Unveiling the cognitive network organization through cognitive performance.

The evaluation of cognitive functions interactions has become increasingly implemented in the cognition exploration. In the present study, we propose to examine the organization of the cognitive network in healthy participants through the analysis of behavioral performances in several cognitive domains. Specifically, we aim to explore cognitive interactions profiles, in terms of cognitive network, and as a function of participants' handedness. To this end, we proposed several behavioral tasks evaluating language, memory, executive functions, and social cognition performances in 175 young healthy right-handed and left-handed participants and we analyzed cognitive scores, from a network perspective, using graph theory. Our results highlight the existence of intricate interactions between cognitive functions both within and beyond the same cognitive domain. Language functions are interrelated with executive functions and memory in healthy cognitive functioning and assume a central role in the cognitive network. Interestingly, for similar high performance, our findings unveiled differential organizations within the cognitive network between right-handed and left-handed participants, with variations observed both at a global and nodal level. This original integrative network approach to the study of cognition provides new insights into cognitive interactions and modulations. It allows a more global understanding and consideration of cognitive functioning, from which complex behaviors emerge.

Frequency doubling and parametric fluorescence in a four-port aluminum gallium arsenide photonic chip.

In this Letter, we report on the fabrication and characterization of a monolithic III-V semiconductor photonic chip, designed to perform nonlinear parametric optical processes for frequency conversion and non-classical state generation. This chip co-integrates an AlGaAs microdisk that is evanescently coupled to two distinct suspended waveguides designed for light injection and collection around 1600 nm and 800 nm, respectively. Quasi-phase matching provided by the resonator geometry and material symmetry, resonant field enhancement, and confinement ensure efficient nonlinear interactions. We demonstrate second-harmonic generation efficiency of 5%W-1 and a biphoton generation rate of 1.2 kHz/µW through spontaneous down-conversion.

Continuous-Variable Triple-Photon States Quantum Entanglement.

We investigate the quantum entanglement of the three modes associated with the three-photon states obtained by triple-photon generation in a phase-matched third-order nonlinear optical interaction. Although the second-order processes have been extensively dealt with, there is no direct analogy between the second and third-order mechanisms. We show, for example, the absence of quantum entanglement between the quadratures of the three modes in the case of spontaneous parametric triple-photon generation. However, we show robust, seeding-dependent, genuine triple-photon entanglement in the fully seeded case.

Novel endoscopic application of a new flexible-fiber CO2 laser for esophageal mucosal ablation in a porcine model.

BACKGROUND AND STUDY AIMS: The CO (2) laser is a surgical tool that is widely used because of its predictable penetration depth and minimal collateral damage due to efficient absorption of CO (2) laser energy by tissue water. Until recently, endoscopic use was limited by lack of an efficient, flexible delivery system. The aim of the current study was to evaluate the performance, efficacy, and safety of a novel, photonic band-gap CO (2) laser configured for esophageal mucosal ablation. MATERIALS AND METHODS: This was an endoscopic experimental study in a porcine survival model. Initial evaluation was done on ex vivo tissue followed by endoscopic studies at 7-, 10-, 15-, and 20-W power and at 0-, 1-, 2-, 5-, and 10-mm distances, using continuous and pulsed currents, to determine optimal performance settings. In an IACUC-approved protocol, six pigs underwent circumferential ablation of the distal 6 cm of the esophagus at 10W continuous current. The animals were monitored for 2 or 4 weeks to evaluate delayed effects. Prior to euthanasia, the proximal esophagus was ablated to evaluate the homogeneity of ablation and depth of injury immediately after single and repeat ablation. RESULTS: The animals resumed normal diets within 24 hours and experienced no dysphagia or weight loss. Pathology at 2 and 4 weeks revealed complete re-epithelialization with minimal histologic injury. A single application of the laser produced complete transepithelial ablation of a mean of 83.3 % of the surface area (range 55 % - 100 %); depth of injury was to the muscularis mucosa in five pigs and to the superficial submucosa in one pig. With ablation, sloughing, and re-ablation, a mean of 95 % transepithelial ablation was achieved (range 80 % -100 %) with similar depth of injury. CONCLUSIONS: Using a novel, flexible CO (2) laser, homogeneous ablation was achieved with predictable penetration and minimal deep tissue injury. These results warrant further evaluation of the laser in Barrett's esophagus, as it may overcome the limitations of current technologies including perforation, stricture, and inhomogeneity.

