The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot

Abstract

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. As a result of the surgical strategies employed at the time of initial repair, chronic pulmonary regurgitation (PR) is prevalent in this population. Despite sustained research efforts, patient selection and timing of pulmonary valve replacement (PVR) to address PR in young asymptomatic patients with repaired tetralogy of Fallot (rToF) remain a fundamental but as yet unanswered question in the field of congenital heart disease. The ability of the heart to compensate for the chronic volume overload imposed by PR is critical in the evaluation of the risks and benefits of PVR. The difficulty in clarifying the functional impact of PR on the cardiovascular capacity may be in part responsible for the uncertainty surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET) may be used to assess abnormal cardiovascular response to increased physiologic demands. However, its use as a tool for risk stratification in asymptomatic adolescents and young adults with rToF is still ill-defined. In this paper, we review the role of CPET as a potentially valuable adjunct to current risk stratification strategies with a focus on asymptomatic rToF adolescents and young adults being considered for PVR. The role of maximal and submaximal exercise measurements to identify young patients with a decreased or borderline low peak VO₂ resulting from impaired ventricular function is explored. Current knowledge gaps and research perspectives are highlighted.

http://ift.tt/2svHXrw

Influence of Micropatterned Silk Fibroin Films on Human Umbilical Endothelial Cell Behaviors

Abstract

To design functional vascular grafts, it is essential to explore the interactions between endothelial cells and the surface of substrate biomaterials. The present study thus aimed at evaluating the influence of micropatterned silk fibroin films on human umbilical vein endothelial cell (HUVEC) behaviors including adhesion, migration, proliferation, and protein expressions. Silk fibroin films with different grafting micropatterns (10 μm × 10 μm, 20 μm × 20 μm, 20 μm × 30 μm, 40 μm × 40 μm) were prepared by soft-lithographic technique. HUVECs were shown to attach and grow well on the silk fibroin films. The results indicated that the 10 × 10 and 40 × 40 gratings induced higher proliferation rates as compared to the 20 × 20 and 20 × 30 groups. However, the increased orientation and alignment degree and stronger protein expressions (CD31, VWF and Vinculin) were observed on the 20 × 20 and 20 × 30 groups. Overall, this study suggested that the HUVEC behaviors could be regulated in vitro by different micropattern topographies. The micropatterned silk fibroin films may offer a potential improvement for the development of functional vascular grafts.

http://ift.tt/2rmOvoR

Detrended Fluctuation Analysis of Oxyhemoglobin Saturation by Pulse Oximetry in Sleep Apnea Syndrome

Abstract

Variability of oxyhemoglobin saturation during sleep has been utilized as diagnostic index for sleep apnea. This work examined the parameters of a detrended fluctuation analysis (DFA) plot created from series data for oxyhemoglobin saturation during a sleep study in 273 subjects. A novel automated algorithm was devised to measure the parameters of a DFA log–log plot that included the slopes of 4 line segments and the coordinates and angles of their intersections. The diagnostic value of the parameters was investigated by receiver operating characteristic (ROC) curves using apnea/hypopnea index (AHI) cutoff values of 5, 15, and 30. Three of the DFA plot parameters exhibited an area under the ROC curve ≥0.89 for all three AHI cutoff values. Principal component analysis found a surrogate variable that increased the areas under ROC curves to greater than 0.92 for all of the AHI cutoff values. The algorithm was "leave-one-out" cross-validated and validated in another 206 subjects receiving polysomnographic studies. The results demonstrate that the DFA plot of oxyhemoglobin saturation is a useful tool for screening subjects with sleep apnea.

http://ift.tt/2sFFqeA

The effect of intravenous lidocaine infusion on bispectral index during major abdominal surgery

Abstract

Intraoperative lidocaine infusion has become widely accepted as an adjunct to general anesthesia where its use has been associated with opioid-sparing and enhanced recovery. The aims of this study were to determine whether or not intravenous (IV) lidocaine infusion (a) has an anesthetic sparing effect during major colorectal procedures and (b) if it also affects level of hypnosis as measured by bispectral index (BIS). Twenty-five patients undergoing laparotomy for resection of colorectal tumours were randomized to receive either IV lidocaine (1.5 mg kg⁻¹ bolus then 1 mg kg⁻¹ per hour) or an equivalent volume of normal saline commenced after intravenous induction of general anesthesia. Anesthesia was maintained with volatile anesthetic agent combined with intermittent IV fentanyl titrated to hemodynamic stability. Minimum alveolar concentration (MAC) of volatile was calculated using an age-adjusted algorithm (corrected MAC). BIS values were recorded throughout; however, treating anesthesiologists were blinded to BIS values and hence they were not used to guide depth of anesthesia. No other regional anesthesia techniques were used. During the maintenance phase of anesthesia, corrected MAC of volatile agent was lower (1.0 versus 1.1, p = 0.003); whereas BIS values were higher (45 versus 39, p < 0.001) in patients who received lidocaine versus placebo. No differences in mean arterial pressure (80 versus 80 mmHg, p = 0.796) or total fentanyl dose (538 versus 444 mcg, p = 0.24) were observed between the two groups. Heart rate was slightly higher in patients who received lidocaine versus placebo (67 versus 64 bpm, p = 0.001). Lidocaine infusion resulted in mean plasma levels of 1.7 mcg ml⁻¹ (1.3–2.0 mcg ml⁻¹, 95% CI). Our results support an anesthetic sparing effect of lidocaine infusion indicated by lower MAC requirements. Higher BIS values in the lidocaine versus placebo group may indicate that levels of hypnosis were not equivalent. Alternatively, BIS may not be a sensitive indicator of synergistic interactions between local anesthetic and volatile agent. Our results advocate a cautious approach to titration of general anesthesia when combined with lidocaine infusion.

http://ift.tt/2sz92KX

Endothelial vascular markers in coronary surgery

Abstract

Coronary heart disease is associated with high morbidity and mortality. Endothelial dysfunction in affected patients is linked to long-term atherosclerotic disease progression and cardiovascular event rates. The present paper reports on changes in the levels of endothelial progenitor cells (VEGFR2/CD133/CD34), essential for endothelial repair, and of endothelial microvesicles (CD31/annexin V) as indicators of endothelial lesion, in patients undergoing coronary bypass surgery with respect both to baseline levels and to counts in healthy subjects. In an observational descriptive study, 31 patients scheduled for coronary revascularization surgery were compared with those of 25 healthy controls. In a subsequent longitudinal study, patients undergoing surgery were monitored at 5 timepoints up until 48 h after surgery. Endothelial progenitor cell (VEGFR2/CD133/CD34) and endothelial microvesicle (CD31/annexin V) levels were quantified by flow cytometry. Baseline endothelial progenitor cell counts in coronary patients were significantly lower than those of healthy controls (p < 0.001); however, after surgery, levels rose steadily over all 5 timepoints to 48 h  with statistically significant differences (p < 0.001) between intra-operative and 48 h after surgery (T5). Endothelial microvesicle levels were significantly higher in coronary patients prior to surgery than in healthy controls (p < 0.001), and despite declining at 48 h remained significantly higher than those of controls (p < 0.001). Coronary surgery has had a positive impact on the endothelium in the patients, prompting a decrease in signs of endothelial dysfunction and a considerable improvement in the endothelial repair mechanisms involved in angiogenesis, playing an important role in the inflammatory response and the remodelling process of ischemic myocardium in postoperative period.

http://ift.tt/2ttAdDz

Time for a standardized clinical assessment for narcolepsy with obstructive sleep apnea

http://ift.tt/2s7TNHF

The antipsychotic agent quetiapine is increasingly not used as such: dispensed prescriptions in Norway 2004–2015

Abstract

Purpose

The antipsychotic agent quetiapine was introduced in Norway in 2003. We have assessed changes in dispensed prescriptions, including dosing, of quetiapine in Norway from 2004 to 2015.

Methods

Data on the sales of antipsychotics and antidepressants were drawn from the Norwegian Prescription Database. A total of 47,474 outpatients filled 195,622 prescriptions of quetiapine. Reimbursement codes, use of antipsychotics or antidepressants 12 months prior to the first prescription of quetiapine and estimated mean volume used measured as defined daily doses (DDDs) per day were used as proxies for diagnoses. We conducted a regression analysis with DDD per day as a function of possible explanatory variables.

Results

The number of users filling at least two prescriptions of quetiapine per year increased from 584 in 2004 to 8506 in 2015 and the mean dose declined from 1.58 DDD per day (SD 8.00) to 0.48 DDD per day (SD 2.27). The latter is much lower than recommended for treatment of psychoses. In 2015, 60.1% of the 8506 quetiapine users did not seek reimbursement for the treatment of a major psychiatric disorder and only 2.6% of the patients were prescribed 1 DDD or more per day and reimbursed in accordance with the drug's primary indication, psychosis. A reported diagnosis of psychosis was not associated with higher quetiapine doses.

