20 research outputs found

    Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

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    Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation

    Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

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    Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Changes in pain-related fear and pain when avoidance behaviour is no longer effective

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    Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behaviour subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task to investigate this. In a between-subjects design both Experimental Group (n=30) and Yoked Control Group (n=30) participants perform either of three movement trajectories (T1-T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behaviour no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behaviour. When avoidance behaviour became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behaviour following the contingency change, albeit at a lower frequency than during acquisition. Perspective Results indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behaviour despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain.status: publishe

    The Effect of High Versus Low Cognitive Load on the Development of Nociceptive Hypersensitivity: The Roles of Sympathetic Arousal, Sex, and Pain-Related Fear

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    BACKGROUND: According to limited-capacity theories of attention, less attentional resources remain available when engaging in a high versus a low demanding cognitive task. This may reduce the perceived intensity and the evoked cortical responses of concomitant nociceptive stimuli. Whether and how the competition for limited attentional resources between a cognitive task and pain impacts the development of long-lasting hypersensitivity is unclear. METHODS: Eighty-four healthy participants were randomized into a low or high cognitive load group. Low Frequency electrical Stimulation (LFS) of the skin was used to induce secondary hypersensitivity. We hypothesized that performing the high load task during LFS would reduce the development of hypersensitivity. We examined whether painfulness, non-pain-related sympathetic arousal, or sex related to hypersensitivity, by assessing intensity and unpleasantness of mechanical pinprick stimulation. During task execution, we recorded steady-state evoked potentials evoked by LFS, and skin conductance level for sympathetic arousal. Afterwards, participants reported task difficulty and LFS-related fear. For the primary outcomes, we used mixed ANOVAs. RESULTS: The results confirmed the difference in cognitive load. Although LFS successfully induced hypersensitivity, the high load task did not reduce its development. Next, the steady-state evoked potentials did not differ between groups. Hypersensitivity correlated positively with pain-related fear and negatively with skin conductance level before LFS, despite the lack of group differences in skin conductance level. We did not find any sex differences in hypersensitivity. CONCLUSIONS: These results do not confirm that high cognitive load or sex modulate hypersensitivity, but show associations with pain-related fear and non-pain-related sympathetic arousal

    Organic matter and palaeoenvironmental signals during the Early Triassic biotic recovery: the Salt Range and Surghar Range records

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    Latest Permian to the Middle Triassic mixed siliciclastic–carbonate shelf deposits of the northern Gondwana margin have been studied in four sections (Nammal, Chhidru, Chitta–Landu, and Narmia) in the Salt Range and Surghar Range of Pakistan. Sedimentological and palynofacies patterns combined with a high resolution ammonoid based age control have been used to assess environmental changes such as sea-level change, distance from the shore, and oxygenation conditions of the sections in the aftermath of the end-Permian mass extinction. The base and the top of the Early Triassic are marked by second order sequence boundaries (SRT1, SRT8). Within the Early Triassic two third order sequence boundaries could be delineated by means of palynofacies analysis and sedimentology, one near the Dienerian–Smithian (SRT2) and the second one near the Smithian–Spathian boundary (SRT5). The extinction event at the Smithian–Spathian boundary seems to be closely associated to the latter globally recorded sea-level low stand. Five additional sequences of undetermined order (SRT3, SRT 4, SRT5/1, SRT6, and SRT7) are reflected in the sedimentological record of the studied sections. The observed changes in the composition of the particulate organic matter (POM) indicate a general shallowing upward trend, which is modulated by smaller transgressive–regressive cycles supporting the sedimentologically defined sequences. The POM is mostly dominated by terrestrial phytoclasts and sporomorphs. The strongest marine signal is reflected by increased abundance of amorphous organic matter (AOM) in the lower part of the Ceratite Marls at Nammal (late Dienerian) and Chhidru (earliest Smithian) and the Lower Ceratite Limestone at Chitta–Landu (late Dienerian). AOM of marine origin is characteristic for deeper, distal basinal settings and is preferentially preserved under dysoxic and anoxic conditions, indicating reduced oxygen conditions during these intervals. Up-section transgressive events are reflected by increased numbers of acritarchs, reaching up to 50% of the POM. Well oxygenated conditions and low total organic carbon contents (TOC) continue up to the top of the Early Triassic (Mianwali Formation). The most pronounced terrestrial influx is expressed in the Middle Triassic. Organic carbon isotope data parallel the carbonate carbon isotope records from the Tethyan realm; therefore, they reflect real global changes in the carbon cycle independent of the OM composition. The biomarker study of the apolar hydrocarbons of three samples from the Nammal section indicates an enhanced bacterial productivity, especially in the Smithian and Spathian, reflected in high relative abundances of hopanes. POM, TOC data and redox sensitive biomarkers together with high resolution biostratigraphy demonstrate that well-oxygenated environmental conditions prevailed in the Early Triassic with the exception of the Dienerian to earliest Smithian interval. The POM assemblages of Late Permian to late Griesbachian age indicate well oxygenated conditions during this time interval. There is no evidence in support of an anoxic event in the late Griesbachian in these sections