had ACE inhibitory activity, which was not significantly different from that of the positive control captopril (0.5 mg/mL). In addition, YPSPV in (EYGF-33) (10 mg/mL) had higher ACE inhibitory activity compared with captopril. These findings indicated a substantial potential for producing valuable peptides with antioxidant and ACE inhibitory activity from egg yolk.

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IJMS, Vol. 16, Pages 29134-29147: Allyl Isothiocyanate Inhibits Actin-Dependent Intracellular Transport in Arabidopsis thaliana

Volatile allyl isothiocyanate (AITC) derives from the biodegradation of the glucosinolate sinigrin and has been associated with growth inhibition in several plants, including the model plant Arabidopsis thaliana. However, the underlying cellular mechanisms of this feature remain scarcely investigated in plants. In this study, we present evidence of an AITC-induced inhibition of actin-dependent intracellular transport in A. thaliana. A transgenic line of A. thaliana expressing yellow fluorescent protein (YFP)-tagged actin filaments was used to show attenuation of actin filament movement by AITC. This appeared gradually in a time- and dose-dependent manner and resulted in actin filaments appearing close to static. Further, we employed four transgenic lines with YFP-fusion proteins labeling the Golgi apparatus, endoplasmic reticulum (ER), vacuoles and peroxisomes to demonstrate an AITC-induced inhibition of actin-dependent intracellular transport of or, in these structures, consistent with the decline in actin filament movement. Furthermore, the morphologies of actin filaments, ER and vacuoles appeared aberrant following AITC-exposure. However, AITC-treated seedlings of all transgenic lines tested displayed morphologies and intracellular movements similar to that of the corresponding untreated and control-treated plants, following overnight incubation in an AITC-absent environment, indicating that AITC-induced decline in actin-related movements is a reversible process. These findings provide novel insights into the cellular events in plant cells following exposure to AITC, which may further expose clues to the physiological significance of the glucosinolate-myrosinase system.

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IJMS, Vol. 16, Pages 29103-29119: Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies

Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations.

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IJMS, Vol. 16, Pages 29179-29206: Bioinformatics Mining and Modeling Methods for the Identification of Disease Mechanisms in Neurodegenerative Disorders

Since the decoding of the Human Genome, techniques from bioinformatics, statistics, and machine learning have been instrumental in uncovering patterns in increasing amounts and types of different data produced by technical profiling technologies applied to clinical samples, animal models, and cellular systems. Yet, progress on unravelling biological mechanisms, causally driving diseases, has been limited, in part due to the inherent complexity of biological systems. Whereas we have witnessed progress in the areas of cancer, cardiovascular and metabolic diseases, the area of neurodegenerative diseases has proved to be very challenging. This is in part because the aetiology of neurodegenerative diseases such as Alzheimer´s disease or Parkinson´s disease is unknown, rendering it very difficult to discern early causal events. Here we describe a panel of bioinformatics and modeling approaches that have recently been developed to identify candidate mechanisms of neurodegenerative diseases based on publicly available data and knowledge. We identify two complementary strategies—data mining techniques using genetic data as a starting point to be further enriched using other data-types, or alternatively to encode prior knowledge about disease mechanisms in a model based framework supporting reasoning and enrichment analysis. Our review illustrates the challenges entailed in integrating heterogeneous, multiscale and multimodal information in the area of neurology in general and neurodegeneration in particular. We conclude, that progress would be accelerated by increasing efforts on performing systematic collection of multiple data-types over time from each individual suffering from neurodegenerative disease. The work presented here has been driven by project AETIONOMY; a project funded in the course of the Innovative Medicines Initiative (IMI); which is a public-private partnership of the European Federation of Pharmaceutical Industry Associations (EFPIA) and the European Commission (EC).

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Risks, Vol. 3, Pages 573-598: Information-Based Trade in German Real Estate and Equity Markets

This paper employs four established market microstructure measures on information-based trade in financial markets. A set of German mid and small caps is used to analyze potential differential information content in real estate stocks compared to other asset classes. After linking substantially lower amounts of information-based trade in real estate stocks to higher liquidity premia, it is found that the evolution of the information content in real estate and other assets follows similar trends. Consequently, interdependence is tested for rolling time windows, revealing strong informational links between real estate and other assets. Particularly, small caps, financials, as well as companies offering consumer goods and services show a close relationship to real estate. Depending on the choice of the measure of information-based trade, up to 75% of the variation in the information content in real estate shares is related to other asset classes, pointing to the notion of high dependence.

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Molecules, Vol. 20, Pages 21854-21869: Comparative Analysis of Amaryllidaceae Alkaloids from Three Lycoris Species

The major active constituents from Amaryllidaceae family were reported to be Amaryllidaceae alkaloids (AAs), which exhibited a wide spectrum of biological activities, such as anti-tumor, anti-viral, and acetyl-cholinesterase-inhibitory activities. In order to better understand their potential as a source of bioactive AAs and the phytochemical variations among three different species of Lycoris herbs, the HPLC fingerprint profiles of Lycoris aurea (L. aurea), L. radiata, and L. guangxiensis were firstly determined and compared using LC-UV and LC-MS/MS. As a result, 39 peaks were resolved and identified as AAs, of which nine peaks were found in common for all these three species, while the other 30 peaks could be revealed as characteristic AAs for L. aurea, L. radiata and L. guangxiensis, respectively. Thus, these AAs can be used as chemical markers for the identification and quality control of these plant species. To further reveal correlations between chemical components and their pharmaceutical activities of these species at the molecular level, the bioactivities of the total AAs from the three plant species were also tested against HepG2 cells with the inhibitory rate at 78.02%, 84.91% and 66.81% for L. aurea, L. radiata and L. guangxiensis, respectively. This study firstly revealed that the three species under investigation were different not only in the types of AAs, but also in their contents, and both contributed to their pharmacological distinctions. To the best of our knowledge, the current research provides the most detailed phytochemical profiles of AAs in these species, and offers valuable information for future valuation and exploitation of these medicinal plants.

