Background The N -methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant ...depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo ( t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9–11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo ( p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.
God's call can be surprising and unexpected. This article evaluates theologies of vocation in light of this potential for surprise. Contemporary Protestant theological interpretations of vocation are ...critiqued as incomplete due to their tendency to present vocation as the expression and utilisation of innate abilities without giving sufficient account of how an individual might be called to something totally new and surprising. It will be suggested that this arises from a focus on creation as the dominant theological lens for interpreting vocation. An alternative focused on eschatology and pneumatology will be proposed in which both natural talents and new abilities are recognised as gifts of the Spirit given for the purpose of anticipatory proleptic participation in the coming Kingdom of God.
Hereby, a precisely controlled one-step electrode modification is presented where the enzyme laccase is immobilized during the potentiostatic deposition of a thin polydopamine film (ePDA) on carbon ...surfaces. The morphology, wettability, optical and electrochemical properties of the modified electrodes were accessed by atomic force microscopy, water contact angle goniometry, ellipsometry and cyclic voltammetry. The results indicate that laccase is robustly immobilized and evenly distributed in the ePDA matrix, not significantly affecting the redox behavior of the polymer. The catalytic activity of the laccase-polymer modified electrodes is confirmed by chronoamperometry for 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) detection, a well-known substrate of laccase. The proposed fast and efficient one-pot procedure is implemented on cheap disposable graphite electrodes, targeting the detection of phenolic compounds: caffeic acid, rosmarinic acid and gallic acid. The catalytic performance of the modified electrodes was evaluated in terms of reproducibility, sensitivity, limits of detection (LOD) and linear range. For gallic acid a calibration curve with a sensitivity of 19.3 mA M−1 cm−2, 1–150 μM linear range and a LOD of 0.29 μM is obtained, allowing the estimation of the low molecular weight phenols content in an extract of chestnut shell industrial waste.
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•Laccase robustly immobilized through one-step potentiostatic growth of polydopamine (ePDA).•Biocompatible ePDA films with evenly distributed laccase display high catalytic properties.•Disposable modified electrodes sensitively and reproducibly detect phenolic compounds.•Gallic acid content on a phenol-rich chestnut shell extract is estimated.
Here we use a chromosome-level genome assembly of a prairie rattlesnake (
), together with Hi-C, RNA-seq, and whole-genome resequencing data, to study key features of genome biology and evolution in ...reptiles. We identify the rattlesnake Z Chromosome, including the recombining pseudoautosomal region, and find evidence for partial dosage compensation driven by an evolutionary accumulation of a female-biased up-regulation mechanism. Comparative analyses with other amniotes provide new insight into the origins, structure, and function of reptile microchromosomes, which we demonstrate have markedly different structure and function compared to macrochromosomes. Snake microchromosomes are also enriched for venom genes, which we show have evolved through multiple tandem duplication events in multiple gene families. By overlaying chromatin structure information and gene expression data, we find evidence for venom gene-specific chromatin contact domains and identify how chromatin structure guides precise expression of multiple venom gene families. Further, we find evidence for venom gland-specific transcription factor activity and characterize a complement of mechanisms underlying venom production and regulation. Our findings reveal novel and fundamental features of reptile genome biology, provide insight into the regulation of snake venom, and broadly highlight the biological insight enabled by chromosome-level genome assemblies.
Endothelial cells lining blood vessels are exposed to various hemodynamic forces associated with blood flow. These include fluid shear, the tangential force derived from the friction of blood flowing ...across the luminal cell surface, tensile stress due to deformation of the vessel wall by transvascular flow, and normal stress caused by the hydrodynamic pressure differential across the vessel wall. While it is well known that these fluid forces induce changes in endothelial morphology, cytoskeletal remodeling, and altered gene expression, the effect of flow on endothelial organization within the context of the tumor microenvironment is largely unknown. Using a previously established microfluidic tumor vascular model, the objective of this study was to investigate the effect of normal (4 dyn/cm
2
), low (1 dyn/cm
2
), and high (10 dyn/cm
2
) microvascular wall shear stress (WSS) on tumor-endothelial paracrine signaling associated with angiogenesis. It is hypothesized that high WSS will alter the endothelial phenotype such that vascular permeability and tumor-expressed angiogenic factors are reduced. Results demonstrate that endothelial permeability decreases as a function of increasing WSS, while co-culture with tumor cells increases permeability relative to mono-cultures. This response is likely due to shear stress-mediated endothelial cell alignment and tumor-VEGF-induced permeability. In addition, gene expression analysis revealed that high WSS (10 dyn/cm
2
) significantly down-regulates tumor-expressed MMP9, HIF1, VEGFA, ANG1, and ANG2, all of which are important factors implicated in tumor angiogenesis. This result was not observed in tumor mono-cultures or static conditioned media experiments, suggesting a flow-mediated paracrine signaling mechanism exists with surrounding tumor cells that elicits a change in expression of angiogenic factors. Findings from this work have significant implications regarding low blood velocities commonly seen in the tumor vasculature, suggesting high shear stress-regulation of angiogenic activity is lacking in many vessels, thereby driving tumor angiogenesis.