Conclusions

In 2015, the pattern of quetiapine dispensing in Norway most likely reflects predominant off-label use. This is unsettling considering poorly documented effects in non-psychotic disorders, profound side effects, significant toxicity and growing concern regarding abuse.

http://ift.tt/2t8sVFX

To Improve Translational Research in Subarachnoid Hemorrhage

http://ift.tt/2suSkf1

Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Abstract

Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90–94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.

http://ift.tt/2svgZQM

Silencing of a second dimethylallyltryptophan synthase of Penicillium roqueforti reveals a novel clavine alkaloid gene cluster

Abstract

Penicillium roqueforti produces several prenylated indole alkaloids, including roquefortine C and clavine alkaloids. The first step in the biosynthesis of roquefortine C is the prenylation of tryptophan-derived dipeptides by a dimethylallyltryptophan synthase, specific for roquefortine biosynthesis (roquefortine prenyltransferase). A second dimethylallyltryptophan synthase, DmaW2, different from the roquefortine prenyltransferase, has been studied in this article. Silencing the gene encoding this second dimethylallyltryptophan synthase, dmaW2, proved that inactivation of this gene does not prevent the production of roquefortine C, but suppresses the formation of other indole alkaloids. Mass spectrometry studies have identified these compounds as isofumigaclavine A, the pathway final product and prenylated intermediates. The silencing does not affect the production of mycophenolic acid and andrastin A. A bioinformatic study of the genome of P. roqueforti revealed that DmaW2 (renamed IfgA) is a prenyltransferase involved in isofumigaclavine A biosynthesis encoded by a gene located in a six genes cluster (cluster A). A second three genes cluster (cluster B) encodes the so-called yellow enzyme and enzymes for the late steps for the conversion of festuclavine to isofumigaclavine A. The yellow enzyme contains a tyrosine-181 at its active center, as occurs in Neosartorya fumigata, but in contrast to the Clavicipitaceae fungi. A complete isofumigaclavines A and B biosynthetic pathway is proposed based on the finding of these studies on the biosynthesis of clavine alkaloids.

http://ift.tt/2t86Lno

Bundles Prevent Surgical Site Infections After Colorectal Surgery: Meta-analysis and Systematic Review

Abstract

Introduction

Colorectal surgeries (CRS) have one of the highest rates of surgical site infections (SSIs) with rates 15 to >30%. Prevention "bundles" or sets of evidence-based interventions are structured ways to improve patient outcomes. The aim sof this study is to evaluate CRS SSI prevention bundles, bundle components, and implementation and compliance strategies.

Methods

A meta-analysis of studies with pre- and post-implementation data was conducted to assess the impact of bundles on SSI rates (superficial, deep, and organ/space). Subgroup analysis of bundle components identified optimal bundle designs.

Results

Thirty-five studies (51,413 patients) were identified and 23 (17,557 patients) were included in the meta-analysis. A SSI risk reduction of 40% (p < 0.001) was noted with 44% for superficial SSI (p < 0.001) and 34% for organ/space (p = 0.048). Bundles with sterile closure trays (58.6 vs 33.1%), MBP with oral antibiotics (55.4 vs 31.8%), and pre-closure glove changes (56.9 vs 28.5%) had significantly greater SSI risk reduction.

Conclusion

Bundles can effectively reduce the risk of SSIs after CRS, by fostering a cohesive environment, standardization, and reduction in operative variance. If implemented successfully and complied with, bundles can become vital to improving patients' surgical quality of care.

http://ift.tt/2sg9lr8

Carbon Nanotube Reinforced Collagen/Hydroxyapatite Scaffolds Improve Bone Tissue Formation In Vitro and In Vivo

Abstract

Current bone regeneration strategies faced major challenges in fabricating the bionic scaffolds with nano-structure, constituents and mechanical features of native bone. In this study, we developed a new porous scaffold by adding the multi-walled carbon nanotube (MWCNT) into collagen (Col)/hydroxyapatite (HA) composites. Data showed that 0.5%CNT/Col/HA (0.5%CNT) group was approximately tenfolds stiffer than Col–HA, and it was superior in promoting bone marrow mesenchymal stem proliferation and spreading, mRNA and protein expressions of bone sialoprotein (BSP) and osteocalcin (OCN) than Col–HA group. Moreover, we utilized 0.5%CNT composite to repair the rat calvarial defects (8 mm diameter) in vivo, and observed the new bone formation by 3D reconstruction of micro CT, HE and Masson staining, and BSP, OCN by immunohistochemical analysis. Results showed that newly formed bone in 0.5%CNT group was significantly higher than that in Col–HA group at 12 weeks. These findings highlighted a promising strategy in healing of large area bone defect with MWCNT added into the Col–HA scaffold as they possessed the combined effects of mechanical strength and osteogenicity.

http://ift.tt/2tsiLiC

A Novel Method for Mouse Retinal Temperature Determination Based on ERG Photoresponses

Abstract

This study introduces a novel retinal temperature determination method based on the temperature dependent properties of photoresponses recorded by electroretinography (ERG). The kinetics and amplitudes of ERG photoresponses depend on retinal temperature. Additionally, raising retinal temperature increases the probability of long-wavelength photon absorption, which manifests as temperature dependence of photoreceptor sensitivity. In this study we extract a number of features that represent these properties from the a- and b-waves of mouse ex vivo ERG flash responses and construct three multivariable regression models between temperature and the selected features. The performance of these models was evaluated against a separate test dataset and for two of the models, an RMS temperature determination error of less than 0.50 °C could be reached. Our results demonstrate that the method can be successfully used for reliable retinal temperature determination ex vivo. The method, reflecting the temperature of distal retina, can be applied also in the estimation of retinal pigment epithelium temperature.

http://ift.tt/2surHXK

Understanding the interactions of human follicle stimulating hormone with single-walled carbon nanotubes by molecular dynamics simulation and free energy analysis

Abstract

Interactions of carbon nanotubes (CNTs) and blood proteins are of interest for nanotoxicology and nanomedicine. It is believed that the interactions of blood proteins and glycoproteins with CNTs may have important biological effects. In spite of many experimental studies of single-walled carbon nanotubes (SWCNT) and glycoproteins with different methods, little is known about the atomistic details of their association process or of structural alterations occurring in adsorbed glycoproteins. In this study, we have applied molecular dynamics simulation to investigate the interaction of follicle stimulating hormone (hFSH) with SWCNT. The aim of this work is to investigate possible mechanisms of nanotoxicity at a molecular level. We present details of the molecular dynamics, structure, and free energy of binding of hFSH on the surface of SWCNT. We find that hFSH in aqueous solution strongly adsorbs onto SWCNT via their concave surface as evidenced by high binding free energies for residues in both protein subunits. It was found that hydrophobic, π–cation, and π–π stacking interactions are the main driving forces for the adsorption of the protein at the nanotube surface.

http://ift.tt/2s5L08Y

Faster, More Reproducible DESI-MS for Biological Tissue Imaging

Abstract

A new, more robust sprayer for desorption electrospray ionization (DESI) mass spectrometry imaging is presented. The main source of variability in DESI is thought to be the uncontrolled variability of various geometric parameters of the sprayer, primarily the position of the solvent capillary, or more specifically, its positioning within the gas capillary or nozzle. If the solvent capillary is off-center, the sprayer becomes asymmetrical, making the geometry difficult to control and compromising reproducibility. If the stiffness, tip quality, and positioning of the capillary are improved, sprayer reproducibility can be improved by an order of magnitude. The quality of the improved sprayer and its potential for high spatial resolution imaging are demonstrated on human colorectal tissue samples by acquisition of images at pixel sizes of 100, 50, and 20 μm, which corresponds to a lateral resolution of 40–60 μm, similar to the best values published in the literature. The high sensitivity of the sprayer also allows combination with a fast scanning quadrupole time-of-flight mass spectrometer. This provides up to 30 times faster DESI acquisition, reducing the overall acquisition time for a 10 mm × 10 mm rat brain sample to approximately 1 h. Although some spectral information is lost with increasing analysis speed, the resulting data can still be used to classify tissue types on the basis of a previously constructed model. This is particularly interesting for clinical applications, where fast, reliable diagnosis is required.

Graphical Abstract

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http://ift.tt/2rwF5eB

English Orthographic Learning in Chinese-L1 Young EFL Beginners

Abstract

English orthographic learning, among Chinese-L1 children who were beginning to learn English as a foreign language, was documented when: (1) only visual memory was at their disposal, (2) visual memory and either some letter-sound knowledge or some semantic information was available, and (3) visual memory, some letter-sound knowledge and some semantic information were all available. When only visual memory was available, orthographic learning (measured via an orthographic choice test) was meagre. Orthographic learning was significant when either semantic information or letter-sound knowledge supplemented visual memory, with letter-sound knowledge generating greater significance. Although the results suggest that letter-sound knowledge plays a more important role than semantic information, letter-sound knowledge alone does not suffice to achieve perfect orthographic learning, as orthographic learning was greatest when letter-sound knowledge and semantic information were both available. The present findings are congruent with a view that the orthography of a foreign language drives its orthographic learning more than L1 orthographic learning experience, thus extending Share's (Cognition 55:151–218, 1995) self-teaching hypothesis to include non-alphabetic L1 children's orthographic learning of an alphabetic foreign language. The little letter-sound knowledge development observed in the experiment-I control group indicates that very little letter-sound knowledge develops in the absence of dedicated letter-sound training. Given the important role of letter-sound knowledge in English orthographic learning, dedicated letter-sound instruction is highly recommended.

http://ift.tt/2s6cco7

Phenotype Transformation of Aortic Valve Interstitial Cells Due to Applied Shear Stresses Within a Microfluidic Chip

Abstract

Despite valvular heart diseases constituting a significant medical problem, the acquisition of information describing their pathophysiology remains difficult. Due to valvular size, role and location within the body, there is a need for in vitro systems that can recapitulate disease onset and progression. This study combines the development of an in vitro model and its application in the mechanical stimulation of valvular cell transformation. Specifically, porcine aortic valvular interstitial cells (PAVIC) were cultured on polydimethylsiloxane microfluidic devices with or without exposure to shear stresses. Mechanobiological responses of valvular interstitial cells were evaluated at shear stresses ranging from 0 to 4.26 dyn/cm². When flow rates were higher than 0.78 dyn/cm², cells elongated and aligned with the flow direction. In addition, we found that shear stress enhanced the formation of focal adhesions and up-regulated PAVIC transformation, assessed by increased expression of α-smooth muscle actin and transforming growth factor β. This study reveals a link between the action of shear forces, cell phenotype transformation and focal adhesion formation. This constitutes the first step towards the development of co-cultures (interstitial-endothelial cells) on organ-on-a-chip devices, which will enable studies of the signaling pathways regulating force-induced valvular degeneration in microtissues and potential discovery of valvular degeneration therapies.

http://ift.tt/2s5A5fw

Comparison of intraoperative neurophysiologic monitoring outcomes between cervical and thoracic spine surgery

Abstract

Purpose

The objective is to compare the intraoperative monitoring (IOM) outcomes between degenerative cervical and thoracic spine decompression surgery.