Fetal and neonatal thrombopoietin levels in alloimmune thrombocytopenia.

Thrombopoietin (Tpo) is the main hematopoietic growth factor for platelet production. Plasma Tpo levels in autoimmune thrombocytopenic patients are normal or slightly elevated. Although thrombocytopenia exists, Tpo levels are not increased because the produced megakaryocytes and platelets can bind circulating Tpo, thereby normalizing Tpo levels. In this study, plasma samples from fetuses and neonates with neonatal alloimmune thrombocytopenia (NAIT), a different form of immune thrombocytopenia, were measured. Umbilical cord samples from 50 fetuses before treatment because of severe thrombocytopenia and 51 fetuses after treatment, and peripheral blood samples of 21 untreated newborns with NAIT were analyzed. As controls, plasma Tpo levels were determined in 21 umbilical cord samples of 14 nonthrombocytopenic fetuses with hemolytic disease resulting from red blood cell alloimmunization and in umbilical cord samples of 51 healthy newborns. The values were also compared with the plasma Tpo levels in 193 healthy adults. Mean Tpo levels from the groups of fetuses and neonates, including both NAIT and control plasma, were slightly but significantly elevated compared with levels in healthy adults. Tpo levels in NAIT samples were not significantly different from the levels in hemolytic disease samples or in samples from healthy newborns. Thus, as in autoimmune thrombocytopenic patients, normal Tpo levels are present in NAIT patients.

[From gene to disease; from a thrombopoietin receptor gene defect to congenital amegakaryocytic thrombocytopenia]. / Van gen naar ziekte; van een trombopoëtinereceptorgendefect naar congenitale amegakaryocytaire trombocytopenie.

Congenital amegakaryocytic thrombocytopenia (CAMT) is an uncommon cause of thrombocytopenia in children. CAMT is characterised by an isolated thrombocytopenia and the near absence of megakaryocytes in the bone marrow. The gene involved in the development of CAMT has recently been described. In a number of CAMT patients, mutations in the thrombopoietin (Tpo) receptor gene, c-mpl, were found to be the likely cause of the thrombocytopenia and the complete bone marrow failure that most patients develop. Measurement of Tpo plasma levels and a study of the megakaryocytopoiesis in vitro, may add to the diagnosis. At present the only curative treatment is allogeneic bone marrow transplantation.

The potential role of thrombopoietin in idiopathic thrombocytopenic purpura.

Thrombopoietin (TPO) plays a central role in the pathogenesis of idiopathic thrombocytopenic purpura (ITP), as it does in other immune-mediated thrombocytopenias. Because TPO is bound and internalized by platelets, it is destroyed together with platelets at an accelerated rate in the macrophage system. Because the spleen acts as a TPO sink, compensation of the decreased platelet count by an increased production in the bone marrow is insufficient. This aspect of ITP, as well as the use of TPO in the treatment of ITP, will be the focus of this article.

The role of thrombopoietin in post-operative thrombocytosis.

Thrombopoietin (Tpo), the main regulator of thrombocytopoiesis, is a probable candidate to play a role in the increase in platelet counts that is frequently seen after surgery. In the current study, serial blood samples of patients that underwent major surgery were analysed with respect to Tpo kinetics, platelet turnover and inflammatory cytokines. Platelet Tpo content and plasma Tpo levels rose before platelet counts increased, suggesting that Tpo was indeed responsible for the elevation in platelet counts. In addition, an increase in interleukin 6 (IL-6) levels, but not in IL-11 and tumour necrosis factor alpha levels, was seen before the rise in Tpo concentration. In vitro, IL-6 was shown to enhance Tpo production by the HepG2 liver cell line. Thus, increased Tpo levels after surgery, possibly resulting from enhanced Tpo production under the influence of IL-6 or other inflammatory cytokines, are involved in an enhanced thrombocytopoiesis.

In multiple myeloma increased thrombopoietin (Tpo) production may be involved in the maintenance of platelet production.