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Molecules, Vol. 20, Pages 21840-21853: Alkylation of Methyl Linoleate with Propene in Ionic Liquids in the Presence of Metal Salts

Vegetable oils and fatty acid esters are suitable precursor molecules for the production of a variety of bio-based products and materials, such as paints and coatings, plastics, soaps, lubricants, cosmetics, pharmaceuticals, printing inks, surfactants, and biofuels. Here, we report the possibility of using Lewis acidic ionic liquids (ILs) to obtain polyunsaturated ester dimerization-oligomerization and/or, in the presence of another terminal alkene (propene), co-polymerization. In particular, we have tested the Lewis acidic mixtures arising from the addition of a proper amount of GaCl3 (Χ > 0.5) to two chloride-based (1-butyl-3-methylimidazolium chloride, [bmim]Cl, and 1-butylisoquinolium chloride, [BuIsoq]Cl) or by dissolution of a smaller amount of Al(Tf2N)3 (Χ = 0.1) in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [bmim][Tf2N]. On the basis of product distribution studies, [bmim][Tf2N]/Al(Tf2N)3 appears the most suitable medium in which methyl linoleate alkylation with propene can compete with methyl linoleate or propene oligomerization.

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Pharmaceutics, Vol. 7, Pages 542-553: Genomic Discoveries and Personalized Medicine in Neurological Diseases

In the past decades, we have witnessed dramatic changes in clinical diagnoses and treatments due to the revolutions of genomics and personalized medicine. Undoubtedly we also met many challenges when we use those advanced technologies in drug discovery and development. In this review, we describe when genomic information is applied in personal healthcare in general. We illustrate some case examples of genomic discoveries and promising personalized medicine applications in the area of neurological disease particular. Available data suggest that individual genomics can be applied to better treat patients in the near future.

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Symmetry, Vol. 7, Pages 2195-2205: Estrada Index of Random Bipartite Graphs

The Estrada index of a graph \(G\) of \(n\) vertices is defined by \(EE(G)=\sum_{i=1}^ne^{\lambda_i}\), where \(\lambda_1,\lambda_2,\cdots,\lambda_n\) are the eigenvalues of \(G\). In this paper, we give upper and lower bounds of \(EE(G)\) for almost all bipartite graphs by investigating the upper and lower bounds of the spectrum of random matrices. We also formulate an exact estimate of \(EE(G)\) for almost all balanced bipartite graphs.

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Sensors, Vol. 15, Pages 30810-30826: Calibration Techniques for Accurate Measurements by Underwater Camera Systems

Calibration of a camera system is essential to ensure that image measurements result in accurate estimates of locations and dimensions within the object space. In the underwater environment, the calibration must implicitly or explicitly model and compensate for the refractive effects of waterproof housings and the water medium. This paper reviews the different approaches to the calibration of underwater camera systems in theoretical and practical terms. The accuracy, reliability, validation and stability of underwater camera system calibration are also discussed. Samples of results from published reports are provided to demonstrate the range of possible accuracies for the measurements produced by underwater camera systems.

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Technologies, Vol. 3, Pages 285-301: Effect of Extraction Solvents and Drying Methods on the Physicochemical and Antioxidant Properties of Helicteres hirsuta Lour. Leaves

Helicteres hirsuta Lour. (H. hirsuta L.) is widely distributed in southeast Asian countries and has been used traditionally as a medicinal plant. However, optimal conditions for preparation of dried materials for further processing and suitable solvents for the extraction of bioactive compounds have not been investigated. The objective of this study was to evaluate the effects of different extraction solvents and different drying conditions on the physicochemical properties and antioxidant capacity of the H. hirsuta L. leaves. The results showed that both extraction solvents and drying conditions had a significant impact on physicochemical and antioxidant properties of H. hirsuta L. leaves. Among the five solvents investigated, water could extract the highest level of solid content and phenolic compounds, whereas methanol was more effective for obtaining flavonoids and saponins than other solvents. The leaves dried under either hot-air drying at 80 °C (HAD80), or vacuum drying at 50 °C (VD50) yielded the highest amount of total phenolic compounds (7.77 and 8.33 mg GAE/g, respectively) and total flavonoid content (5.79 and 4.62 mg CE/g, respectively), and possessed the strongest antioxidant power, while leaves dried using infrared drying at 30 °C had the lowest levels of bioactive compounds. Phenolic compounds including flavonoids had a strong correlation with antioxidant capacity. Therefore, HAD80 and VD50 are recommended for the preparation of dried H. hirsuta L. leaves. Water and methanol are suggested solvents to be used for extraction of phenolic compounds and saponins from H. hirsuta L. leaves for the potential application in the nutraceutical and pharmaceutical industries.

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Sensors, Vol. 15, Pages 30827-30838: Maximum-Likelihood Estimator of Clock Offset between Nanomachines in Bionanosensor Networks

Recent advances in nanotechnology, electronic technology and biology have enabled the development of bio-inspired nanoscale sensors. The cooperation among the bionanosensors in a network is envisioned to perform complex tasks. Clock synchronization is essential to establish diffusion-based distributed cooperation in the bionanosensor networks. This paper proposes a maximum-likelihood estimator of the clock offset for the clock synchronization among molecular bionanosensors. The unique properties of diffusion-based molecular communication are described. Based on the inverse Gaussian distribution of the molecular propagation delay, a two-way message exchange mechanism for clock synchronization is proposed. The maximum-likelihood estimator of the clock offset is derived. The convergence and the bias of the estimator are analyzed. The simulation results show that the proposed estimator is effective for the offset compensation required for clock synchronization. This work paves the way for the cooperation of nanomachines in diffusion-based bionanosensor networks.