Abstract Cells cultured within a three-dimensional (3D) in vitro environment have the ability to acquire phenotypes and respond to stimuli analogous to in vivo biological systems. This approach has ...been utilized in tissue engineering and can also be applied to the development of a physiologically relevant in vitro tumor model. In this study, collagen I hydrogels cultured with MDA-MB-231 human breast cancer cells were bioengineered as a platform for in vitro solid tumor development. The cell–cell and cell-matrix interactions present during in vivo tissue progression were encouraged within the 3D hydrogel architecture, and the biocompatibility of collagen I supported unconfined cellular proliferation. The development of necrosis beyond a depth of ∼150–200 μm and the expression of hypoxia-inducible factor (HIF)-1α were demonstrated in the in vitro bioengineered tumors. Oxygen and nutrient diffusion limitations through the collagen I matrix as well as competition for available nutrients resulted in growing levels of intra-cellular hypoxia, quantified by a statistically significant ( p < 0.01) upregulation of HIF-1α gene expression. The bioengineered tumors also demonstrated promising angiogenic potential with a statistically significant ( p < 0.001) upregulation of vascular endothelial growth factor (VEGF)-A gene expression. In addition, comparable gene expression analysis demonstrated a statistically significant increase of HIF-1α ( p < 0.05) and VEGF-A ( p < 0.001) by MDA-MB-231 cells cultured in the 3D collagen I hydrogels compared to cells cultured in a monolayer on two-dimensional tissue culture polystyrene. The results presented in this study demonstrate the capacity of collagen I hydrogels to facilitate the development of 3D in vitro bioengineered tumors that are representative of the pre-vascularized stages of in vivo solid tumor progression.
The transformative potential of pattern-based sensing techniques is often hampered by their difficulty in dealing with mixtures of analytes, a drawback that severely limits the applications of this ...sensing approach (the “problem of mixtures”). We show here that this is not an intrinsic limitation of the pattern sensing method. Indeed, we developed general guidelines for the design of the sensing, signal detection, and data interpretation methods to avoid this constraint, which resulted in chemical fingerprinting systems capable of recognizing unknown mixtures of analytes in a single experiment, without separation or pre-treatment before data acquisition. In support of these design principles, we report their successful application to an important analytical problem, metal ion discrimination and quantitation, by constructing a sensor array that provided a linear colorimetric response over a wide range of analyte concentrations. The resulting data set was interpreted using common multivariate data processing algorithms to achieve quantitative identification and concentration determination for pure and mixture samples, with excellent predictive ability on unknowns. Separation and detection methods for analyte mixtures, normally envisioned as independent processes, were successfully integrated in a single system.
This study demonstrates the capability of multiwalled carbon nanotubes (MWNTs) coupled with laser irradiation to enhance treatment of cancer cells through enhanced and more controlled thermal ...deposition, increased tumor injury, and diminished heat shock protein (HSP) expression. We also explored the potential promise of MWNTs as drug delivery agents by observing the degree of intracellular uptake of these nanoparticles. To determine the heat generation capability of MWNTs, the absorption spectra and temperature rise during heating were measured. Higher optical absorption was observed for MWNTs in water compared with water alone. For identical laser parameters, MWNT-containing samples produced a significantly greater temperature elevation compared to samples treated with laser alone. Human prostate cancer (PC3) and murine renal carcinoma (RENCA) cells were irradiated with a 1,064-nm laser with an irradiance of 15.3 W/cm(2) for 2 heating durations (1.5 and 5 minutes) alone or in combination with MWNT inclusion. Cytotoxicity and HSP expression following laser heating was used to determine the efficacy of laser treatment alone or in combination with MWNTs. No toxicity was observed for MWNTs alone. Inclusion of MWNTs dramatically decreased cell viability and HSP expression when combined with laser irradiation. MWNT cell internalization was measured using fluorescence and transmission electron microscopy following incubation of MWNTs with cells. With increasing incubation duration, a greater number of MWNTs were observed in cellular vacuoles and nuclei. These findings offer an initial proof of concept for the application of MWNTs in cancer therapy.
Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully ...described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.
Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.
The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.
In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.
ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.
The present study examined the relative contribution of recent or long-term heading to neuropsychological function in amateur adult soccer players.
Soccer players completed a baseline questionnaire ...(HeadCount-12m) to ascertain heading during the prior 12 months (long-term heading, LTH) and an online questionnaire (HeadCount-2w) every 3 months to ascertain heading during the prior 2 weeks (recent heading, RH). Cogstate, a battery of six neuropsychological tests, was administered to assess neuropsychological function. Generalized estimating equations were used to test if LTH or RH was associated with neuropsychological function while accounting for the role of recognized concussion.
A total of 311 soccer players completed 630 HeadCount-2w. Participants had an average age of 26 years. Participants headed the ball a median of 611 times/year (mean=1,384.03) and 9.50 times/2 weeks (mean=34.17). High levels of RH were significantly associated with reduced performance on a task of psychomotor speed (p=.02), while high levels of LTH were significantly associated with poorer performance on tasks of verbal learning (p=.03) and verbal memory (p=.04). Significantly better attention (p=.02) was detectable at moderately high levels of RH, but not at the highest level of RH. One hundred and seven (34.4%) participants reported a lifetime history of concussion, but this was not related to neuropsychological function and did not modify the association of RH or LTH with neuropsychological function.
High levels of both RH and LTH were associated with poorer neuropsychological function, but on different domains. The clinical manifestations following repetitive exposure to heading could change with chronicity of exposure. (JINS, 2018, 24, 147-155).
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