Method

A total of 97 patients with cervical compression myelopathy (CCM) and 75 patients with thoracic compression myelopathy (TCM) were prospectively collected between December 2012 and June 2015 in our spine center. Somatosensory-evoked potentials (SSEP) and motor-evoked potentials (MEP) were used for IOM. The postoperative neurologic status of each patient was assessed immediately after surgery. And the IOM and neurological outcomes were mainly analyzed in this study.

Results

Under the same alarm criteria, the IOM changes present significant difference between the cervical and thoracic surgery. During the patients with monitoring alerts, the MEPs usually manifest as sudden loss in TCM whereas the gradual loss in CCM. And there were three permanent neurologic injuries in the thoracic cases, but none in cervical cases.

Conclusion

The IOM loss between CCM and TCM patients present obvious difference and the sudden MEPs loss associated with spinal decompression need to be taken seriously especially in TCM.

http://ift.tt/2traKe0

Reply to the Letter to the Editor of C. Brembilla et al. concerning “Spinal metallosis: a systematic review” by Goldenberg Y, Tee JW, Salinas-La Rosa CM, Murphy M (Eur Spine J; 2016, 25:1467–1473)

http://ift.tt/2stVvnb

Performance of Novel Patient Interface for Electrical Impedance Tomography Applications

Abstract

In electrical impedance tomography (EIT) currents are applied to a body, for example to the human thorax, and resulting voltages are measured to estimate the intra-thoracic impedance distribution. For this purpose 16 or 32 individual electrodes need to be placed onto the patient. The electrical contact with skin is one of the most important performance factors for EIT measurements. In this study, the electrical skin contact of a novel, textile-based electrode assembly comprising 32 active electrodes integrated in a vest-like structure was assessed in 10 volunteers and in 40 patients. Skin contact impedance was measured with dry and wetted electrodes; mid-term stability was measured over a period of 4 h. Results showed that the skin contact impedance of the dry electrodes was higher than 2 kΩ at a frequency of 144 kHz, after applying contact agent, the skin contact impedance dropped below 500 Ω and remained there for the next 4 h. We conclude that the new patient interface in combination with the special contact agent provides a stable electrical contact between electrodes and skin for at least 4 h.

http://ift.tt/2rla3lM

Mechanisms underlying extensive Ser129-phosphorylation in α-synuclein aggregates

Abstract

Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar α-synuclein, termed Lewy bodies (LBs). Approximately 90% of α-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total α-synuclein is phosphorylated at Ser129 in brains with normal individuals. It is unclear why extensive phosphorylation occurs in the pathological process of PD. To address this issue, we investigated a mechanism and role of Ser129-phosphorylation in regulating accumulation of α-synuclein. In CHO cells, the levels of Ser129-phosphorylated soluble α-synuclein were maintained constantly to those of total α-synuclein in intracellular and extracellular spaces. In SH-SY5Y cells and rat primary cortical neurons, mitochondrial impairment by rotenone or MPP⁺ enhanced Ser129-phosphorylation through increased influx of extracellular Ca²⁺. This elevation was suppressively controlled by targeting Ser129-phosphorylated α-synuclein to the proteasome pathway. Rotenone-induced insoluble α-synuclein was also targeted by Ser129-phosphoryation to the proteasome pathway. Experiments with epoxomicin and chloroquine showed that proteasomal targeting of insoluble Ser129-phosphorylated α-synuclein was enhanced under lysosome inhibition and it reduced accumulation of insoluble total α-synuclein. However, in a rat AAV-mediated α-synuclein overexpression model, there was no difference in the number of total α-synuclein aggregates between A53T mutant and A53T plus S129A double mutant α-synuclein, although Ser129-phosphorylated α-synuclein-positive aggregates were increased in rats expressing A53T α-synuclein. These findings suggest that Ser129-phosphorylation occurs against stress conditions, which increases influx of extracellular Ca²⁺, and it prevents accumulation of insoluble α-synuclein by evoking proteasomal clearance complementary to lysosomal one. However, Ser129-phosphorylation may provide an ineffective signal for degradation-resistant aggregates, causing extensive phosphorylation in aggregates.

http://ift.tt/2s5uypc

Multireflection propagation of conformational kinks in a two-component model of DNA as the transfer mode of the transcriptional replication fork

Abstract

The propagation, or movement, of a conformational kink along a linear structure can occur in capture, transfer, or multireflection modes. Here we use a model for two-component bistable polymer molecules with energetically non-equivalent stable states to model the propagation of the DNA transcription bubble via movement of a non-linear longitudinal stretching region along the DNA chain. We show that under certain conditions the longitudinal excitation can act as a reflector for a conformational kink and, furthermore, that conformational switching may propagate in a multireflection mode alongside conformational kink transition and conformational kink trapping.

http://ift.tt/2swNlvp

Magnetic Fenton and Photo-Fenton-Like Catalysts Supported on Carbon Nanotubes for Wastewater Treatment

Abstract

Carbon nanotubes (CNTs) synthesized by the catalytic decomposition of methane were used as the support for magnetic Fenton and photo-Fenton catalysts to treat real wastewater contaminated with dyes and Escherichia coli. The effect of methane flow, the use of diluent (N₂), and the reaction time in the production of CNTs were studied. An increase in the production of CNTs with increased CH₄ flow and a decrease over the reaction time were recorded. Catalysts with 1, 3, and 5% w/w Fe were obtained and characterized by several spectroscopic and microscopic techniques. Multi-walled CNTs and bamboo-like carbon nanofibers with average diameters of 44.0 nm and average lengths of 237.0 nm were obtained. The catalysts had Fe_x O_y (oxide species) crystallite sizes between 10 and 18 nm and soft ferromagnetic properties. A factorial 3³ design was used for selecting variables for the catalytic tests, wherein the concentration of H₂O₂, the catalyst mass, and the percentage of iron were evaluated. Subsequently, kinetic experiments were performed. The photo-Fenton process (5% Fe, 200 mg, and 0.4 M H₂O₂) showed the best results in terms of total organic carbon (TOC) abatement, discoloration, and E. coli inactivation without leaching of Fe.

Graphical Abstract

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http://ift.tt/2rvDXbi

Alteration of Arterial Mechanical Impedance Greater than that of Photoplethysmogram and Laser Doppler Flowmetry during Endoscopic Thoracic Sympathectomy

Abstract

Blood flow monitoring systems such as photoplethysmogram (PPG) and laser Doppler flowmetry (LDF) are useful for intraoperative determination of a successful endoscopic thoracic sympathectomy (ETS) procedure, as they are able to indicate a sympatholytic response. A recently developed novel arterial mechanical impedance monitor has been shown able to provide a value for peripheral arterial stiffness, shown as K. In this retrospective cohort study, we compared the intensity of K with that of PPG and LDF during ETS procedures. Seventy-nine patients with hyperhidrosis underwent a surgical sympathectomy procedure under general anesthesia, during which they were managed by monitors attached to the tips of their fingers. Circulatory variables before and after the surgical procedure were recorded during ETS, then the ratios of those indices were statistically compared. With a statistical significance level of p < 0.05, K was shown to have a greater alteration as compared to PPG and LDF at the time of skin incision as well as neural clipping in both hands. We concluded that arterial mechanical impedance shown by K is a more sensitive monitor of sympathetic activity derived from vasoconstriction and vasodilation during an ETS procedure as compared to PPG and LDF.

http://ift.tt/2rv9NVu

Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer

Abstract

Background and Objectives

Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population.

Methods

Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM^®.

Results

The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V ₁), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy.

Conclusion

The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

http://ift.tt/2rA8H5N

The Standardized Postoperative Checklist for Bariatric Surgery; a Tool for Safe Early Discharge?

Abstract

Background

Morbidly obese patients are at higher risk of complications after surgery. In bariatric surgery, pre- and intra-operative checklists are commonly used to identify high-risk patients preoperatively, to decrease the number of postoperative complications. This pilot study evaluates the effect of a postoperative checklist in bariatric surgery, addressing regularly measured parameters, on the occurrence and early recognition of complications.

Methods

An in-house developed postoperative checklist was used on the first postoperative day after bariatric surgery and included information on nausea, pain, temperature, heart rate, and laboratory markers. Complications were scored using the Clavien-Dindo (CD) classification, and three groups were formed: no complications (CD0), minor complications (CD1 and 2), and major complications (≥CD3a). Differences between groups were analyzed using nonparametric tests.

Results

Six hundred ninety-four subjects were included (79.5% female, age 42.6 ± 10.8 years, BMI 43.8 ± 5.8 kg/m²). Twenty-nine subjects developed major complications within 30 days postoperatively. There were no significant differences in baseline characteristics between groups. Subjects with major complications were less willing to be discharged due to complaints, compared to subjects with no or minor complications (14.8 vs. 3.6 and 4.6%, respectively) and had a higher decrease of hemoglobin level (0.8 vs. 0.6 and 0.65 mmol/l, respectively).