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Buildings, Vol. 5, Pages 1346-1360: The Use of Sound Absorbing Shading Systems for the Attenuation of Noise on Building Façades. An Experimental Investigation

The problem of solar irradiation in building façades with large windows is often solved with the use of external shading devices, such as brise-soleil systems, but their potential acoustic effects on building façades are usually neglected. The purpose of this work is a preliminary consideration of the acoustic behaviour of brise-soleil systems and, furthermore, the evaluation of the possibility to improve their performances, in terms of Sound Pressure Level (SPL) abatement over glass surfaces. The paper reports the results of a study on two portions of the same office building, with shading devices installed in front of large windows. Both airborne sound insulation measurements and SPL measurements over the glass surfaces of the windows were carried out to compare different situations, with or without louvers, and with sound absorbing experimental louvers as well. Results show that the louvers' presence can produce an increase in the SPL over the glass surface as a consequence of the reflection of the sound. Results further show that sound absorbing louvers improve the noise protection of the system, in terms of the SPL reduction, over glass surfaces, cancelling out the negative effect of the standard shading devices.

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Micromachines, Vol. 6, Pages 1914-1922: High Speed Pump-Probe Apparatus for Observation of Transitional Effects in Ultrafast Laser Micromachining Processes

A pump-probe experimental approach has been shown to be a very efficient tool for the observation and analysis of various laser matter interaction effects. In those setups, synchronized laser pulses are used to create an event (pump) and to simultaneously observe it (probe). In general, the physical effects that can be investigated with such an apparatus are restricted by the temporal resolution of the probe pulse and the observation window. The latter can be greatly extended by adjusting the pump-probe time delay under the assumption that the interaction process remains fairly reproducible. Unfortunately, this assumption becomes invalid in the case of high-repetition-rate ultrafast laser material processing, where the irradiation history strongly affects the ongoing interaction process. In this contribution, the authors present an extension of the pump-probe setup that allows to investigate transitional and dynamic effects present during ultrafast laser machining performed at high pulse repetition frequencies.

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Micromachines, Vol. 6, Pages 1923-1934: A Simple and Reliable PDMS and SU-8 Irreversible Bonding Method and Its Application on a Microfluidic-MEA Device for Neuroscience Research

Polydimethylsiloxane (PDMS) and SU-8 are currently two very commonly used polymeric materials in the microfluidics field for biological applications. However; there is a pressing need to find a simple, reliable, irreversible bonding method between these two materials for their combined use in innovative integrated microsystems. In this paper; we attempt to investigate the aminosilane-mediated irreversible bonding method for PDMS and SU-8 with X-Ray Photoelectron Spectroscopy (XPS) surface analysis and bonding strength tests. Additionally; the selected bonding method was applied in fabricating a microelectrode array (MEA) device, including microfluidic features, which allows electrophysiological observations on compartmentalized neuronal cultures. As there is a growing trend towards microfluidic devices for neuroscience research, this type of integrated microdevice, which can observe functional alterations on compartmentalized neuronal culture, can potentially be used for neurodegenerative disease research and pharmaceutical development.

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Gels, Vol. 1, Pages 235-255: Precise Control over the Rheological Behavior of Associating Stimuli-Responsive Block Copolymer Gels

"Smart" materials have considerably evolved over the last few years for specific applications. They rely on intelligent macromolecules or (supra-)molecular motifs to adapt their structure and properties in response to external triggers. Here, a supramolecular stimuli-responsive polymer gel is constructed from heterotelechelic double hydrophilic block copolymers that incorporate thermo-responsive sequences. These macromolecular building units are synthesized via a three-step controlled radical copolymerization and then hierarchically assembled to yield coordination micellar hydrogels. The dynamic mechanical properties of this particular class of materials are studied in shear flow and finely tuned via temperature changes. Notably, rheological experiments show that structurally reinforcing the micellar network nodes leads to precise tuning of the viscoelastic response and yield behavior of the material. Hence, they constitute promising candidates for specific applications, such as mechano-sensors.

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Laws, Vol. 4, Pages 755-770: Embryonic Human Life and Dignity: The French Connection

Human dignity is considered by a number of commentators as a normative concept that could potentially bridge the gap between bioethics and human rights. The purpose of this article is to question this assumption insofar as it applies to embryonic human life by way of a case study. The article will chart the way dignity has been historically used in French political and legal debates since the 1990s to attempt to afford constitutional protection to human embryos. It then proposes an interpretation of why such attempts failed, which could have wider significance for current debates.

