The level of representation of irrelevant stimuli-Distractor-response binding within and between the senses.

Binding theories assume that features of stimuli and executed responses can be integrated together in one event file (Hommel, Visual Cognition, 5, 183-216, 1998; Hommel, Cognitive Sciences, 8, 494-500, 2004). Every reencounter with one or more of the stored features leads to an automatic retrieval of the previously constructed event file and hence of the response-even the repetition of a task-irrelevant distractor stimulus can retrieve a previously encoded response. This so-called distractor-response binding effect is typically investigated using a sequential prime-probe design that allows the orthogonal variation of response relation (response repetition vs. resporrevertnse change) and distractor relation (distractor repetition vs. distractor change), while probe response times and error rates are measured as dependent variable. Previous research has shown that task-relevant stimuli can be represented at different levels (e.g., perceptual and conceptual; see Henson et al., Trends in Cognitive Sciences, 18, 376-384, 2014), yet it is not clear at which level of representation distractor stimuli are processed. In the present study, we focused on the level of representation of response-irrelevant distractor stimuli. To this end, a crossmodal distractor-response binding paradigm was used that enables the differentiation between the perceptual and conceptual representation of the distractor by allowing the systematic repetition and change of conceptual distractor features independent of perceptual repetitions. The results suggest that the repetition of perceptual distractor features is indispensable for the initiation of the retrieval process while the sole repetition of conceptual distractor features is not sufficient to start the retrieval process.

Brightness versus darkness: The influence of stimulus intensity on the distractor-response binding effect.

The intensity of a stimulus has been found to have a distinct impact upon response processes (e.g., response speed, response force, & response selection). For instance, reaction times are faster to bright than to dim stimuli (e.g., Kohfeld, 1971). In the present study, we investigated the possible influence of stimulus intensity on binding processes. According to binding theories, stimulus and response features are integrated together in short-lived memory traces, called event files (Hommel, 1998). Any re-encounter with one of these integrated features leads to the automatic retrieval of the previously constructed event file and thus of the response. Thereby bindings between stimuli (relevant and irrelevant) and responses have a direct impact on behavior. In the present experiment, we presented distractors with increasing stimulus intensity and found that intensity did exert an influence on binding processes. However, our results suggest that distractor intensity per se has no direct influence on the binding effect (the more intense a distractor is, the larger the binding effect), but that distractor intensity has an indirect effect on binding via grouping due to similarity between target and distractor intensity.

Why star retrieves scar: Binding and retrieval of perceptual distractor features.

If a target stimulus is presented together with a response-irrelevant distractor stimulus, both stimuli can be encoded together with the response in an event file (see Hommel, 2004). The repetition of any feature of such an event-file can then retrieve the previously encoded response. This kind of feature-based retrieval is an important mechanism in action control. Typically, a direct link between perception and action is assumed, whereas the possible role of semantics is unspecified so far. Only a couple of previous studies analyzed whether the repetition of semantic features can elicit event-file retrieval. Yet, in these studies, semantic repetition often included perceptual repetition as well; even more problematic is trying to analyze perceptual repetitions while excluding semantic repetitions. Thus, here we used a different approach by repeating perceptual features but contrasted semantic and perceptual repetitions. In particular, in 2 experiments we found evidence that perceptual features of a distractor (the letters of an irrelevant word) are integrated with the response and can later retrieve the response, even if only some of these features are repeated thus forming a semantically different concept (i.e., presenting Buch [book] retrieves the response made to Bach [brook]). Our result shed new light on the relation between perception, action, and semantics in action control. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Distractor-based retrieval in action control: the influence of encoding specificity.

If a target stimulus is presented together with a response irrelevant distractor stimulus, both stimuli can be encoded together with the response in an event file [see Hommel (Trends Cogn Sci 8:494-500, 2004)]. The repetition of the distractor can retrieve the encoded response. This kind of distractor-based retrieval is an important mechanism in action control. In the present experiment, we investigate whether and how distractor-based retrieval of event files is influenced by encoding specificity-a retrieval principle that has been suggested to affect retrieval in short-term and long-term memory. Using a prime-probe design, the number of identical distractors on each display was varied. The results showed that the distractor-based retrieval process is modulated by encoding specificity, in that only high (low) number of distractors retrieves former event files with high (low) number of distractors. Taken together, distractor-based retrieval in action control follows principles known from short-term memory and long-term memory retrieval.

Dissecting stimulus-response binding effects: Grouping by color separately impacts integration and retrieval processes.