In multiple myeloma (MM), suppression of haematopoiesis occurs as a result of expansion of malignant cells in the bone marrow. Thrombopoietin (Tpo) levels in patients with impaired platelet production are generally found to be highly elevated. To examine the circulating Tpo levels in patients with MM, Tpo levels were measured in 50 serum samples from 34 patients. Tpo levels were subsequently related to disease stage, and cell numbers and markers, i.e. platelet count, leukocyte count and haemoglobin (Hb) concentration. Elevated Tpo levels were found in association with decreased platelet counts (n=8), but also in patients with normal platelet counts (n=14). The latter group included patients without and with signs of impaired haematopoiesis, i.e. with decreased Hb concentration and decreased leukocyte count. These results show that neither platelet counts nor Tpo levels are reliable parameters to judge bone-marrow failure in patients with MM. Furthermore, in patients with MM, increased Tpo levels may play a role in the maintenance of thrombocytopoiesis. The origin of the increased Tpo levels remains to be determined.

[Diagnostics for classification of anemia]. / De diagnostiek van anemie.

Examining peripheral blood smears provides valuable information in the diagnosis of anaemia despite large inter- and intraobserver variation. The classification of anaemia is usually based on the average erythrocyte size, referred to as the mean corpuscular volume (MCV). Microcytosis indicates a reduced haemoglobin synthesis caused by either an iron deficiency or haemoglobinopathy, a congenital disorder. Macrocytosis is the result of a disruption to the division and maturing of proerythroblasts in the bone marrow, due, for example, to vitamin B12 (folic acid) deficiency or excessive alcohol use. Furthermore, a high number of reticulocytes in the blood indicates an increased production of erythrocytes whereas a low total indicates an inadequate production level. In addition to the case history and the physical examination, the MCV and number of reticulocytes can provide guidance with respect to further diagnostic investigation.

Analysis of the kinetics of TPO uptake during platelet transfusion.

BACKGROUND: It has been shown in several studies that platelets play a role in the removal of TPO from the circulation. For instance, in vitro studies have shown that platelets can bind and internalize TPO, and transfusion studies have shown that the concentration of circulating TPO decreased after platelet transfusion. In the current study, the in vivo kinetics of plasma TPO levels and TPO uptake by transfused platelets is analyzed in more detail. STUDY DESIGN AND METHODS: Serial blood samples from patients who received a platelet transfusion were analyzed with respect to platelet count, plasma TPO concentration, and TPO content per platelet. In addition, the capacity of transfused platelets to bind TPO in vitro was assessed. RESULTS: Platelet counts increased immediately after transfusion, but subsequently started to decrease. Conversely, TPO levels decreased significantly but then returned to baseline level by 44 hours after transfusion. Platelet count and plasma TPO concentration were inversely correlated (r(p) = -0.9; p<0.05). The decrease in TPO concentration upon transfusion was accompanied by a significant increase in the platelet-associated TPO concentration. After transfusion, platelets isolated from the patient still displayed functional TPO receptors, as indicated by their intact capacity to bind TPO in vitro. CONCLUSION: The decrease in plasma TPO followed by the increase in platelet TPO provides evidence that platelets are responsible for the clearance of TPO in circulation. In vivo, platelets can bind and may degrade TPO upon platelet transfusion.

Effect of locally applied GM-CSF on oral mucositis after stem cell transplantation: a prospective placebo-controlled double-blind study.

Oral mucositis is a frequent side effect of myeloablative chemo- and radiotherapy preceding stem cell transplantation. It causes pain, poor food intake, and is a port of entry for infection. We studied whether GM-CSF applied topically in the oral cavity can prevent or ameliorate this mucositis. In 36 consecutive patients undergoing a stem cell transplantation, we performed a double-blind placebo-controlled study of 300 micrograms GM-CSF in a 2% methylcellulose gel daily versus a 2% methylcellulose gel alone. Both were locally applied in the oral cavity. The primary end-point was mucositis as measured by the WHO toxicity scale for mucositis, oral assessment scale, and a subjective pain scale, all scored daily. The secondary end-points were need to give parenteral nutrition and morphine, incidence of fever and infections, and duration of neutropenia and hospitalization. No differences were found in the median subjective pain scores, WHO scores, and oral assessment scores between the placebo and the GM-CSF groups. In both groups, nine patients required morphine for pain control. Ten patients in the placebo group and 11 in the GM-CSF group received parenteral nutrition. Documented infections, use of broad-spectrum antibiotics, and number of days with fever were similar in the placebo and the GM-CSF groups. The duration of neutropenia below 0.5 x 10(9)/l (median 14.5 days in the placebo group versus 17 days in the GM-CSF group) and the duration of hospitalization (28.5 versus 29 days) was also not significantly different. We found no beneficial effect of 300 micrograms GM-CSF dissolved in a 2% methylcellulose gel applied locally for chemo- and radiotherapy-induced mucositis in patients undergoing a stem cell transplantation.

Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy.

Antigen receptor gene rearrangements are applied for the PCR-based minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL). It is known that ongoing rearrangements result in subclone formation, and that the relapsing subclone(s) can contain antigen receptor rearrangement(s) that differ from the rearrangements found in the major clone(s) at diagnosis. However, the mechanism leading to this so-called clonal evolution is not known, particularly at which time point in the disease the relapsing subclone obtains its (relative) therapy resistance. To obtain insight in clonal evolution, we followed the kinetics of several subclones in three oligoclonal ALL patients during induction therapy. Clone-specific nested PCR for immunoglobulin heavy chain or T cell receptor delta gene rearrangements were performed in limiting dilution assays on bone marrow samples taken at diagnosis, at the end of induction therapy and at possible relapse in three children with oligoclonal B-precursor ALL. We demonstrated that in all three patients the subclones were behaving differently in response to therapy. Moreover, in the two patients who relapsed, the clones that grew out during relapse showed the slowest regression or even evoluated during induction therapy and the clones that were not present at relapse showed good response to induction therapy. These results support the hypothesis that at least in some patients already at diagnosis or in the very first weeks, subclones have important differences in respect to resistance. Hence, these data give experimental evidence for the need to develop, during the first months after diagnosis, quantitative PCR assays for at least two different Ig/TCR gene rearrangement targets for every ALL patient.

Influence of medium components on ex vivo megakaryocyte expansion.

Reinfusion of ex vivo-expanded autologous megakaryocytes together with a stem cell transplantation may be useful to prevent or reduce the period of chemotherapy-induced thrombocytopenia. In this study, we analyzed several serum-containing and serum-free media to identify the most suitable medium for megakaryocyte expansion. Moreover, two thrombopoietin (Tpo)-mimetic peptides were tested to evaluate whether they could replace Tpo in an expansion protocol. To analyze the effects of different media on megakaryocyte expansion, we used an in vitro liquid culture system. For this purpose, CD34(+) cells were isolated from peripheral blood and cultured for 8 days in the presence of Tpo and interleukin-3 (IL-3). The presence of megakaryocytes was analyzed by flow cytometric analysis after staining for CD41 expression. For our standard culture procedure, megakaryocyte medium (MK medium) supplemented with 10% AB plasma was used. Addition of 5% or 2.5% AB plasma yielded higher numbers of megakaryocytes, implying the presence of inhibitory factors in plasma. However, some plasma components are required for optimal megakaryocyte expansion because addition of less than 1% AB plasma or addition of human serum albumin instead of AB plasma resulted in the formation of lower numbers of megakaryocytes. Two commercially available serum-free media were also tested: Cellgro and Stemspan. If CD34(+) cells were cultured in Cellgro medium similar numbers of megakaryocytes were obtained as when CD34(+) cells were cultured in MK medium supplemented with 10% AB plasma. In MK medium with 2.5% AB plasma, higher numbers of megakaryocytes were cultured than in MK medium supplemented with 10% AB plasma. Therefore, Cellgro medium is not the best alternative medium. In cultures with Stemspan medium, higher numbers of megakaryocytes were obtained compared to MK medium with 10% AB plasma. Stemspan is thus a good alternative for MK medium. Two Tpo-mimetic peptides, AF13948 and PK1M, were tested for their ability to replace Tpo. In cultures with AF13948, comparable numbers of megakaryocytes were obtained as in the presence of Tpo, but in cultures with PK1M the number of megakaryocytes was lower. This study shows that high concentrations of plasma in medium inhibits megakaryocyte formation, but some plasma components are required for optimal megakaryocyte expansion. For an ex vivo expansion protocol, it is worthwhile to test several media, because the number of megakaryocytes differs widely with the medium used.