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Editorial Board/Aims and Scope

Publication date: 10 December 2015
Source:Vaccine, Volume 33, Issue 50





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A Brazilian report using serological and molecular diagnosis to monitoring acute ocular toxoplasmosis

Background: Toxoplasmosis was recently included as a neglected disease by the Center for Disease Control. Ocular toxoplasmosis is one clinical presentation of congenital or acquired infection. The laboratory diagnosis is being used worldwide to support the clinical diagnosis and imaging. The aim of this study was to evaluate the use of serology and molecular methods to monitor acute OT in immunocompetent patients during treatment. Methods: Five immunocompetent patients were clinically diagnosed with acute OT. The clinical evaluation was performed by ophthalmologic examination using the Early Treatment Diabetic Retinopathy Study, best-corrected visual acuity, slit lamp biomicroscopy, fundoscopic examination with indirect binocular ophthalmoscopy color fundus photography, fluorescein angiography and spectral optical coherence tomography (OCT). Serology were performed by ELISA (IgA, IgM, IgG) and confirmed by ELFA (IgG, IgM). Molecular diagnoses were performed in peripheral blood by cPCR using the Toxoplasma gondii B1 gene as the marker. Follow-up exams were performed on day +15 and day +45. Results: Only five non-immunocompromised male patients completed the follow up and their data were used for analysis. The mean age was 41.2 ± 11.3 years (median: 35; range 31–54 years). All of them were positive for IgG antibodies but with different profiles for IgM and IgA, as well as PCR. For all patients the OCT exam showed active lesions with the inner retinal layers being abnormally hyper-reflective with full-thickness disorganization of the retinal reflective layers, which assumed a blurred reflective appearance and the retina was thickened. Conclusions: The presence of IgA and IgM confirmed the acute infection and thus was in agreement with the clinical evaluation. Our results show the adopted treatment modified the serological profile of IgM antibodies and the PCR results, but not the IgG and IgA antibodies and that imaging is a good tool to follow-up patients.

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Emotion socialization practices in Italian and Hong Kong-Chinese mothers

Background: Parents' emotion socialization practices are their ways of handling their children's emotional experiences in light of cultural expectations surrounding emotions. Such practices are thought to significantly affect children's social adjustment. We compared the parenting practices of Italian and Hong Kong Chinese samples in an ethnological validation study of the maternal responses to children's emotion scale (MRCES). Participants were 71 Italian mothers (M = 39.45) and 71 Hong Kong-Chinese mothers (M = 37.75) with children aged 6–9 years.FindingsThe results confirmed the two-factor structure identified by the scale's authors, namely coaching/emotion-encouraging and emotion dismissing approaches, respectively. Each of the two factors displayed satisfactory internal consistency. The Chinese mothers obtained higher scores than the Italian mothers on both subscales. Conclusions: Our findings suggested that parents' emotion socialization practices for coping with children's emotions received different degrees of emphasis and were underpinned by different meaning in the Hong Kong and Italian cultural groups. These cultural differences are discussed in relation to their effect on children's socio-emotional development.

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The Role of Toll-Like Receptors and Myeloid Differentiation Factor 88 in Bjerkandera adusta-Induced Lung Inflammation

Background: Recently, a cluster of patients with an intractable allergic fungal cough who were characterized by sensitization to Bjerkandera adusta was reported. In the present study, the role of Toll-like receptors and myeloid differentiation factor 88 (MyD88) in B. adusta-induced lung inflammation was investigated. Methods: Wild-type (WT), TLR2^-/-,TLR4^-/-, and MyD88^-/- BALB/c mice were intratracheally challenged with B. adusta 4 times at 2-week intervals. Lung pathology, bronchoalveolar lavage fluid (BALF) cytological profiles, and inflammatory mediators in BALF were investigated. Bone marrow-derived macrophages (BMDM) from TLR2^-/-,TLR4^-/-, TLR2/4^-/-, TLR7/9^-/-,MyD88^-/-, and WT C57BL/6J mice were stimulated with B. adusta for 12 h, and inflammatory mediators in the culture medium were measured. Results:B. adusta caused lung inflammation along with Th2 cytokine [interleukin (IL)-5 and IL-13] and eosinophil-related chemokine [eotaxin and monocyte chemotactic protein (MCP-3)] production, an increase in eosinophils in BALF, and eosinophil infiltration in the airways in WT and TLR4^-/- mice. However, Th2 and eosinophil-related responses in TLR2^-/- and MyD88^-/- mice were low or undetectable. The induction of neutrophils and IL-6, IL-12, IL-17A, and MCP-1 in the BALF of MyD88^-/- mice was attenuated compared to that in WT mice. The induction of IL-6, TNF-α, MCP-1, and macrophage inflammatory protein-1α was reduced or undetectable in B. adusta-stimulated BMDM from TLR7/9^-/- and MyD88^-/- mice compared to WT mice. Conclusions: These results suggest that TLR2 and the adapter protein MyD88 may play an important role in the induction of eosinophils by B. adusta. However, TLR7/9-MyD88 might be important in the induction of neutrophils and the relevant inflammatory mediators, especially IL-17A.
Int Arch Allergy Immunol 2015;168:96-106

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Protective effects of exercise in metabolic disorders are mediated by inhibition of mitochondrial-derived sterile inflammation

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Maghsoud Peeri, Shayan Amiri
While beneficial properties of physical activity and exercise on human health have been extensively reported in literature, the exact mechanism(s) underpinning impacts of exercise are not well understood. Focusing on metabolic disorders, as the main causes of social and economic burden in current century, exercise exhibited promising effects in prevention, alleviation and retardation of these disorders including, type 2 diabetes (T2D), Alzheimer's disease (AD), major depressive disorder (MDD) and obesity. Recent evidence has unmasked the role of mitochondrial dysfunction and chronic inflammation in pathophysiology of these disorders. Despite of the wealth of research on the etiology of metabolic disorders, intimate connections between these diseases, complex pathophysiology and their comorbidity still remains a challenging dilemma. In addition, although physical activity has improving effects on human health, it is not clear that how exercise is able to exert its modulatory effects on outcomes of metabolic disorders. Among several mechanisms, we assumed the hypothesis that exercise mitigates the production of mitochondrial-induced reactive oxygen species (ROS) and danger associated molecular patterns (DAMPs) as the main triggering factors for inflammasome formation. Since inflammasomes are of highly deleterious molecules relevant to pathogenesis of metabolic disorders, we hypothesized that beneficial effects of exercise may be associated with its ability to enhance the mitochondrial biogenesis and glucose transportation through generation of brain derived neurotrophic factor (BDNF). Also, we proposed that boosting impact of exercise on autophagy process accelerates the elimination of damaged mitochondria and thus, results in considerable decrease in production of ROS and DAMPs and consequently sterile inflammation.