In selection tasks, target and distractor features can be encoded together with the response into the same short-lived memory trace, or event file (see Hommel, 2004), leading to bindings between stimulus and response features. The repetition of a stored target or distractor feature can lead to the retrieval of the entire episode, including the response-so-called "binding effects." Binding effects due to distractor repetition are stronger for grouped than for nongrouped target and distractor stimulus configurations. Modulation of either of two mechanisms that lead to the observed binding effects might be responsible here: Grouping may influence either stimulus-response integration or stimulus-response retrieval. In the present study we investigated the influences of grouping on both mechanisms independently. In two experiments, target and distractor letters were grouped (or nongrouped) via color (dis)similarity separately during integration and retrieval. Grouping by color similarity affected integration and retrieval mechanisms independently and in different ways. Color dissimilarity enhanced distractor-based retrieval, whereas color similarity enhanced distractor integration. We concluded that stimulus grouping is relevant for binding effects, but that the mechanisms that contribute to binding effects should be carefully separated.

Disentangling inhibition-based and retrieval-based aftereffects of distractors: Cognitive versus motor processes.

Selective attention refers to the ability to selectively act upon relevant information at the expense of irrelevant information. Yet, in many experimental tasks, what happens to the representation of the irrelevant information is still debated. Typically, 2 approaches to distractor processing have been suggested, namely distractor inhibition and distractor-based retrieval. However, it is also typical that both processes are hard to disentangle. For instance, in the negative priming literature (for a review Frings, Schneider, & Fox, 2015) this has been a continuous debate since the early 1980s. In the present study, we attempted to prove that both processes exist, but that they reflect distractor processing at different levels of representation. Distractor inhibition impacts stimulus representation, whereas distractor-based retrieval impacts mainly motor processes. We investigated both processes in a distractor-priming task, which enables an independent measurement of both processes. For our argument that both processes impact different levels of distractor representation, we estimated the exponential parameter (τ) and Gaussian components (µ, σ) of the exponential Gaussian reaction-time (RT) distribution, which have previously been used to independently test the effects of cognitive and motor processes (e.g., Moutsopoulou & Waszak, 2012). The distractor-based retrieval effect was evident for the Gaussian component, which is typically discussed as reflecting motor processes, but not for the exponential parameter, whereas the inhibition component was evident for the exponential parameter, which is typically discussed as reflecting cognitive processes, but not for the Gaussian parameter. (PsycINFO Database Record

Pneumococcal antibody levels in children with PID receiving immunoglobulin.

OBJECTIVES: Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization. METHODS: Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion. RESULTS: Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17-7.96 µg/mL). In patients (89%-100%), antibodies against most serotypes reached trough levels ≥ 0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥ 1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product. CONCLUSIONS: In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.

Stability of therapeutic albumin solutions used for molecular adsorbent recirculating system-based liver dialysis.

Mounting evidence suggests beneficial effects of albumin dialysis-based liver support in patients suffering from acute-on-chronic liver failure. Molecular adsorbent recirculating system (MARS) is a nonbiological liver support device, based on the exchange of albumin-bound toxins between the patient's blood and a 20% human serum albumin solution in a secondary circuit. Bound toxins are continuously removed from the circulating albumin by exposure to activated charcoal and an ion-exchange resin. The aim of the present in vitro study was to determine the impact of exposure to charcoal and resin on the ligand binding properties of albumins, containing various levels of stabilizers and obtained from different suppliers (Baxter, CAF-DCF [Red Cross], and Sigma-Aldrich). Albumin binding properties were assessed by measuring equilibrium binding properties of warfarin, diazepam, and salicylate before and after incubation (for up to 7 h) with adsorbing materials; albumin-associated esterase-like activities were also determined. Notable changes in albumin binding upon incubation with adsorbing materials were only observed when using warfarin as a ligand. Affinity of warfarin for the Baxter and Sigma albumins showed a pronounced decrease (higher K(d) ) after the 1-7-h exposure to charcoal or resin. In the absence of adsorbing materials, similar effects were found, indicating that incubation time per se affects albumin binding properties. Following exposure to resin, Baxter albumin binding capacity (B(max)) increased about twofold. For albumin obtained from CAF-DCF, binding affinity and capacity for warfarin were constant under all conditions tested. Esterase-like activities associated with these albumins were either maintained or enhanced (up to 2.5-fold in case of Sigma albumin) following 7-h incubations with adsorbing materials. Our data suggest limited direct influence of the presence of stabilizers in therapeutic albumin solutions on baseline binding properties of human albumin. However, in vitro incubations of these albumins for several hours resulted in supplier-specific changes in warfarin binding, suggesting an influence of stabilizers on the stability of binding properties. Further preclinical and clinical studies are required to elucidate the clinical relevance of these in vitro results, that is, to what extent these changes in albumin binding properties result in altered performance of albumins in the secondary circuit during the MARS procedure.

