Cytokine profiles of cord and adult blood leukocytes: differences in expression are due to differences in expression and activation of transcription factors

<p>Abstract</p> <p>Background</p> <p>Stem cell transplantation as therapy for hematological disorders is often hampered by severe graft-versus-host-disease. This may be reduced by umbilical cord blood transplantation, an effect that has been attributed to qualitative differences between neonatal and adult T cells. We compared levels of secreted proteins and cytokine mRNA induced in cord blood leukocytes (CBL) and adult blood leukocytes (ABL) by various stimuli.</p> <p>Results</p> <p>While interleukin-2 (IL-2) levels were similar in CBL and ABL, there was less induction of the Th1 cytokine interferon-γ in CBL. Production of the Th2 cytokines IL-4, IL-5, and IL-13 and the hematopoietic cytokine IL-3 was much lower in CBL versus ABL after T-cell receptor-mediated stimulation, whereas production of GM-CSF was comparable in the 2 cell types. The lower levels of Th1 and Th2 cytokines were maintained in CBL during a 4-day time-course study, while after 12 hours IL-3 and GM-CSF reached in CBL levels similar to those in ABL. For all cytokines except IFNγ, the IC₅₀values for inhibition by cyclosporin A were similar in ABL and CBL. In contrast, there was less expression and activation of transcription factors in CBL. Activation of NF-κB by TPA/ionomycin was detected in ABL but not CBL. Furthermore, there was less expression of the Th subset-specific transcription factors T-bet and c-maf in CBL versus ABL, whereas GATA-3 expression was similar. Expression of T-bet and c-maf correlated with expression of the Th1 and Th2 cytokines, respectively. Time course experiments revealed that T-bet expression was stimulated in both cell types, whereas c-maf and GATA-3 were induced only in ABL.</p> <p>Conclusion</p> <p>The diminished capability of CBL to synthesize cytokines is probably due to decreased activation of NF-κB, whereas differences in Th subsets are due to differences in regulation of Th lineage-specific transcriptions factors. We propose that the reduced incidence and severity of GvHD after allogeneic transplantation of umbilical CB cells is due to lesser activation of specific transcription factors and a subsequent reduction in production of certain cytokines.</p

Development of the symmetrical laser shock test for weak bond inspection

This study aims to assess the capability of the LAser Shock Adhesion Test to detect weak bonds in assemblies made of carbon fibre reinforced polymer laminates as well as understand the behaviour of different bonded composite structure under a shock load. A specific setup based on symmetrical laser shocks has been used. After each test, ultrasounds are used to determine if the bond has been damaged or not. At first, samples with two contaminants - de-icing fluid and finger prints - were studied. Then, the bond quality of two partially contaminated aircraft parts were investigated. These original results demonstrate the efficiency of the symmetrical laser shocks method as a Non-Destructive Test for bonded carbon fibre reinforced polymer assemblies

Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype

Blockade of prostaglandin (PG) production by COX inhibitors is the treatment of choice for inflammatory pain but is also prone to severe side effects. Identification of signaling elements downstream of COX inhibition, particularly of PG receptor subtypes responsible for pain sensitization (hyperalgesia), provides a strategy for better-tolerated analgesics. Here, we have identified PGE 2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia. Mice deficient in EP2 receptors (EP2 -/-mice) completely lack spinal PGE 2 -evoked hyperalgesia. After a peripheral inflammatory stimulus, EP2 -/-mice exhibit only short-lasting peripheral hyperalgesia but lack a second sustained hyperalgesic phase of spinal origin. Electrophysiological recordings identify diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of EP2 receptor-dependent hyperalgesia. Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition

Virtual faces as a tool to study emotion recognition deficits in schizophrenia

Studies investigating emotion recognition in patients with schizophrenia predominantly presented photographs of facial expressions. Better control and higher flexibility of emotion displays could be afforded by virtual reality (VR). VR allows the manipulation of facial expression and can simulate social interactions in a controlled and yet more naturalistic environment. However, to our knowledge, there is no study that systematically investigated whether patients with schizophrenia show the same emotion recognition deficits when emotions are expressed by virtual as compared to natural faces. Twenty schizophrenia patients and 20 controls rated pictures of natural and virtual faces with respect to the basic emotion expressed (happiness, sadness, anger, fear, disgust, and neutrality). Consistent with our hypothesis, the results revealed that emotion recognition impairments also emerged for emotions expressed by virtual characters. As virtual in contrast to natural expressions only contain major emotional features, schizophrenia patients already seem to be impaired in the recognition of basic emotional features. This finding has practical implication as it supports the use of virtual emotional expressions for psychiatric research: the ease of changing facial features, animating avatar faces, and creating therapeutic simulations makes validated artificial expressions perfectly suited to study and treat emotion recognition deficits in schizophrenia

Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery—a pilot study

The perioperative administration of selective cyclooxygenase-2 (COX-2)-inhibitors to avoid postoperative pain is an attractive option: they show favorable gastro-intestinal tolerability, lack inhibition of blood coagulation, and carry a low risk of asthmatic attacks. The purpose of this study was to determine the cerebrospinal fluid (CSF), plasma, and tissue pharmacokinetics of orally administered etoricoxib and to compare it with effect data, i.e., COX-2-inhibition in patients after hip surgery. The study was performed in a blinded, randomized, parallel group design. A total of 12 adult patients were included who received 120 mg etoricoxib (n = 8) or placebo (n = 4) on day 1 post-surgery. Samples from plasma, CSF, and tissue exudates were collected over a period of 24 h post-dosing and analyzed for etoricoxib and prostaglandin E2 (PGE2) using liquid chromatography-tandem mass spectrometry and immuno-assay techniques. CSF area under the curve (AUC) [AUCs(O–24h)] for etoricoxib amounted to about 5% of the total AUC in plasma (range: 2–7%). Individual CSF lag times with respect to (50%) peak plasma concentration were ≤2 h in all but one case (median: 1 h). PGE2 production in tissue was significantly blocked by the COX-2 inhibitor starting with the appearance of etoricoxib in tissue and lasting for the whole observation period of 24 h (P < 0.01). In conclusion, etoricoxib reaches the CSF and site of surgery at effective concentrations and reduces PGE2 production at the presumed site of action

Social Cognitive Role of Schizophrenia Candidate Gene GABRB2

10.1371/journal.pone.0062322PLoS ONE84

Cognitive neuroscience of delusions in aging

Assessments and clinical understanding of late-onset delusions in the elderly are inconsistent and often incomplete. In this review, we consider the prevalence, neurobehavioral features, and neuroanatomic correlations of delusions in elderly persons – those with documented cognitive decline and those with no evidence of cognitive decline. Both groups exhibit a common phenotype: delusions are either of persecution or of misidentification. Late-onset delusions show a nearly complete absence of the grandiose, mystical, or erotomanic content typical of early onset psychoses. Absent also from both elderly populations are formal thought disorders, thought insertions, and delusions of external control. Neuroimaging and behavioral studies suggest a frontotemporal localization of delusions in the elderly, with right hemispheric lateralization in delusional misidentification and left lateralization in delusions of persecution. We propose that delusions in the elderly reflect a common neuroanatomic and functional phenotype, and we discuss applications of our proposal to diagnosis and treatment

Extension and Dynamics of the Andes inferred from the 2016 Parina (Huarichancara) Earthquake

The M w 6.1 2016 Parina earthquake led to extension of the south Peruvian Andes along a normal fault with evidence of Holocene slip. We use InSAR, seismology and field mapping to determine a source model for this event and show that extension at Parina is oriented NE-SW, which is parallel to the shortening direction in the adjacent sub-Andean lowlands. In addition, we use earthquake source models and GPS data to demonstrate that shortening within the sub-Andes is parallel to topographic gradients. Both observations imply that forces resulting from spatial variations in gravitational potential energy are important in controlling the geometry of the deformation in the Andes. We calculate 9 the horizontal forces per unit length acting between the Andes and South America due to these potential energy contrasts to be 4 − 8 × 10 12 N per metre along-strike of the mountain range. Normal faulting at Parina implies that the Andes in south Peru have reached the maximum elevation that can be supported by the forces transmitted across the adjacent foreland, which requires that the foreland faults have an effective coefficient of friction <0.2. Additionally, the onset of extension in parts of the central Andes following orogen-wide compression in the late Miocene suggests there has been a change in the force balance within the mountains. We propose that shortening on weak detachment faults within the Andean foreland since ∼5-9 Ma reduced the shear tractions acting along the base of the upper crust in the eastern Andes, leading to extension in the highest parts of the range

Inducing Ni Sensitivity in the Ni Hyperaccumulator Plant Alyssum inflatum Nyárády (Brassicaceae) by Transforming with CAX1, a Vacuolar Membrane Calcium Transporter

The importance of calcium in nickel tolerance was studied in the nickel hyperaccumulator plant Alyssum inflatum by gene transformation of CAX1, a vacuolar membrane transporter that reduces cytosolic calcium. CAX1 from Arabidopsis thaliana with a CaMV35S promoter accompanying a kanamycin resistance gene was transferred into A. inflatum using Agrobacterium tumefaciens. Transformed calli were subcultured three times on kanamycin-rich media and transformation was confirmed by PCR using a specific primer for CAX1. At least 10 callus lines were used as a pool of transformed material. Both transformed and untransformed calli were treated with varying concentrations of either calcium (1–15 mM) or nickel (0– 500 lM) to compare their responses to those ions. Increased external calcium generally led to increased callus biomass, however, the increase was greater for untransformed callus. Further, increased external calcium led to increased callus calcium concentrations. Transformed callus was less nickel tolerant than untransformed callus: under increasing nickel concentrations callus relative growth rate was significantly less for transformed callus. Transformed callus also contained significantly less nickel than untransformed callus when exposed to the highest external nickel concentration (200 lM). We suggest that transformation with CAX1 decreased cytosolic calcium and resulted in decreased nickel tolerance. This in turn suggests that, at low cytosolic calcium concentrations, other nickel tolerance mechanisms (e.g., complexation and vacuolar sequestration) are insufficient for nickel tolerance. We propose that high cytosolic calcium is an important mechanism that results in nickel tolerance by nickel hyperaccumulator plants