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Identification of the specific epigenetic alterations associated with chemo-resistance via reprogramming of cancer cells

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Jong Joo Kim, Rajani Rai
BackgroundChemo-resistance is the main obstacle in cancer therapy, limiting the effectiveness of drug treatment. Epigenetics-mediated changes are suggested as a critical factor paying the chemo-resistance phenotype. Since epigenetic modulations are a reversible phenomenon, reversion of epigenetic changes represents a promising therapeutic approach for cancer. However, heterogeneity in epigenetic marks in tumor cells makes it difficult to identify the specific epigenetic aberrations contributing to chemo-resistance. Our hypothesis aimed to explore this issue to add therapeutic options for cancer.Presentation of the hypothesisEpigenetic alterations, the main mediator of cellular reprogramming, occur rapidly upon exposure to chemotherapy. Recent studies have demonstrated that reprogramming resets/erases the epigenetic marks established during differentiation to specific somatic cell types. To overcome the heterogeneous nature of cancer cells, we will attempt to make homogenous cancer cell colonies by reprogramming. Comparison of the drug-resistant cancer cells obtained from these colonies to parent cancer cells and reprogrammed cancer cells is an effective way to determine the precise epigenetic alterations underlying specific chemo-resistance.Testing the hypothesisCellular reprogramming of cancer cells led to generation of homogenous colonies. Following lineage specification and long term drug treatment, the obtained drug resistance cells will be compared with parent cancer cells for whole genome epigenetic signature.Implications of the hypothesisA key implication of this hypothesis is that determination of the usefulness of cellular reprogramming of cancer cells enabling the identification of specific epigenetic modulation associated with particular drug resistance will enable exploration of new research avenues for cancer treatment.



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“Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis”; hypothesis that explores new horizons in treatment of cystic fibrosis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Arsalan Azimi
Cystic fibrosis, the most common inherited disease of white population, is a disease of CFTR channels, in which mucosal function of many organs especially respiratory tract is impaired. Decreased mucociliary clearance and accumulation of mucus in airways facilitates colonization of infectious microorganisms, followed by infection. Following chronic infection, persistent inflammation ensues, which results in airway remodeling and deterioration of mucociliary clearance and result in a vicious cycle. Here, it is hypothesized that cholera toxin (CT) could ameliorate symptoms of cystic fibrosis as CT could dilute the thickened mucus, improve mucociliary clearance and alleviate airway obstruction. CT strengthens immunity of airway mucosa and it could attenuates bacterial growth and reduce persistency of infection. CT also modulates cellular immune response and it could decrease airway inflammation, hinder airway remodeling and prevent respiratory deterioration. Thereby it is hypothesized that CT could target and ameliorate many of pathophysiologic steps of the disease and it explores new horizons in treatment of CF.



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A suggestion about the cause of inflammation in acute atherosis complicating poor placentation in preeclampsia

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Arnold E. Eggers
The hypothesis is set forth that maternal release of epinephrine in the adrenal medulla causes systemic platelet activation (SPA) which, in turn, initiates coagulation via the intrinsic pathway and leads to thrombin generation. Thrombin causes inflammation, which is the underlying cause of acute atherosis in preeclampsia (PE). Each step of this cascade is examined in detail and supporting literature documented. SPA is associated with migraine headaches, which are a prominent clinical feature of PE and may help explain why PE is a risk factor for future maternal cardiovascular disease.



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A hypothesis about how to achieve anticoagulation without bleeding

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Arnold E. Eggers
The hypothesis is set forth that a prothrombotic state is frequently caused by epinephrine-activated platelets initiating the intrinsic coagulation cascade by binding factor XII, a pathway which is enhanced by stasis. This pathway explains spontaneous non-injury related thrombosis in atrial fibrillation on the arterial side of the circulation and deep vein thrombosis/pulmonary embolism on the venous side of the circulation. Pharmacological interventions directed against targets in this pathway, for example factor XII, the putative factor XII receptor on activated platelets, and the α2-adrenoceptor on platelets, would be expected to provide effective anticoagulation for most clinical indications for anticoagulation without incurring the bleeding risk associated with pharmacological blockade of the extrinsic pathway, which is the limiting factor for conventional anticoagulants. Thrombotic stroke is another possible indication for such a treatment.



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Title page/Editorial Board

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6





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Possible scenarios of the influence of low-dose ionizing radiation on neural functioning

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Vladimir E. Zakhvataev
Possible scenarios of the influence of ionizing radiation on neural functioning and the CNS are suggested. We argue that the radiation-induced bystander mechanisms associated with Ca²⁺ flows, reactive nitrogen and oxygen species, and cytokines might lead to modulation of certain neuronal signaling pathways. The considered scenarios of conjugation of the bystander signaling and the neuronal signaling might result in modulation of certain synaptic receptors, neurogenesis, neurotransmission, channel conductance, synaptic signaling, different forms of neural plasticity, memory formation and storage, and learning. On this basis, corresponding new possible strategies for treating neurodegenerative deceases and mental disorders are proposed. The mechanisms considered might also be associated with neuronal survival and relevant to the treatment for brain injuries. At the same time, these mechanisms might be associated with detrimental effects and might facilitate the development of some neurological and psychiatric disorders.