High levels of reticulated platelets and thrombopoietin characterize fetal thrombopoiesis.

To characterize fetal thrombopoiesis, we determined plasma thrombopoietin (TPO) and glycocalicin levels, platelet counts and reticulated platelets (RP) of fetuses and compared them with the respective values of their mothers. Percutaneous umbilical vein sampling in abnormal pregnancies revealed twofold higher thrombopoietin levels and 20-fold higher reticulated platelet counts, but lower levels of glycocalicin in fetuses compared with their mothers (P < 0.05). Neither the expression of platelet glycoprotein Ib and IIb on platelets nor the platelet counts were different between mothers and their fetuses. These data indicate enhanced thrombopoiesis and/or increased platelet turnover in fetuses.

Effects of anticoagulation on thrombopoietin release during endotoxemia.

Several lines of evidence suggest that coagulation may induce the release of thrombopoietin (TPO) into plasma and that TPO levels are higher in disseminated intravascular coagulation. Therefore we set out to illuminate the mechanism of TPO release in the setting of experimental endotoxemia, which induces activation of coagulation and platelets. Endotoxin (lipopolysachharide [LPS], 2 ng/kg) was infused into a total of 54 healthy men in two subsequent studies. Volunteers received infusions of unfractionated heparin, low-molecular-weight heparin, lepirudin, or placebo in a randomized, placebo-controlled fashion after bolus injection of LPS. TPO levels increased on average by 27% to 38% in all groups at 6 hours (P <.05 vs baseline), although all active drugs effectively blocked coagulation. Platelet counts dropped by about 15% at 1 hour after LPS infusion, recovered after 2 days, and exceeded baseline values by 8% to 18% after 7 days (P <.001 vs baseline for all groups). Yet lepirudin blunted the LPS-induced increase in circulating P-selectin by one half (P <.005 vs placebo), whereas both heparins did not diminish the increase in this platelet or endothelial activation marker as compared with placebo. Endotoxemia enhances TPO plasma levels independent of the degree of coagulation induction, which eventually results in increased platelet numbers. Of potential clinical interest is the observation that the direct thrombin inhibitor lepirudin, in contrast to heparins, mitigated LPS-induced platelet activation.

E-selectin and very late activation antigen-4 mediate adhesion of hematopoietic progenitor cells to bone marrow endothelium.

Adhesion of CD34+ hematopoietic progenitor cells (HPCs) to sinusoidal endothelium probably plays a key role in homing of transplanted CD34+ HPCs to the bone marrow (BM). We have investigated the role of various adhesion molecules in the interaction of purified CD34+ HPCs derived from BM or peripheral blood (PB) and a human BM-derived endothelial cell line. Adhesion of CD34+ HPCs to endothelial cells was measured with the use of a double-color flow microfluorimetric adhesion assay. In this assay, adhesion is measured under stirring conditions, simulating blood flow in sinusoidal marrow vessels. Adhesion of PB CD34+ cells to human BM endothelial cells (HBMECs) was observed only after interleukin (IL)-1beta prestimulation of the endothelial cells. This adhesion was strongly increased after addition of phorbol-myristate acetate (PMA). Adhesion of PB CD34+ cells to IL-1beta-prestimulated HBMECs was inhibited by blocking monoclonal antibodies (mAbs) against E-selectin and by neuraminidase treatment of the PB CD34+ cells. mAbs against very late activation antigen (VLA)-4 inhibited adhesion only when the E-selectin-mediated interaction was prevented. No clear inhibiting effect was found with blocking mAbs against beta2-integrins. Stimulation with the beta1-integrin-activating mAb, 8A2, induced adhesion of CD34+ cells to endothelial cells. In conclusion, stimulation of both endothelial cells and CD34+ HPCs is necessary for adhesion of CD34+ HPCs to endothelial cells. We furthermore demonstrated that E-selectin and VLA-4 mediated this adhesion.