Apoptosis: a target for potentiation of UV-induced IL-1Ra synthesis by IVIg.

IL-1Ra prevents IL-1 induced inflammatory signalling, a mechanism potentially important for several pathological conditions characterized by inflammation. When administered as a drug in the recombinant form, it displays a protective effect towards them. We postulated that this action could also be achieved by pharmacological activation of endogenous IL-1Ra production. We previously showed that photochemotherapy and UV-light increased monocyte/macrophages IL-1Ra secretion. A similar effect has been shown for IVIg. The aim of this study was to define optimal in vitro conditions for induction of IL-1Ra secretion. As both agents induce lymphocytes apoptosis, we focused our analysis on the influence of IVIg on UV-induced-IL-1Ra production on this mechanism. After overnight preincubation at 37 degrees C, UV-irradiated PBL mixed with two IVIg concentrations (1 and 25 mg/ml) were cocultured with autologous PBMC. Apoptosis was measured by annexin V/PI. IL-1Ra secretion was evaluated by RT-PCR and Luminex microbead array assay. A significant additive dose-dependent influence of IVIg (+85%; p=0.0005) on UV-induced IL-1Ra secretion, involved both Fc-receptor activation at a low dose (1 mg/ml) and a potent apoptotic action on PBL reinforcing the UV effect at high concentrations (25 mg/ml). We conclude that lymphocyte apoptosis represents an important pathway contributing to enhancement of UV-induced monocyte/macrophages IL-1Ra production by IVIg and that these findings should be considered when evaluating in vivo protocols for photochemotherapy and IVIg treatment, in hope of improving efficacy.

In silico prediction of FVIII epitopes recognised by natural autoantibodies in polyvalent immunoglobulin concentrates.

Inhibitory antibodies directed against blood coagulation factor VIII (FVIII) impair FVIII replacement therapy, constituting a serious complication in haemophilic and autoimmune patients. Identifying B-cell FVIII epitopes and mapping them on the molecule remain important challenges. Using a combination of different algorithms, more than 30 hypothetical linear epitopes were predicted on the FVIII molecule surface. We selected several major predicted sequences, spanning all FVIII domains, for specific antibody induction in rabbits. All peptides tested successfully induced production of specific anti-FVIII rabbit antibodies, supporting the relevance of our approach. To investigate the presence of FVIII-reactive antibodies in the healthy donor population, a pooled fraction rich in all IgG subclasses was purified on peptide-Sepharose columns. Substantial amounts of Ig, specific for each FVIII peptide, were purified with yields ranging from 8 to 223 ng/mg immunoglobulins. Our results confirm the diversity of FVIII epitopes recognised by natural human anti-FVIII autoantibodies. All IgG subclasses were found in the affinity-isolated anti-peptide material, with overrepresentation of IgG2 and IgG4. Evidence was also found for new FVIII epitopes. Five human anti-peptide preparations displayed FVIII-neutralising activity, ranging from 1.3 to 5.3 BU/mg. Although the presence of naturally occurring anti-FVIII antibodies in healthy donors has been previously described, our methodology has allowed, for the first time, a fine mapping of several inhibitory and non-inhibitory epitopes. Our observations support the hypothesis that FVIII inhibitors in haemophilia A and autoimmune disease may originate from the proliferation of natural FVIII-specific B-cell clones.

Anti-inflammatory effects of UV-irradiated lymphocytes: induction of IL-1Ra upon phagocytosis by monocyte/macrophages.

One of the mechanisms proposed to explain immunomodulatory actions of ultraviolet light (UV) is production of endogenous anti-inflammatory cytokines. The purpose of the present study is to evaluate how UV light affects the production of IL-10 and IL-1Ra and to provide insight as to the role of phagocytosis of apoptotic lymphocytes in this process. Cytokine production was evaluated in a coculture system consisting in UV-treated lymphocytes in the presence of autologous PBMC. The impact of phagocytosis was tested by two blocking agents cytochalasin E and anti-CD36 mAb. The apoptotic process affecting irradiated lymphocytes was progressive, culminating at 48 h. To achieve significant cytokine production, irradiated lymphocytes were incubated overnight at 37 degrees C. Coculture of apoptotic lymphocytes with autologous PBMC resulted in a significant increase of IL-1Ra mRNA (+340%; P = 0.001) and protein (+72%; P = 0.001) production. This synthesis was blocked by cytochalasin E but upregulated by CD36 receptor cross-linking. Our study shows that UV light induces lymphocyte apoptosis followed by its phagocytosis by monocyte/macrophages, a step that preferentially activates IL-1Ra.