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Adiponutrin (PNPLA3) in liver fibrogenesis: Is unaltered HepG2 cell line a better model system compared to murine models?

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Atanu Kumar Dutta
Alcoholic liver disease is a major source of morbidity and mortality worldwide. Twin studies had demonstrated heritability of alcoholic liver disease. Although to date only Adiponutrin (PNPLA3) rs738409 polymorphism (I148M) had been unequivocally proved to be associated with increased risk of alcoholic liver disease across different ethnicities. This protein was previously thought to have a predominant lipolytic role. However, recent investigations have provided evidence of lipogenic activity of this protein. The current hypothesis paper is summarizing the recent evidences gleaned in biological role of Adiponutrin and bioinformatic pointers towards a role in lipid trafficking. A critical appraisal of the utility of murine models and cell based systems in investigating Adiponutrin is also presented. As the HepG2 cell line harbors the I148M mutation in homozygous state it is hypothesized that this should represent an ideal model system for PNPLA3 biology. Thus, as Adiponutrin is proposed as having both lipolytic and lipogenic/lipid trafficking roles it is termed as a Yin–Yang protein in analogy to ancient Chinese wisdom.



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Effect of protein arginine methyltransferase-1 inhibition on hypoxia-induced vasoconstriction

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Chellan Kumarasamy, Gurpreet Singh, Pachaiappan Raman, Kanchana Mala
Hypoxia is defined as a decrease in the oxygen supply to a level below physiological levels which is insufficient to maintain cellular function, in the presence of unrestricted coronary inflow. It is one of the leading causes of global mortality and morbidity, due to its association with the pathology of cancer, cardiovascular disease and stroke. The common feature in these pathologies is the limitation of oxygen availability that participates in the development of these conditions. The pulmonary response to hypoxia, when hypoxia is localized, is hypoxic pulmonary vasoconstriction (HPV). HPV is a physiological and self-regulatory mechanism by which pulmonary capillary blood flow is automatically adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, HPV occurs as an acute episode during progressive critical illness or as a sustained response with vascular remodeling and pulmonary hypertension. Inspite of the hypoxia-induced shift in the redox status to a more oxidized state, the endothelium-dependent mediators of HPV that cause vasoconstrictor response to hypoxia include nitric oxide (NO), endothelin-1 and angiotensin-II. Indeed, in chronic hypoxia, due to the enhanced reactive oxygen species (ROS) generation, inhibition of endothelial nitric oxide synthase (eNOS) activity and reduced nitric oxide (NO) production there is an imbalance in the vasoconstriction–vasodilation status toward constriction. It is our hypothesis that, in hypoxic stress, a key player in initiating this imbalance is the enzyme, protein arginine methyltransferase-1 (PRMT1) which indirectly affects eNOS activity by increased production of asymmetric dimethylarginine (ADMA), a NOS-inhibitor. Thus, pharmacological inhibition of PRMT1 should restore the cellular and vascular homeostasis in hypoxic conditions.



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The transcription, translation, transport-trail and autoimmunity: Guilt by association

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Clement E. Tagoe
The autoimmune connective tissue diseases (ACTD) are a group of diseases which share clinical features and genetic inheritance. They are characterized by systemic autoimmunity and autoantibody production with a striking predilection for cellular components involved in transcription, translation and cellular transport. Although multiple triggers of autoimmunity have been proposed for this group of diseases including microbial agents such as viruses and bacteria, drugs, ultraviolet light, environmental toxins, stress, hormones and heavy metals, the prominence of autoantibodies to components of the transcription, translation, cellular transport-trail (TTTT) suggests that the agent(s) triggering the autoimmune response potentially utilize the TTTT. For the ACTD, viruses and viral agents are the likely triggers of autoimmunity as a result of aberrant viral latency with the production of autoantibodies to the components of the cellular TTTT machinery through multiple mechanisms, perhaps including molecular mimicry, bystander activation and epitope spreading.



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Size of quadriceps femoris may contribute to thyrotoxic periodic paralysis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Zi-Wei Tang, Ying He, Yu Yao, Li Qiu, Hao-Ming Tian
Thyrotoxic periodic paralysis (TPP) frequently occurs on male individuals at their third and forth decades. The major site of involvement is the proximal muscles of lower limbs. Increasing evidence has shown that the occurrence of TPP is determined by multiple factors. We hypothesized that apart from hormonal fluctuations, skeletal muscle itself may explain for the age and sex variance as well. Our study was established to explore whether the size of lower limb skeletal muscles were related to TPP. We conducted a clinical experiment including 43 patients diagnosed with TPP (Group 1) and 39 pure hyperthyroidism individuals (Group 2). Current age, body mass index (BMI), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), average girth of bilateral upper arm and thigh, physical activity level (PAL) were measured. We also adopted B mode ultrasound to quantify the muscle thickness (MT) of the major muscle involved in the disease, the quadriceps femoris (QF, including rectus femoris, RF; vastus intermedius, VI; vastus medialis, VM and vastus lateralis, VL). Patients were matched in TSH, FT4 and FT3. PAL was also statistically identical between groups. Age, BMI, thigh girth, the average of bilateral MT of QF were statistically different. After adjusting for age, BMI and girth, Group 1 still presented with larger MT of QF than Group 2, regardless of their current thyroid hormone level. There indeed exists an independent relationship between muscle thickness and TPP.