Conclusion

The patient's willingness for discharge, in combination with hemoglobin decrease, may be the best early predictors of major complications after bariatric surgery. This postoperative checklist may be an adequate instrument to identify patients who can be safely discharged home on the first postoperative day and thereby play a part in patient management after bariatric surgery.

http://ift.tt/2swZdx8

Novel AIDS therapies based on gene editing

Abstract

HIV/AIDS remains a major public health issue. In 2014, it was estimated that 36.9 million people are living with HIV worldwide, including 2.6 million children. Since the advent of combination antiretroviral therapy (cART), in the 1990s, treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS has become increasingly rare. However, while people with HIV can expect to live a normal life span with cART, lifelong medication is required and cardiovascular, renal, liver, and neurologic diseases are still possible, which continues to prompt research for a cure for HIV. Infected reservoir cells, such as CD4+ T cells and myeloid cells, allow persistence of HIV as an integrated DNA provirus and serve as a potential source for the re-emergence of virus. Attempts to eradicate HIV from these cells have focused mainly on the so-called "shock and kill" approach, where cellular reactivation is induced so as to trigger the purging of virus-producing cells by cytolysis or immune attack. This approach has several limitations and its usefulness in clinical applications remains to be assessed. Recent advances in gene-editing technology have allowed the use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells or knocking out HIV receptors. Here, we review this strategy and its potential to eliminate the latent HIV reservoir resulting in a sterile cure of AIDS.

http://ift.tt/2rAbAnv

ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population

Abstract

Bile salts are natural detergents required to solubilise dietary fat and lipid soluble vitamins. They are synthesised in hepatocytes and secreted into the luminal space of the biliary tree by the bile salt export pump (BSEP), an ATP-binding cassette (ABC) transporter in the canalicular membrane. BSEP deficiency causes cytotoxic accumulation of bile salts in the hepatocyte that results in mild-to-severe forms of cholestasis. The resulting inflammation can also progress to hepatocellular cancer via a novel mechanism involving upregulation of proliferative signalling pathways. A second ABC transporter of the canalicular membrane is also critical for bile formation. ABCB4 flops phosphatidylcholine into the outer leaflet of the membrane to be extracted by bile salts in the canalicular space. These mixed micelles reduce the detergent action of the bile salts and protect the biliary tree from their cytotoxic activity. ABCB4 deficiency also causes cholestasis, and might be expected to cause cholangitis and predispose to liver cancer. Non-synonymous SNPs in ABCB4 have now been described in patients with liver cancer or with inflammatory liver diseases that are known to predispose to cancer, but data showing that the SNPs are sufficiently deleterious to be an etiological factor are lacking. Here, we report the first characterisation at the protein level of six ABCB4 variants (D243A, K435T, G535D, I490T, R545C, and S978P) previously found in patients with inflammatory liver diseases or liver cancer. All significantly impair the transporter with a range of phenotypes exhibited, including low abundance, intracellular retention, and reduced floppase activity, suggesting that ABCB4 deficiency is the root cause of the pathology in these cases.

http://ift.tt/2s5mqp2

Deciphering the BAR code of membrane modulators

Abstract

The BAR domain is the eponymous domain of the "BAR-domain protein superfamily", a large and diverse set of mostly multi-domain proteins that play eminent roles at the membrane cytoskeleton interface. BAR domain homodimers are the functional units that peripherally associate with lipid membranes and are involved in membrane sculpting activities. Differences in their intrinsic curvatures and lipid-binding properties account for a large variety in membrane modulating properties. Membrane activities of BAR domains are further modified and regulated by intramolecular or inter-subunit domains, by intermolecular protein interactions, and by posttranslational modifications. Rather than providing detailed cell biological information on single members of this superfamily, this review focuses on biochemical, biophysical, and structural aspects and on recent findings that paradigmatically promote our understanding of processes driven and modulated by BAR domains.

http://ift.tt/2rzZPgx

Germline-specific dgcr8 knockout in zebrafish using a BACK approach

Abstract

Zebrafish is an important model to study developmental biology and human diseases. However, an effective approach to achieve spatial and temporal gene knockout in zebrafish has not been well established. In this study, we have developed a new approach, namely bacterial artificial chromosome-rescue-based knockout (BACK), to achieve conditional gene knockout in zebrafish using the Cre/loxP system. We have successfully deleted the DiGeorge syndrome critical region gene 8 (dgcr8) in zebrafish germ line and demonstrated that the maternal-zygotic dgcr8 (MZdgcr8) embryos exhibit MZdicer-like phenotypes with morphological defects which could be rescued by miR-430, indicating that canonical microRNAs play critical role in early development. Our findings establish that Cre/loxP-mediated tissue-specific gene knockout could be achieved using this BACK strategy and that canonical microRNAs play important roles in early embryonic development in zebrafish.

http://ift.tt/2s54g6t

Interactions between mesenchymal stem cells and the immune system

Abstract

In addition to being multi-potent, mesenchymal stem cells (MSCs) possess immunomodulatory functions that have been investigated as potential treatments in various immune disorders. MSCs can robustly interact with cells of the innate and adaptive immune systems, either through direct cell–cell contact or through their secretome. In this review, we discuss current findings regarding the interplay between MSCs and different immune cell subsets. We also draw attention to the mechanisms involved.

http://ift.tt/2rAv1MQ

S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

Abstract

DNA replication stress, an important source of genomic instability, arises upon different types of DNA replication perturbations, including those that stall replication fork progression. Inhibitors of the cellular pool of deoxynucleotide triphosphates (dNTPs) slow down DNA synthesis throughout the genome. Following depletion of dNTPs, the highly conserved replication checkpoint kinase pathway, also known as the S-phase checkpoint, preserves the functionality and structure of stalled DNA replication forks and prevents chromosome fragmentation. The underlying mechanisms involve pathways extrinsic to replication forks, such as those involving regulation of the ribonucleotide reductase activity, the temporal program of origin firing, and cell cycle transitions. In addition, the S-phase checkpoint modulates the function of replisome components to promote replication integrity. This review summarizes the various functions of the replication checkpoint in promoting replication fork stability and genome integrity in the face of replication stress caused by dNTP depletion.

http://ift.tt/2s57siL

Regulation of end-binding protein EB1 in the control of microtubule dynamics

Abstract

The regulation of microtubule dynamics is critical to ensure essential cell functions, such as proper segregation of chromosomes during mitosis or cell polarity and migration. End-binding protein 1 (EB1) is a plus-end-tracking protein (+TIP) that accumulates at growing microtubule ends and plays a pivotal role in the regulation of microtubule dynamics. EB1 autonomously binds an extended tubulin-GTP/GDP-Pi structure at growing microtubule ends and acts as a molecular scaffold that recruits a large number of regulatory +TIPs through interaction with CAP-Gly or SxIP motifs. While extensive studies have focused on the structure of EB1-interacting site at microtubule ends and its role as a molecular platform, the mechanisms involved in the negative regulation of EB1 have only started to emerge and remain poorly understood. In this review, we summarize recent studies showing that EB1 association with MT ends is regulated by post-translational modifications and affected by microtubule-targeting agents. We also present recent findings that structural MAPs, that have no tip-tracking activity, physically interact with EB1 to prevent its accumulation at microtubule plus ends. These observations point out a novel concept of "endogenous EB1 antagonists" and emphasize the importance of finely regulating EB1 function at growing microtubule ends.

http://ift.tt/2rzTB0p

On glioblastoma and the search for a cure: where do we stand?

Abstract

Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term "glioblastoma multiforme". Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.

http://ift.tt/2s5qWDT

Nucleic acid sensing pattern recognition receptors in the development of colorectal cancer and colitis

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related deaths that is often associated with inflammation initiated by activation of pattern recognition receptors (PRRs). Nucleic acid sensing PRRs are one of the major subsets of PRRs that sense nucleic acid (DNA and RNA), mainly including some members of Toll-like receptors (TLR3, 7, 8, 9), AIM2-like receptors (AIM2, IFI16), STING, cGAS, RNA polymerase III, and DExD/H box nucleic acid helicases (such as RIG-I like receptors (RIG-I, MDA5, LPG2), DDX1, 3, 5, 7, 17, 21, 41, 60, and DHX9, 36). Activation of these receptors eventually leads to the release of cytokines and activation of immune cells, which are well known to play crucial roles in host defense against intracellular bacterial and virus infection. However, the functions of these nucleic acid sensing PRRs in the other diseases such as CRC and colitis remain largely unknown. Recent studies indicated that nucleic acid sensing PRRs contribute to CRC and/or colitis development, and therapeutic modulation of nucleic acid sensing PRRs may reduce the risk of CRC development. However, until now, a comprehensive review on the role of nucleic acid sensing PRRs in CRC and colitis is still lacking. This review provided an overview of the roles as well as the mechanisms of these nucleic acid sensing PRRs (AIM2, STING, cGAS, RIG-I and its downstream molecules, DDX3, 5, 6,17, and DHX9, 36) in CRC and colitis, which may aid the diagnosis, therapy, and prognostic prediction of CRC and colitis.

http://ift.tt/2rzZhY6

More preoperative flexibility implies adequate neural pliability for curve correction without prophylactic untethering in scoliosis patients with asymptomatic tethered spinal cord, a retrospective study

Abstract

Background

Tethered spinal cord is frequently associated with scoliosis. It is still controversial whether a prophylactic untethering is necessary before correction procedure in scoliosis patients with tethered spinal cord. In this study we determined the clinical outcome of a one-stage posterior scoliosis correction without a prophylactic untethering for treating scoliosis with an asymptomatic tethered spinal cord.

Methods

Seventeen (5 males and 12 females) scoliosis patients with tethered spinal cords were retrospectively reviewed. All patients underwent a one-stage posterior scoliosis correction without preventive untethering. Parameters of radiograph were used to assess correction result. The Scoliosis Research Society (SRS)-22 questionnaire was analyzed pre- and post-operatively to evaluate the clinical outcomes. The modified Japanese Orthopaedic Association (mJOA) score was used to assess the pre- and post-operative spinal cord function.

Results

The post-operative coronal Cobb angle was significantly decreased compared with preoperative. (23.8 ± 6.4° vs. 58.4 ± 12.6°, P < 0.01). The coronal Cobb angle was 22.4 ± 6.8° at the final follow-up evaluation. The apical vertebral translation (AVT) was also decreased significantly. (27.5 mm vs. 60.9 mm, P < 0.01). The SRS-22 total score was improved at the 1-year follow-up evaluation compared with the pre-operative SRS-22 total score (87 ± 4 vs. 70 ± 5, p < 0.05). The functional activities, pain, self-image, mental health, and surgery satisfactory scores at the final follow-up evaluation were all improved compared with the corresponding pre-operative scores, especially the self-image and mental health scores (p < 0.05). The spinal cord function was stable and there was no new neurological symptoms after scoliosis correction. No difference existed between the pre- and post-operative total mJOA score (26 ± 2 vs. 27 ± 2, p = 0.39), which including subjective symptom (p = 0.07), clinical symptom (p = 0.33), daily activities (p = 0.44) and bladder function (p = 0.67).