Hypoxia enables B19 erythrovirus to yield abundant infectious progeny in a pluripotent erythroid cell line.

B19 may cause mild to severe clinical manifestations. Owing to the remarkable tropism of B19 for red blood cell progenitors, there is a lack of satisfactory cell lines fully permissive for B19. Because the local oxygen pressure may influence viral replication, we used hypoxia to improve the sensitivity of our infectivity assay in order to link B19 DNA detected by PCR to the presence of infectious B19 particles in plasma. Plasma samples and the WHO International Standard for B19 DNA detection by PCR were used to infect the pluripotent human erythroid cell line KU812F under different oxygen pressures. Specific human anti-B19 IgG was found to reduce infectivity. Low oxygen pressure led to higher yields of infectious B19 progeny and to a higher level of viral transcription than observed under normoxia. This sensitive infectivity assay is a promising model for studying B19 biology, identifying neutralising antibodies, and evaluating new virus inactivation methods.

An assay for parvovirus B19 neutralizing antibodies based on human hepatocarcinoma cell lines.

BACKGROUND: Although intravenous immune globulin (IVIG) is used widely for managing parvovirus B19 infections, IVIG products are not monitored routinely for the presence of parvovirus B19 neutralizing antibody. STUDY DESIGN AND METHODS: An assay has been developed to measure parvovirus B19 infectivity and neutralization activity based on two hepatocarcinoma cell lines (HepG2 and HuH7). The sources of parvovirus B19 were B19-DNA-containing plasma samples. Neosynthesized progeny in supernatants of infected cells were quantified by nested polymerase chain reaction. To validate the model, purified rabbit antibodies to different capsid protein sequences and IVIG preparations were tested. RESULTS: The number of parvovirus B19 infectious neovirions in supernatants of infected cells increased with infection time. Both rabbit antibodies and IVIG products inhibited parvovirus B19 infectivity when incubated overnight with virus. The efficacy of IVIG to neutralized parvovirus B19 was product-related. CONCLUSION: This assay for parvovirus B19 neutralization activity provides an improved and more specific method for selecting donors to produce IVIG with a high titer of parvovirus B19 neutralizing activity.

Continuous-flow UVC irradiation: a new, effective, protein activity-preserving system for inactivating bacteria and viruses, including erythrovirus B19.

Despite the increasing number of screening tests being introduced, ensuring the inactivation of blood-borne pathogens in blood-derived therapeutic material is a major concern. Dynamic continuous-flow UVC irradiation is a new way to inactivate a large range of pathogens without adding any photosentizers. The efficacy of different methods was evaluated against the following viruses: murine parvovirus MVMp, human B19, the encephalomyocarditis virus (EMC, a picornavirus used as a model for model for hepatitis A virus), and bovine herpes virus type 1 (BHV, a model for enveloped viruses such as hepatitis B virus). We show that continuous-flow UVC irradiation is very effective, particularly against resistant pathogens (e.g. parvoviruses and bacteria) at UVC doses preserving protein activity. It may be applicable to newly emerging related viruses or variants.

Parvoviruses and blood products.

Erythrovirus B19 (B19), a small isocahedral, non-enveloped virus (18-26 nm), is a ubiquitous infection agent in industrialised countries. Depending on the infected host, B19 has a wide range of disease manifestations from asymptomatic (the majority) to severe, including persistent infection. The risk of B19 transmission by blood products is enhanced by a high virus titre in the infected donor, by pooling of a large number of donations, and by the virus's resistance to effective inactivation methods such as heat and solvent-detergent treatments. B19-DNA has been detected in single donations, in manufacture plasma pools and in plasma derivatives (clotting factors, albumin, antithrombin III and immunoglobulins) produced by different processes. B19 transmission is mostly found in patients treated with clotting factors, as shown by a higher seroprevalence in treated haemophiliacs, by the presence of B19 DNA, and by active seroconversion. Chronic B19 infection can successfully be treated with polyvalent intravenous immunoglobulins. The key role of neutralising anti-B19 antibodies and of the virus titre has been demonstrated by B19 transmission after infusion of several B19-positive plasma batches treated with solvent-detergent. Two strategies can be followed to reduce the B19 risk: (1) reducing the viral load in the manufacture plasma pool by discarding B19-DNA-positive donations; (2) developing new strong virus inactivation methods. The physico-resistant properties of B19 make it a good model for new emergent viruses capable of infecting blood products.