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Fatty acyl composition of lysophosphatidylcholine is important in atherosclerosis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): O.A. Akerele, S.K. Cheema
Atherosclerosis is a major cause of death for mankind. Although the pathophysiology of atherosclerosis is a complex and multifactorial process, growing body of evidence has identified phospholipids-mediated signaling as an important factor in the induction and progression of atherosclerosis. Lysophosphatidylcholine (LPC) is a major phospholipid in oxidized low-density lipoprotein, and is generally considered to be atherogenic. However, some studies have shown anti-atherogenic properties of LPC. The controversial findings surrounding the pro- or anti-atherogenic properties of LPC appear to be due to the chain length and the degree of saturation of the fatty acyl moiety of LPC. Studies have suggested that the presence of omega (n)-polyunsaturated fatty acids (PUFA) at the sn-1 position of LPC modulates the inflammatory response thereby making LPC anti-atherogenic. We have recently shown that feeding a diet high in n-3 PUFA resulted in the enrichment of LPC in both plasma and liver of C57BL/6 mice with n-3 PUFA. Others have also shown that supplementation with fish oil leads to preferential incorporation of n-3 PUFA into LPC. We also found that plasma obtained from mice fed a diet high in n-3 PUFA showed higher cholesterol efflux capacity compared to animals fed a low n-3 PUFA diet, despite no changes in high-density lipoprotein concentrations. We are therefore hypothesizing that n-3 PUFA enriched LPC has anti-atherogenic properties by promoting cholesterol efflux from macrophages and by reducing inflammation. Our anticipated long term objective is to establish that the fatty acyl moiety of LPC can be used as a potential biomarker for the risk of developing atherosclerosis. Validating this hypothesis would have a substantial impact on the public health with respect to early diagnosis of cardiovascular risks, and designing dietary based therapeutic strategies for the prevention and management of atherosclerosis and other heart related diseases.



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Possible role of granulysin in pathogenesis of osteoarthritis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Tatjana Kehler, Gordana Laskarin, Drazen Massari, Marin Dominovic, Viktor Persic, Ivan Rosovic, Josip Laginja, Daniel Rukavina
Increased presence of immune mediator and cytotoxic/apoptotic molecule granulysin was noticed in different tissues during pathological processes with the domination of Th1 over Th2 mediated immunity. Beside granulysin expression in T and NKT cells, activated NK cells are thought to be the major source of chemotactic 15kDa and cytotoxic 9kDa granulysin in vivo. As NK cells are the principal joint's tissue-infiltrating lymphocyte subset, we hypothesized that granulysin mediated human cell death (apoptosis) could be responsible for the relatively silent damage of the joint's tissue without clinically notable signs of systemic inflammation in the patients with osteoarthritis (OA). The analyzes of the presence and frequency of granulysin expressing lymphocytes at protein and gene levels in peripheral blood and synovial samples and/or the samples of joint's tissue after the joint replacement therapy in patients with OA could give the initial insight to evaluate our hypothesis. It would be of the particular interest to differentiate the expression of 9kDa and 15kDa granulysin forms in the effector cells, since only the shorter form exhibits cytotoxic properties. The measurement of granulysin mediated early apoptosis in human NK sensitive K562 cells could be suitable in vitro model for evaluating granulysin activity. Furthermore, disturbed balance of pro-inflammatory and anti-inflammatory cytokines in OA patients, could influence the level of the granulysin expression. Having in mind that the granulysin and its regulation is still unknown in the pathogenesis of OA, it could be worth to explore this important pro-inflammatory, cytotoxic/apoptotic mediator.



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Baicalin may have a therapeutic effect in attention deficit hyperactivity disorder

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Rongyi Zhou, Xinmin Han, Jiaojiao Wang, Jichao Sun
Baicalin is a flavonoid purified from Scutellaria baicalensis Georgi. It possesses a variety of pharmacological properties, such as anti-inflammatory, antioxidant, antiapoptotic, and neuro-protective properties, and provides protection against cerebral hemorrhage. However, it is seldom considered a therapeutic in mental disorders. Recent studies showed that baicalin protects cerebral functions against ischemia and has sedative and anxiolytic-like effects. Animal experiments showed that it protects dopaminergic neurons in the striatum, hippocampus and substantia nigra. It also has effects such as anti-depressive and anti-epileptic and offers resistance to Parkinson's disease. Attention deficit hyperactivity disorder (ADHD) pathogenesis is closely related to dopamine deficiency. However, the therapeutic effect of baicalin in ADHD has not been studied. We hypothesize that baicalin may protect dopaminergic neurons and increase brain dopamine levels, thus serving as an effective novel treatment for ADHD.



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Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): R.A. Underhill
The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients' blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.



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Mechanism of failure of the Cabrol procedure: A computational fluid dynamic analysis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): M. Poullis, M. Pullan
Sudden failure of the Cabrol graft is common and frequently fatal. We utilised the technique of computational fluid dynamic (CFD) analysis to evaluate the mechanism of failure and potentially improve on the design of the Cabrol procedure. CFD analysis of the classic Cabrol procedure and a number of its variants was performed. Results from this analysis was utilised to generate further improved geometric options for the Cabrol procedure. These were also subjected to CFD analysis. All current Cabrol and variations of the Cabrol procedure are predicated by CFD analysis to be prone to graft thrombosis, secondary to stasis around the right coronary artery button. The right coronary artery flow characteristics were found to be the dominant reason for Cabrol graft failure. A simple modification of the Cabrol geometry is predicated to virtually eliminate any areas of blood stasis, and graft failure. Modification of the Cabrol graft geometry, due to CFD analysis may help reduce the incidence of graft thrombosis. A C shaped Cabrol graft with the right coronary button anastomosed to its side along its course from the aorta to the left coronary button is predicted to have the least thrombotic tendency. Clinical correlation is needed.