Conclusion

One-stage posterior scoliosis correction is a safe and effective surgical procedure for scoliosis patients combined with asymptomatic tethered spinal cord who have adequate spinal cord function reserve.

http://ift.tt/2swjkLV

Treatment of thoracolumbar burst fractures by short-segment pedicle screw fixation using a combination of two additional pedicle screws and vertebroplasty at the level of the fracture: a finite element analysis

Abstract

Background

Traditional one-above and one-below four-screw posterior short-segment instrumentation is used for unstable thoracolumbar burst fractures. However, this method has a high rate of implant failure and early loss of reduction. The purpose of this study was to use finite element (FE) analysis to determine the effect of treating thoracolumbar burst fractures by short-segment pedicle screw fixation using a combination of two additional pedicle screws and vertebroplasty at the level of the fracture.

Methods

An intact T11-L1 spine FE model was created from the computed tomography images of a male subject. Four fixation models with posterior fusion devices (pedicle screws, rods, cross-link) were established to simulate an unstable thoracolumbar fracture with different fusion surgeries: short-segment fixation with: 1) a link (S-L); 2) intermediate bilateral screws (S-I); 3) a link and calcium sulfate cement (S-L-C); 4) intermediate bilateral screws and calcium sulfate cement (S-I-C). Different loading conditions (flexion, extension, lateral bending, and axial rotation) were applied on the models and analyzed with a FE package. The range of motion (ROM), and the maximum value and distribution of the implant stress, and the stress in the facet joint, were compared between the intact and fixation models.

Results

The ROM in flexion, extension, axial rotation, and lateral bending was the smallest in the S-I-C model, followed by the S-I, S-L-C, and S-L models. Maximum von Mises stress values were larger under lateral bending and axial rotation loadings than under flexion and extension loading. High stress was concentrated at the crosslink and rod junctions. Maximal von Mises stress on the superior vertebral body for all loading conditions was larger than that on the inferior vertebral body. The maximal von Mises stress of the pedicle screws during all states of motion were 265.3 MPa in S-L fixation, 192.9 MPa in S-I fixation, 258.4 MPa in S-L-C fixation, and 162.3 MPa in S-I-C fixation.

Conclusions

Short-segment fixation with two intermediate pedicle screws together with calcium sulfate cement at the fractured vertebrae may provide a stiffer construct and less von Mises stress of the pedicle screws and rods as compared to other types of short-segment fixation.

http://ift.tt/2t64hpj

Critical shoulder angle combined with age predict five shoulder pathologies: a retrospective analysis of 1000 cases

Abstract

Background

Acromial morphology has previously been defined as a risk factor for some shoulder pathologies. Yet, study results are inconclusive and not all major shoulder diseases have been sufficiently investigated. Thus, the aim of the present study was to analyze predictive value of three radiological parameters including the critical shoulder angle, acromion index, and lateral acromion angle in relationship to symptomatic patients with either cuff tear arthropathy, glenohumeral osteoarthritis, rotator cuff tear, impingement, and tendinitis calcarea.

Methods

A total of 1000 patients' standardized true-anteroposterior radiographs were retrospectively assessed. Receiver-operating curve analyses and multinomial logistic regression were used to examine the association between shoulder pathologies and acromion morphology. The prediction model was derived from a development cohort and applied to a validation cohort. Prediction model's performance was statistically evaluated.

Results

The majority of radiological measurements were significantly different between shoulder pathologies, but the critical shoulder angle was an overall better parameter to predict and distinguish between the different pathologies than the acromion index or lateral acromion angle. Typical critical shoulder angle-age patterns for the different shoulder pathologies could be detected. Patients diagnosed with rotator cuff tears had the highest, whereas patients with osteoarthritis had the lowest critical shoulder angle. The youngest patients were in the tendinitis calcarea and the oldest in the cuff tear arthropathy group.

Conclusions

The present study showed that critical shoulder angle and age, two easily assessable variables, adequately predict different shoulder pathologies in patients with shoulder complaints.

http://ift.tt/2swLjLN

Effect of low-magnitude different-frequency whole-body vibration on subchondral trabecular bone microarchitecture, cartilage degradation, bone/cartilage turnover, and joint pain in rabbits with knee osteoarthritis

Abstract

Backgroud

Whole-body vibration(WBV) has been suggested for the prevention of subchondral bone loss of knee osteoarthritis (OA) . This study examined the effects of different frequency of whole-body vibration on subchondral trabecular bone microarchitecture, cartilage degradation and metabolism of the tibia and femoral condyle bone, and joint pain in an anterior cruciate ligament transection (ACLT)–induced knee osteoarthritisrabbit model.

Method

Ninety adult rabbits were divided into six groups: all groups received unilateral ACLT; Group 1, ACLT only; Group 2, 5 Hz WBV; Group 3, 10 Hz WBV; Group 4, 20 Hz WBV; Group 5, 30 Hz WBV; and Group 6, 40 Hz WBV. Pain was tested via weight-bearing asymmetry. Subchondral trabecular bone microarchitecture was examined using in vivo micro-computed tomography. Knee joint cartilage was evaluated by gross morphology, histology, and ECM gene expression level (aggrecan and type II collagen [CTX-II]). Serum bone-specific alkaline phosphatase, N-mid OC, cartilage oligometric protein, CPII, type I collagen, PIIANP, G1/G2 aggrecan levels, and urinary CTX-II were analyzed.

Results

After 8 weeks of low-magnitude WBV, the lower frequency (10 Hz and 20 Hz) WBV treatment decreased joint pain and cartilage resorption, accelerated cartilage formation, delayed cartilage degradation especially at the 20 Hz regimen. However, the higher frequencies (30 Hz and 40 Hz) had worse effects, with worse limb function and cartilage volume as well as higher histological scores and cartilage resorption. In contrast, both prevented loss of trabeculae and increased bone turnover. No significant change was observed in the 5 Hz WBV group.

Conclusion

Our data demonstrate that the lower frequencies (10 Hz and 20 Hz) of low-magnitude WBV increased bone turnover, delayed cartilage degeneration, and caused a significant functional change of the OA-affected limb in ACLT-induced OA rabbit model but did not reverse OA progression after 8 weeks of treatment.

http://ift.tt/2t6j4AD

Appearance of cell-adhesion factor in osteoblast proliferation and differentiation of apatite coating titanium by blast coating method

Abstract

We have already reported that the apatite coating of titanium by the blast coating (BC) method could show a higher rate of bone contact from the early stages in vivo, when compared to the pure titanium (Ti) and the apatite coating of titanium by the flame spraying (FS) method. However, the detailed mechanism by which BC resulted in satisfactory bone contact is still unknown. In the present study, we investigated the importance of various factors including cell adhesion factor in osteoblast proliferation and differentiation that could affect the osteoconductivity of the BC disks. Cell proliferation assay revealed that Saos-2 could grow fastest on BC disks, and that a spectrophotometric method using a LabAssay^TM ALP kit showed that ALP activity was increased in cells on BC disks compared to Ti disks and FS disks. In addition, higher expression of E-cadherin and Fibronectin was observed in cells on BC disks than Ti disks and FS disks by relative qPCR as well as Western blotting. These results suggested that the expression of cell-adhesion factors, proliferation and differentiation of osteoblast might be enhanced on BC disks, which might result higher osteoconductivity.

http://ift.tt/2seAoTO

“Inflammatory skin march” in atopic dermatitis and psoriasis

Abstract

Background

Comorbidities of cardiovascular diseases (CVDs), metabolic syndrome and autoimmune diseases with systemic inflammation are recent topics in medicine. Inflammatory skin diseases such as atopic dermatitis and psoriasis are an active source of diverse proinflammatory cytokines and chemokines, which are readily detectable in the circulation and are likely to be involved in developing comorbidities.

Evidence

Both atopic dermatitis and psoriasis are frequently comorbid with CVD, metabolic syndrome and autoimmune diseases, the consequence of which is called "inflammatory skin march", "psoriatic march" or "march of psoriasis".

Conclusion

In this review, we summarize the epidemiological evidence and pathogenetic concepts regarding inflammatory skin march in atopic dermatitis and psoriasis.

http://ift.tt/2seMKv9

Late-onset jaw and teeth pain mimicking trigeminal neuralgia associated with chronic vagal nerve stimulation: case series and review of the literature

Abstract

Background

Vagal nerve stimulation (VNS) for refractory epilepsy is well established. Trigeminal neuralgia itself is a common disease in adults, and thus, late-onset pain in the trigeminal region under VNS, which is extremely rare, may not be recognized as caused by VNS.

Case presentation

Two patients with drug-resistant symptomatic epilepsy treated with chronic VNS experienced stimulation-related pain in the lower and upper jaw and teeth on the side of stimulation. No evidence of local spread of the stimulation current was present. The pain started with a delay of years after device implantation and weeks after the last increase in the pacing parameters. At the time of onset, the pain was not recognized as VNS-related, leading to extensive examinations. The trigeminal neuralgia-like pain resolved after adjustment of the stimulation current intensity. In one of the patients, the pain disappeared within one to two days following every epileptic seizure. To our knowledge, this is the first case report of late-onset trigeminal pain under VNS revealing a direct link between epileptogenic and pain processes.

Conclusion

A painless interval between the last change of the pacing parameters and trigeminal pain can lead to the erroneous interpretation that this is a typical trigeminal neuralgia. The lack of its recognition as a side effect of VNS can lead to unnecessary examinations and delayed adjustment of stimulation parameters. In patients with signs of late-onset trigeminal pain under VNS with normal electrode impedance and no evidence of local current spread, the replacement of the VNS lead does not seem to be beneficial. A review of the literature on VNS side effects including pain and device malfunctions was undertaken.

http://ift.tt/2s4Xg9Z

To be active through indoor-climbing: an exploratory feasibility study in a group of children with cerebral palsy and typically developing children

Abstract

Background

Cerebral Palsy (CP) is the most common cause of motor disabilities in children and young adults and it is also often associated with cognitive and physiological challenges. Climbing requires a multifaceted repertoire of movements, participants at all levels of expertise may be challenged functionally and cognitively, making climbing of great potential interest in (re)habilitation settings. However, until now only few research projects have investigated the feasibility of climbing as a potential activity for heightening physical activity in children with CP and the possible beneficial effects of climbing activities in populations with functional and/or cognitive challenges. The aim of this study was therefore to test the feasibility of an intensive 3 weeks indoor-climbing training program in children with CP and typically developing (TD) peers. In addition we evaluated possible functional and cognitive benefits of 3 weeks of intensive climbing training in 11 children with cerebral palsy (CP) aged 11–13 years and six of their TD peers.

Method

The study was designed as a feasibility and interventional study. We evaluated the amount of time spent being physically active during the 9 indoor-climbing training sessions, and climbing abilities were measured. The participants were tested in a series of physiological, psychological and cognitive tests: two times prior to and one time following the training in order to explore possible effects of the intervention.

Results

The children accomplished the training goal of a total of nine sessions within the 3-week training period. The time of physical activity during a 2:30 h climbing session, was comparably high in the group of children with CP and the TD children. The children with CP were physically active on average for almost 16 h in total during the 3 weeks. Both groups of participants improved their climbing abilities, the children with CP managed to climb a larger proportion of the tested climbing route at the end of training and the TD group climbed faster. For the children with CP this was accompanied by significant improvements in the Sit-to-stand test (p < 0.01), increased rate of force development in the least affected hand during an explosive pinch test and increased muscular-muscular coherence during a pinch precision test (p < 0.05). We found no improvements in maximal hand or finger strength and no changes in cognitive abilities or psychological well-being in any of the groups.

Conclusions

These findings show that it is possible to use climbing as means to make children with CP physically active. The improved motor abilities obtained through the training is likely reflected by increased synchronization between cortex and muscles, which results in a more efficient motor unit recruitment that may be transferred to daily functional abilities.

Trial registration

ISRCTN18006574; day of registration: 09/05/2017; the trial is registered retrospectively

http://ift.tt/2rzw8fM

Anatomy-driven multiple trajectory planning (ADMTP) of intracranial electrodes for epilepsy surgery

Abstract

Purpose

Epilepsy is potentially curable with resective surgery if the epileptogenic zone (EZ) can be identified. If non-invasive imaging is unable to elucidate the EZ, intracranial electrodes may be implanted to identify the EZ as well as map cortical function. In current clinical practice, each electrode trajectory is determined by time-consuming manual inspection of preoperative imaging to find a path that avoids blood vessels while traversing appropriate deep and superficial regions of interest (ROIs). We present anatomy-driven multiple trajectory planning (ADMTP) to find safe trajectories from a list of user-defined ROIs within minutes rather than the hours required for manual planning.

Methods

Electrode trajectories are automatically computed in three steps: (1) Target Point Selection to identify appropriate target points within each ROI; (2) Trajectory Risk Scoring to quantify the cumulative distance to critical structures (blood vessels) along each trajectory, defined as the skull entry point to target point. (3) Implantation Plan Computation: to determine a feasible combination of low-risk trajectories for all electrodes.

Results

ADMTP was evaluated on 20 patients (190 electrodes). ADMTP lowered the quantitative risk score in 83% of electrodes. Qualitative results show ADMTP found suitable trajectories for 70% of electrodes; a similar portion of manual trajectories were considered suitable. Trajectory suitability for ADMTP was 95% if traversing sulci was not included in the safety criteria. ADMTP is computationally efficient, computing between 7 and 12 trajectories in 54.5 (17.3–191.9) s.

Conclusions

ADMTP efficiently compute safe and surgically feasible electrode trajectories.

http://ift.tt/2seXKbS

Meningocele manqué: a comprehensive review of this enigmatic finding in occult spinal dysraphism

Abstract

The term meningocele manqué (MM) was coined in 1972 to describe a broad range of surgical findings characterized by intradural bands tethering neural structures to the dorsal dura. Over the following decades, reports continued to lump intradural tethering bands associated with a variety of comorbidities under the umbrella term MM. In more recent years, disorders previously called MM have been identified as embryologically distinct and were reclassified. While this sectioning continues, there remains a set of intradural tethering disorders for which no better term than MM exists. Herein, we comprehensively review the literature surrounding MM, including embryological disorders, clinical, radiographic, and surgical presentation, as well as alternative classification methods and MM treatment.

http://ift.tt/2swgHdd

Pharmacokinetics of linezolid in plasma and cerebrospinal fluid in patients with cerebral hemorrhage post-surgical intervention

http://ift.tt/2nvWbWB

Influence of genetic and non-genetic factors on phenytoin-induced severe cutaneous adverse drug reactions

Abstract

Purpose

The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients.

Methods

Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied. Variants in HLA-B, CYP2C9, and CYP2C19 genes were genotyped. Fisher's exact test and multiple logistic regression analysis were performed to test the association of genetic and non-genetic factors with specific type of SCARs.

Results

Multiple logistic regression models showed that genetic and non-genetic factors associated with PHT-induced SCARs were specified to its phenotype. HLA-B*13:01, HLA-B*56:02/04, CYP2C19*3, and omeprazole co-medication were strong risk factors of DRESS/DHS (adjusted OR = 13.29, p = 0.0001; adjusted OR = 56.23, p = 0.0007; adjusted OR = 6.75, p = 0.0414; and adjusted OR = 9.21, p = 0.0020, respectively). While CYP2C9*3 and having Chinese ancestry were significant risk factors of SJS (adjusted OR = 10.41, p = 0.0042 and adjusted OR = 5.40, p = 0.0097, respectively). Combined genetic and non-genetic risk factors optimized sensitivity and increased specificity for predicting PHT-induced SCARs.

Conclusion

This study showed that distinct genetic markers were associated with phenotype-specific PHT-induced SCARs. Non-genetic factor, omeprazole co-medication, was strongly associated with PHT-induced DRESS/DHS in addition to variants in HLA-B and CYP2C genes. Combined markers may be better predictors for PHT-induced SCARs.

http://ift.tt/2o09Ge0

Application challenges of the new EU Clinical Trials Regulation

Abstract

Purpose

The purpose of this paper is to discuss the challenges of the upcoming policy change in the field of clinical drug trials due to the shift from the Clinical Trials Directive 2001/20/EC to the new Clinical Trials Regulation 536/2014, adopted in 2014. Although it is expected that the new EU Clinical Trials Regulation will increase Europe's competitiveness in clinical research, the paper argues that some measures to assure protection of research subjects should be taken before the Regulation comes into application in 2018.

Methods

The methods used in this paper are comparative analysis of legal documents and related academic papers.

Results

The new Regulation serves as an efficient means to harmonize the clinical drug trial evaluation procedures across the EU. However, its application also raises potential challenges regarding interests and safety of research subjects: first, due to the possibility of skipping the assessment and balancing of benefits and risks from the scope of ethical review and limiting such a review to only Part II issues of the assessment report; second, due to direct applicability of the Regulation's rather vague and too general requirements for investigator's qualifications which does not allow the assessors (ethics committees and (or) competent authorities) to introduce higher qualification requirements for the investigators conducting high-risk clinical drug trials in the national legislation.

Conclusions

There is an urgent need to raise awareness and facilitate debate on potential application challenges of the new Regulation.

http://ift.tt/2ssrVi6

Do position and size matter? An analysis of cage and placement variables for optimum lordosis in PLIF reconstruction

Abstract

Purpose

To examine monosegmental lordosis after posterior lumbar interbody fusion (PLIF) surgery and relate lordosis to cage size, shape, and placement.

Methods

Eighty-three consecutive patients underwent single-level PLIF with paired identical lordotic cages involving a wide decompression and bilateral facetectomies. Cage parameters relating to size (height, lordosis, and length) and placement (expressed as a ratio relative to the length of the inferior vertebral endplate) were recorded. Centre point ratio (CPR) was the distance to the centre of both cages and indicated mean position of both cages. Posterior gap ratio (PGR) was the distance to the most posterior cage and indicated position and cage length indirectly. Relationships between lordosis and cage parameters were explored.

Results

Mean lordosis increased by 5.98° (SD 6.86°). The cages used varied in length from 20 to 27 mm, in lordosis from 10° to 18°, and in anterior cage height from 10 to 17 mm. The mean cage placement as determined by CPR was 0.54 and by PGR was 0.16. The significant correlations were: both CPR and PGR with lordosis gain at surgery (r = 0.597 and 0.537, respectively, p < 0.001 both), cage lordosis with the final lordosis (r = 0.234, p < 0.05), and anterior cage height was negatively correlated with a change in lordosis (r = −0.297, p < 0.01).

Conclusion

Cage size, shape, and position, in addition to surgical technique, determine lordosis during PLIF surgery. Anterior placement with sufficient "clear space" behind the cages is recommended. In addition, cages should be of moderate height and length, so that they act as an effective pivot for lordosis.

http://ift.tt/2s4ITSO

Lipophilic Statins and the Risk of Intracranial Hemorrhage Following Ischemic Stroke: A Population-Based Study

Abstract

Background

Statins are commonly prescribed for the secondary prevention of ischemic stroke, but there is conflicting evidence as to whether they increase the risk of intracranial hemorrhage. Lipophilic statins cross the blood–brain barrier more freely than hydrophilic statins and may therefore increase the risk of intracranial hemorrhage.

Objective

To determine whether, in older patients following ischemic stroke, receipt of lipophilic statins was associated with differences in the risk of intracranial hemorrhage.

Methods

We conducted a population-based nested case-control study linking multiple healthcare databases between 1 April, 2001 and 31 March, 2015 in Ontario, Canada. Cases were Ontarians aged 66 years or older receiving a statin within 100 days preceding the development of intracranial hemorrhage within 1 year following ischemic stroke. Each case was matched with up to four controls who experienced ischemic stroke not complicated by intracranial hemorrhage but who also received a statin. We classified statins as lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, and cerivastatin) or hydrophilic (pravastatin and rosuvastatin) based on their octanol/water partition coefficients. We calculated the odds ratio for the association between intracranial hemorrhage and receipt of lipophilic statins, with hydrophilic statins as the reference group.

Results

We identified 2766 individuals who experienced intracranial hemorrhage during statin therapy after ischemic stroke and 11,060 matched controls. Relative to hydrophilic statins, lipophilic statins were not associated with an increased risk of intracranial hemorrhage (adjusted odds ratio 1.07; 95% confidence interval 0.97–1.19).