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Review of Amyotrophic Lateral Sclerosis, Parkinson’s and Alzheimer’s diseases helps further define pathology of the novel paradigm for Alzheimer’s with heavy metals as primary disease cause

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): Franco Cavaleri
Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases – Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) – and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult.One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies.This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer's disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions.



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Non-pharmacological treatment for neuropathic pain in children with cancer

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): C. Casanova-García, S. Lerma Lara, M. Pérez Ruiz, D. Ruano Domínguez, E. Santana Sosa
Neuropathic pain (NP) associated with childhood cancer is currently a difficult problem to control. It is treated with drugs that not only fail to provide the expected improvements, but which also have side effects. Therefore, the main aim of this pilot study is to assess whether non-pharmacological treatments, Graded Motor Imagery (GMI) and Neural Mobilization (NM), have a positive effect on this pain, thus improving the associated comorbid factors and, consequently, the quality of life of the children. In an n=6, the results after 4weeks of treatment show a 10-point improvement in the pain threshold and a 3.1-point improvement in the perception of pain.



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On the origins of autism: The Quantitative Threshold Exposure hypothesis

Publication date: December 2015
Source:Medical Hypotheses, Volume 85, Issue 6
Author(s): S. Crawford
The Quantitative Threshold Exposure (QTE) hypothesis is a multifactorial threshold model that accounts for the cumulative effects of risk factor exposure in both the causation of autism spectrum disorder (ASD) and its dramatic increase over the past 30years. The QTE hypothesis proposes that ASD is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical developmental stages. The quantitative threshold parameters that comprise a cumulative risk for the development of ASD are identified by the assessment of documented epidemiological factors that, in sum, determine the likelihood that ASD will occur as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. The model proposes an explanation for the relationship between critical developmental stages of brain/immune system development in conjunction with the quantitative effects of genetic and environmental risk factors that may interface with these critical developmental windows. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates.



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PET Radioligands Reveal the Basis of Dementia in Parkinson's Disease and Dementia with Lewy Bodies

Background: Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD. Summary: We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies. Key Messages: Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.
Neurodegener Dis

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IJERPH, Vol. 12, Pages 15516-15530: Adult Lifespan Cognitive Variability in the Cross-Sectional Cam-CAN Cohort

This study examines variability across the age span in cognitive performance in a cross-sectional, population-based, adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study (n = 2680). A key question we highlight is whether using measures that are designed to detect age-related cognitive pathology may not be sensitive to, or reflective of, individual variability among younger adults. We present three issues that contribute to the debate for and against age-related increases in variability. Firstly, the need to formally define measures of central tendency and measures of variability. Secondly, in addition to the commonly addressed location-confounding (adjusting for covariates) there may exist changes in measures of variability due to confounder sub-groups. Finally, that increases in spread may be a result of floor or ceiling effects; where the measure is not sensitive enough at all ages. From the Cam-CAN study, a large population-based dataset, we demonstrate the existence of variability-confounding for the immediate episodic memory task; and show that increasing variance with age in our general cognitive measures is driven by a ceiling effect in younger age groups.

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IJERPH, Vol. 12, Pages 15531-15539: Association of Vitamin A Status with Overnutrition in Children and Adolescents

This study was conducted to examine the possible association between vitamin A status and overnutrition in Chinese urban children and adolescents. Weight, height and serum retinol were assessed in total 3457 children (7–9.9 years of age) and adolescents (10–17 years of age), using urban region data from the China National Nutrition and Health Survey 2010–2013 (CHNNS2010-2013) which is a nationally representative cross-sectional study. Prevalence of low serum concentration of retinol was 26.8% and 12.24% for overweight. Retinol inadequacy was significantly higher in children (32.13%) than in adolescents (24.48%). The average of retinol was significantly higher in overnutrified 42.32 μg/dL versus non-overnutrified 41.05 μg/dL (p = 0.00) children and adolescents. Overnutrified children and adolescents presented a greater chance of an increase in serum concentration of retinol (odds ratio 1.34, 95% confidence interval 1.10–1.63, and 1.48, 95% confidence interval (1.26–1.74) when compared with non-overnutrified children. An important correspondence between vitamin A deficiency and overnutrition was found. Non-overnutrified children and adolescents may have a greater chance of presenting low concentrations of retinol. Future public health strategies focused on the overnutrified population and vitamin A supplements should consider the effect of retinol on urban children and adolescents in China.

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IJERPH, Vol. 12, Pages 15498-15515: A Systematic Review and Meta-Regression Analysis of Lung Cancer Risk and Inorganic Arsenic in Drinking Water

High levels (> 200 µg/L) of inorganic arsenic in drinking water are known to be a cause of human lung cancer, but the evidence at lower levels is uncertain. We have sought the epidemiological studies that have examined the dose-response relationship between arsenic levels in drinking water and the risk of lung cancer over a range that includes both high and low levels of arsenic. Regression analysis, based on six studies identified from an electronic search, examined the relationship between the log of the relative risk and the log of the arsenic exposure over a range of 1–1000 µg/L. The best-fitting continuous meta-regression model was sought and found to be a no-constant linear-quadratic analysis where both the risk and the exposure had been logarithmically transformed. This yielded both a statistically significant positive coefficient for the quadratic term and a statistically significant negative coefficient for the linear term. Sub-analyses by study design yielded results that were similar for both ecological studies and non-ecological studies. Statistically significant X-intercepts consistently found no increased level of risk at approximately 100–150 µg/L arsenic.

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