Conclusion

Among patients treated with a statin following ischemic stroke, the risk of intracranial hemorrhage is not influenced by statin lipophilicity.

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Effect of high-intensity aerobic exercise on aerobic fitness and HbA1c in patients with type 2 diabetes

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Effects of 4 weeks of low-load unilateral resistance training, with and without blood flow restriction, on strength, thickness, V wave, and H reflex of the soleus muscle in men

Abstract

Purpose

To test the effects of 4 weeks of unilateral low-load resistance training (LLRT), with and without blood flow restriction (BFR), on maximal voluntary contraction (MVC), muscle thickness, volitional wave (V wave), and Hoffmann reflex (H reflex) of the soleus muscle.

Methods

Twenty-two males were randomly distributed into three groups: a control group (CTR; n = 8); a low-load blood flow restriction resistance training group (BFR-LLRT; n = 7), who were an inflatable cuff to occlude blood flow; and a low-load resistance training group without blood flow restriction (LLRT; n = 7). The training consisted of four sets of unilateral isometric LLRT (25% of MVC) three times a week over 4 weeks.

Results

MVC increased 33% (P < 0.001) and 22% (P < 0.01) in the trained leg of both BFR-LLRT and LLRT groups, respectively. The soleus thickness increased 9.5% (P < 0.001) and 6.5% (P < 0.01) in the trained leg of both BFR-LLRT and LLRT groups, respectively. However, neither MVC nor thickness changed in either of the legs tested in the CTR group (MVC −1 and −5%, and muscle thickness 1.9 and 1.2%, for the control and trained leg, respectively). Moreover, V wave and H reflex did not change significantly in all the groups studied (V_wave/M _wave ratio −7.9 and −2.6%, and H _max/M _max ratio −3.8 and −4%, for the control and trained leg, respectively).

Conclusions

Collectively, the present data suggest that in spite of the changes occurring in soleus strength and thickness, 4 weeks of low-load resistance training, with or without BFR, does not cause any change in neural drive or motoneuronal excitability.

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Evidence in the human of a hypotensive and a bradycardic effect after mouth opening maintained for 10 min

Abstract

Purpose

We have recently shown that in humans submaximal mouth opening associated with partial masticatory movements for 10 min is followed by a small but significant and prolonged reduction of blood pressure and heart rate. We here report the effects of a fixed mouth opener.

Methods

In 22 seated normotensive volunteers the effect on blood pressure and heart rate was studied in randomized order after fixed mandibular extension and after a control procedure consisting in keeping a stick between the incisor teeth (both for 10 min). Automated recordings every 10 min were done for 40 min before and 120 min following the procedure.

Results

Two-way ANOVA for repeated measures on absolute values (actual recordings) and on changes from baseline revealed that, compared to controls, systolic, diastolic and mean blood pressure and heart rate were significantly lower after mandibular extension. Compared to controls, mandibular extension induced an average blood pressure drop of 2.88 mmHg (systolic), 2.55 mmHg (diastolic) and 2.42 mmHg (mean) over the entire observation period. The average decline over the central part of the observation period (30th to 80th min) was, respectively, of 3.62, 3.70 and 3.61 mmHg. The decrements of heart rate were of 2.11 and 2.66 beats per min. All these differences were statistically significant. The hypotensive and bradycardic responses persisted for 70–120 min.

Conclusions

This study shows that, in normotensives, a single fixed submaximal mouth opening for 10 min is followed by prolonged albeit small reductions of blood pressure and heart rate.

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Comparison of the recovery response from high-intensity and high-volume resistance exercise in trained men

Abstract

Purpose

The purpose of this study was to compare the physiological responses of a high-volume (HV; 8 sets of 10 repetitions) versus high-intensity (HI; 8 sets of 3 repetitions) exercise protocol in resistance-trained men.

Methods

Twelve men (24.5 ± 4.2 years; 82.3 ± 8.4 kg; 175.2 ± 5.5 cm) with 6.3 ± 3.4 years of resistance training experience performed each protocol in a counterbalanced, randomized order. Performance [counter movement jump peak power (CMJP), isokinetic (ISOK) and isometric leg extension (MVIC), isometric mid-thigh pull (IMTP), and isometric squat (ISQ)] and muscle morphological [cross-sectional area (CSA) of vastus lateralis] assessments were performed at baseline (BL), 30-min (P-30 min), 24-h (P-24 h), 48-h (P-48 h), and 72-h (P-72 h) post-exercise for each testing session. In addition, endocrine (testosterone and cortisol), inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)], and markers of muscle damage [creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin (Mb)] were assessed at the same time points.

Results

Significantly greater reductions in CMJP (p < 0.001), and peak torque during both ISOK (p = 0.003) and MVIC (p = 0.008) at P-30 min were detected in HV compared to HI protocol. MVIC was still impaired at P-72 h following the HV protocol, while no differences were noted following HI. Markers of muscle damage (LDH, CK, and Mb) were significantly elevated following both HV and HI (p < 0.05), while cortisol and IL-6 concentrations were significantly elevated at P-30 min following HV only (p < 0.001 and p < 0.05, respectively).

Conclusions

Results indicate that high-volume resistance exercise results in greater performance deficits, and a greater extent of muscle damage, than a bout of high-intensity resistance exercise.

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Acute effects of static stretching on muscle–tendon mechanics of quadriceps and plantar flexor muscles

Abstract

Purpose

This study aimed to determine the acute effects of static stretching on stiffness indexes of two muscle groups with a contrasting difference in muscle–tendon proportion.

Methods

Eleven active males were tested on an isokinetic dynamometer during four sessions randomly presented. Two sessions were dedicated to quadriceps and the two others to triceps surae muscles. Before and immediately after the stretching procedure (5 × 30 s), gastrocnemius medialis and rectus femoris fascicle length and myotendinous junction elongation were determined using ultrasonography. Passive and maximal voluntary torques were measured. Fascicle and myotendinous junction stiffness indexes were calculated.

Results

After stretching, maximal voluntary torque similarly decreased for both muscle groups. Passive torque significantly decreased on triceps surae and remained unchanged on quadriceps muscles. Fascicle length increased similarly for both muscles. However, myotendinous junction elongation remained unchanged for gastrocnemius medialis and increased significantly for rectus femoris muscle. Fascicle stiffness index significantly decreased on medial gastrocnemius and remained unchanged on rectus femoris muscle. In contrast, myotendinous junction stiffness index similarly decreased on both muscles.

Conclusion

Depending on the muscle considered, the present results revealed different acute stretching effects. This muscle dependency appeared to affect primarily fascicle stiffness index rather than the myotendinous junction.

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Response to comments on “High-intensity aerobic interval training improves aerobic fitness and HbA1c among persons diagnosed with type 2 diabetes”

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Mind-muscle connection training principle: influence of muscle strength and training experience during a pushing movement

Abstract

Purpose

To investigate the effect of different attentional focus conditions on muscle activity during the push-up exercise and to assess the possible influence of muscle strength and training experience.

Methods

Eighteen resistance-trained men performed 1RM bench press testing and were familiarized with the procedure during the first session. In the second session, three different conditions were randomly performed: regular push-up and push-up focusing on using the pectoralis major and triceps brachii muscles, respectively. Surface electromyography (EMG) was recorded and analyzed (EMG normalized to max; nEMG) for the triceps brachii and pectoralis major muscles.

Results

Participants had on average 8 (SD 6) years of training experience and 1RM of 1.25 (SD 0.28) kg per kg bodyweight. Focusing on using pectoralis major increased activity in this muscle by 9% nEMG (95% CI 5–13; Cohen's d 0.60) compared with the regular condition. Triceps activity was not significantly influenced by triceps focus although borderline significant, with a mean difference of 5% nEMG (95% CI 0–10; Cohen's d 0.30). However, years of training experience was positively associated with the ability to selectively activate the triceps (β = 0.41, P = 0.04), but not the pectoralis. Bench press 1RM was not significantly associated with the ability to selectively activate the muscles.

Conclusion

Pectoralis activity can be increased when focusing on using this muscle during push-ups, whereas the ability to do this for the triceps is dependent on years of training experience. Maximal muscle strength does not appear to be a decisive factor for the ability to selectively activate these muscles.

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Oral contraceptive pill use and the susceptibility to markers of exercise-induced muscle damage

Abstract

Purpose

Firstly, to establish whether oral contraceptive pill (OCP) users are more susceptible to muscle damage compared to non-users, and secondly, to establish whether differences can be attributed to differences in patella tendon properties.

Methods

Nine female OCP users and 9 female non-users participated in the investigation. Combining dynamometry, electromyography and ultrasonography, patella tendon properties and vastus lateralis architectural properties were measured pre and during the first of 6 sets of 12 maximal voluntary eccentric knee extensions. Serum oestrogen levels were measured on the 7th day of the pill cycle and the 14th day of menstrual cycle in OCP users and non-users, respectively. Maximal voluntary isometric knee extension torque loss, creatine kinase and muscle soreness were measured 48 h pre-damage, post-damage, and 48, 96 and 168 h post-damage.

Results

Oestrogen levels were significantly lower in OCP users compared to non-users (209 ± 115 and 433 ± 147 pg/ml, respectively, p = 0.004). Proposed determinants of muscle damage, patella tendon stiffness and maximal eccentric torque did not differ between OCP users and non-users. The change in creatine kinase from pre to peak was significantly higher in OCP users compared to non-users (962 ± 968 and 386 ± 474 Ul, respectively, p = 0.016). There were no other differences in markers of muscle damage.

Conclusion

Although our findings suggest that, when compared to non-users, the OCP may augment the creatine kinase response following eccentric exercise, it does not increase the susceptibility to any other markers of muscle damage.

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A tale of three cuffs: the hemodynamics of blood flow restriction

Abstract

Introduction

The blood flow response to relative levels of blood flow restriction (BFR) across varying cuff widths is not well documented. With the variety of cuff widths and pressures reported in the literature, the effects of different cuffs and pressures on blood flow require investigation.

Purpose

To measure blood pressure using three commonly used BFR cuffs, examine possible venous/arterial restriction pressures, and measure hemodynamic responses to relative levels of BFR using these same cuffs.

Methods

43 participants (Experiment 1, brachial artery blood pressure assessed) and 38 participants (Experiment 2, brachial artery blood flow assessed using ultrasound, cuff placed at proximal portion of arm) volunteered for this study.

Results

Blood pressure measurement was higher in the 5 cm cuff than in the 10 and 12 cm cuffs. Sub-diastolic relative pressures appear to occur predominantly at <60% of arterial occlusion pressure (AOP). Blood flow under relative levels of restriction decreases in a non-linear fashion, with minimal differences between cuffs [resting: 50.3 (44.2) ml min⁻¹; 10% AOP: 42.0 (36.8); 20%: 33.6 (28.6); 30%: 23.6 (20.4); 40%: 17.1 (15.9); 50%: 12.5 (9.4); 60%: 11.5 (8.1); 70%: 11.4 (7.0); 80%: 10.3 (6.3); 90%: 7.9 (4.8); 100%: 1.5 (2.9)]. Peak blood velocity remains relatively constant until higher levels (>70% of AOP) are surpassed. Calculated mean shear rate decreases in a similar fashion as blood flow.

Conclusions

Under relative levels of restriction, pressures from 40 to 90% of AOP appear to decrease blood flow to a similar degree in these three cuffs. Relative pressures appear to elicit a similar blood flow stimulus when accounting for cuff width and participant characteristics.

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Associations of human skeletal muscle fiber type and insulin sensitivity, blood lipids, and vascular hemodynamics in a cohort of premenopausal women

Abstract

Purpose

Cardiometabolic disease remains a leading cause of morbidity and mortality in developed nations. Consequently, identifying and understanding factors associated with underlying pathophysiological processes leading to chronic cardio metabolic conditions is critical. Metabolic health, arterial elasticity, and insulin sensitivity (SI) may impact disease risk, and may be determined in part by myofiber type. Therefore, the purpose of this study was to test the hypothesis that type I myofiber composition would be associated with high SI, greater arterial elasticity, lower blood pressure, and blood lipids; whereas, type IIx myofibers would be associated with lower SI, lower arterial elasticity, higher blood pressure, blood lipids.

Methods

Muscle biopsies were performed on the vastus lateralis in 16 subjects (BMI = 27.62 ± 4.71 kg/m², age = 32.24 ± 6.37 years, 43% African American). The distribution of type I, IIa, and IIx myofibers was determined via immunohistochemistry performed on frozen cross-sections. Pearson correlation analyses were performed to assess associations between myofiber composition, SI, arterial elasticity, blood pressure, and blood lipid concentrations.

Results

The percentage of type I myofibers positively correlated with SI and negatively correlated with systolic blood pressure SBP, diastolic blood pressure, and mean arterial pressure (MAP); whereas, the percentage of type IIx myofibers were negatively correlated with SI and large artery elasticity, and positively correlated with LDL cholesterol, SBP, and MAP.

Conclusions

These data demonstrate a potential link between myofiber composition and cardiometabolic health outcomes in a cohort of premenopausal women. Future research is needed to determine the precise mechanisms in which myofiber composition impacts the pathophysiology of impaired glucose and lipid metabolism, as well as vascular dysfunction.

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Effects of breaking up prolonged sitting following low and high glycaemic index breakfast consumption on glucose and insulin concentrations

Abstract

Purpose

Breaking up prolonged sitting can attenuate the postprandial rise in glucose and insulin. Whether such effects are dependent of the glycaemic index (GI) of the consumed carbohydrate is unknown. This study examined the acute effects of breaking up prolonged sitting following a low GI and a high GI breakfast on postprandial glucose and insulin concentrations.

Procedures

Fourteen adult males aged 22.1 ± 1.2 years completed four, 4 h experimental conditions: high GI breakfast followed by uninterrupted sitting (HGI-SIT), low GI breakfast followed by uninterrupted sitting (LGI-SIT), high GI breakfast followed by 2 min activity breaks every 20 min (HGI-ACT), and low GI breakfast followed by 2 min activity breaks every 20 min (LGI-ACT). Positive incremental area under the curve (iAUC) for glucose and insulin (mean [95% CI]) for each 4 h experimental condition was calculated. Statistical analyses were completed using linear mixed models.

Results

The sitting × breakfast GI interaction was not significant for glucose positive iAUC (P = 0.119). Glucose positive iAUC (mmol/L 4 h⁻¹) was significantly lower in the activity breaks conditions than the uninterrupted sitting conditions (2.07 [2.24, 2.89] vs. 2.56 [1.74, 2.40], respectively, P = 0.004) and significantly lower in the low GI conditions than the high GI conditions (2.13 [1.80, 2.45] vs. 2.51 [2.18, 2.84], respectively, P = 0.022). Insulin concentrations did not differ between conditions (P ≥ 0.203).

Conclusions

Breaking up prolonged sitting and lowering breakfast GI independently reduced postprandial glucose responses. This indicates that interrupting prolonged sitting and reducing dietary GI are beneficial approaches for reducing cardiometabolic disease risk.

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Adaptations in corticospinal excitability and inhibition are not spatially confined to the agonist muscle following strength training

Abstract

Purpose

We used transcranial magnetic stimulation (TMS) to determine the corticospinal responses from an agonist and synergist muscle following strength training of the right elbow flexors.

Methods

Motor-evoked potentials were recorded from the biceps brachii and flexor carpi radialis during a submaximal contraction from 20 individuals (10 women, 10 men, aged 18–35 years; training group; n = 10 and control group; n = 10) before and after 3 weeks of strength training at 80% of 1-repetition maximum (1-RM). To characterise the input–output properties of the corticospinal tract, stimulus–response curves for corticospinal excitability and inhibition of the right biceps brachii and flexor carpi radialis were constructed and assessed by examining the area under the recruitment curve (AURC).

Results

Strength training resulted in a 29% (P < 0.001) increase in 1-RM biceps brachii strength and this was accompanied by a 19% increase in isometric strength of the wrist flexors (P = 0.001). TMS revealed an increase in corticospinal excitability AURC and a decrease in silent period duration AURC for the biceps brachii and flexor carpi radialis following strength training (all P < 0.05). However, the changes in corticospinal function were not associated with increased muscle strength.

Conclusion

These findings show that the corticospinal responses to strength training of a proximal upper limb muscle are not spatially restricted, but rather, results in a change in connectivity, among an agonist and a synergistic muscle relevant to force production.

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Cross-resistance between voriconazole and fluconazole for non- albicans Candida infection: a case-case-control study

Abstract

Cross-resistance (CR) between voriconazole and fluconazole for non-albicans Candida (NAC) species is not uncommon, but little is known about the risk factors and clinical consequences associated with this resistance phenotype. A case-case-control study was performed at a university-affiliated hospital in China between November 2012 and April 2016. The two case groups respectively comprised patients with a mono-resistance (MR) NAC infection (fluconazole or voriconazole resistance) and patients with a CR NAC infection (fluconazole and voriconazole resistance). Patients with a no-resistance (NR) NAC infection were included as the control group. Models were adjusted for demographic and clinical risk factors, and the risk of resistance associated with exposure to specific antibiotics or non-antibiotics were assessed. Of 259 episodes, 33 (12.7%) and 27 (10.4%) were identified as MR and CR NAC infections, respectively. The broad use of azoles was strongly associated with the emergence of MR and CR NAC infections (adjusted odds ratio [95% confidence interval] = 2.69 [1.10–6.58] and 2.53 [1.02–6.28], respectively). The time at risk (1.02 [1.00–1.03]) with 12 days as a breakpoint was also an independent risk factor for CR NAC infection. The number of species associated with a high minimum inhibitory concentration (≥128 μg/mL) of fluconazole was higher for CR NAC infections than for MR NAC infections. Different resistance phenotypes (CR vs. MR vs. NR) were associated with all-cause mortality rates. These findings indicate a worrisome propensity of CR NAC infections and emphasize the need for strict antifungal stewardship.

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A potential new, stable state of the E-cadherin strand-swapped dimer in solution

Abstract

E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.

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Sex differences of cognitive load effects on object-location binding memory

Abstract

In this study, we investigated where the sex differences of object-location binding memory performance were influenced by the cognitive load. We used the fractal objects version of the 'What was where?' task to measure object memory, location memory and objection-location binding memory. Cognitive load was controlled by task difficulty presented two sessions: one session randomly displayed three or four fractal objects (Session 34) and the other session four or five objects (Session 45). The results showed that females outperformed males on object-location binding memory. Interestingly, even when the four object trials were compared between Session 34 and Session 45, in which we believed that the level of difficulty was similar while cognitive load varied, the swap error of males was significantly increased in Session 45 compared to females. In conclusion, there may be sex differences in object-location binding memory and the males could be more sensitive about the cognitive load than females.

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FTY720 Attenuates Infection-Induced Enhancement of Aβ Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation

Abstract

It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3 days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Aβ containing plaques and soluble Aβ and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Aβ phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD.

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Clinical Management of Dystonia in Childhood

Abstract

Dystonia is one of the most frequent movement disorders in childhood. It can impede normal motor development and cause significant motor disability. The diagnostic evaluation of childhood dystonia is challenging due to the phenotypic variability and heterogeneous etiologies. Evidence to guide the diagnostic evaluation and treatment is limited. Assessment is primarily directed by clinical history and distinctive examination findings. Neuroimaging is typically necessary to evaluate for acquired or complex inherited dystonias. A trial of levodopa can be both diagnostic and therapeutic in children with dopa-responsive dystonia. However, for the majority of children with early-onset dystonia, treatment is symptomatic with varying efficacy. There is a paucity of therapeutic trials for childhood dystonia and most treatment recommendations are consensus or expert opinion driven. This review summarizes the available evidence and guidelines on the diagnostic evaluation and pharmacological treatment of childhood-onset dystonia and provides practical frameworks to approach both issues based on best evidence.

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