Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice.

Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross-reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their F(ab')2 and Fab fragments was compared in nude mice bearing grafts of a serially transplanted, CEA-producing, human colon carcinoma. The distribution of radiolabeled MAb and their fragments after intravenous injection was analyzed by direct measurement of radioactivity in tumor and normal organs, as well as by whole-body scanning and by autoradiography of tumor sections. Paired labeling experiments, in which 131I-labeled antibody or fragments and 125I-labeled control IgG are injected simultaneously, were undertaken to determine the relative tumor uptakes of each labeled protein. The tumor antibody uptake divided by that of control IgG defines the specificity index of localization. Tumor antibody uptakes (as compared with the whole mouse), ranging between 7 and 15, and specificity indices ranging between 3.4 and 6.8, were obtained with the four intact MAb at day 4-5 after injection. With F(ab')2 fragments of the four MAb, at day 3, the tumor antibody uptakes ranged between 12 and 24 and the specificity indices between 5.3 and 8.2. With the Fab fragments prepared from the two most promising MAb, the antibody uptakes reached values of 34 and 82 at day 2-3 and the specificity indices were as high as 12 and 19. The scanning results paralleled those obtained by direct measurement of radioactivity. With intact MAb, tumor grafts of 0.5-1 g gave very contrasted positive scans 3 d after injection. Using MAb fragments, tumors of smaller size were detectable earlier. The best results were obtained with Fab fragments of MAb 35, which gave clear detections of tumors weighing only 0.1 g as early as 48 h after injection. Autoradiographs of tumor sections from mice injected with 125I-labeled MAb demonstrated that the radioactivity was localized in the tumor tissues and not in the stromal connective tissue of mouse origin. The highest radioactivity concentration was localized in areas known to contain CEA such as the pseudolumen of glands and the apical side of carcinoma cells. The penetration of radioactivity in the central part of tumor nodules and the pseudolumen appeared to be increased with the use of MAb fragments.

Discovery of an albite gneiss from the Ile de Groix (Armorican Massif, France): Geochemistry and LA-ICP-MS U-Pb geochronology of its Ordovician protolith

For the first time, an albite orthogneiss has been recognised and dated within the HP-LT blueschist facies metabasites and metapelites of the Ile de Groix. It is characterised by a peraluminous composition, high LILE, Th and U contents, MORB-like HREE abundances and moderate Nb and Y values. A U-Pb age of 480.8 +/- A 4.8 Ma was obtained by LA-ICP-MS dating of zircon and titanite. It is interpreted as the age of the magmatic emplacement during the Early Ordovician. Morphologically different zircon grains yield late Neoproterozoic ages of 546.6-647.4 Ma. Zircon and titanite U-Pb ages indicate that the felsic magmatism from the Ile de Groix is contemporaneous with the acid, pre-orogenic magmatism widely recognised in the internal zones of the Variscan belt, related to the Cambro-Ordovician continental rifting. The magmatic protolith probably inherited a specific chemical composition from a combination of orogenic, back-arc and anorogenic signatures because of partial melting of the Cadomian basement during magma emplacement. Besides, the late Devonian U-Pb age of 366 +/- A 33 Ma obtained for titanite from a blueschist facies metapelite corresponds to the age of the HP-LT peak metamorphism.

Low-grade metamorphism of the Gets nappe (Western Alps)

The Gets nappe, a decollement cover nappe located at the top of the Prealps, is characterized by the occurrence of ophiolitic rocks. The metamorphic grade in the Gets nappe was determined using illite crystallinity and clay mineral assemblages. Samples from the same locality were analyzed to estimate variations in illite crystallinity values and in the parageneses of clay minerals, both in sedimentary elements of a breccia and in the embedding shaly flysch. For samples from one and the same locality, the range in illite crystallinity data between breccia elements and the shaly flysch is comparable to the variation between different shaly beds. Two S-N transects along the Gets nappe reveal the same metamorphic gradient, with the internal parts of the nappe being characterized by middle anchizonal metamorphism and the external parts showing diagenetic conditions. The metamorphic grade is higher within the Gets nappe than in its hangingwall (i.e. the Breche and Simme nappes), suggesting that the metamorphism in the Gets unit is transported. The timing and conditions of thrusting of the Gets Nappe onto the Br che and the Simme nappes is constrained by stratigraphic and metamorphic data.

Effect of ganglion blockade with pentolinium on circulating neuropeptide Y levels in conscious rats.

The vasoconstrictor peptide, neuropeptide Y (NPY), is present in perivascular noradrenergic neurons of all mammals studied and may be important in the regulation of blood pressure. High plasma levels of NPY have been measured in the rat. To investigate partially the source and factors controlling the release of the circulating peptide, the effect of pentolinium tartrate administration has been studied in conscious rats. Pentolinium given as a bolus (5 mg/kg) followed by an infusion of a further 5 mg/kg/30 min produced a highly significant reduction in blood pressure of more than 40 mm Hg, when compared to either basal values or control animals treated with saline. Pentolinium treatment resulted in significantly lower plasma neuropeptide Y levels (31.0 +/- 6.7 fmol/ml) compared with those of control animals (78.6 +/- 8.2 fmol/ml). Circulating catecholamines were also significantly reduced in those animals receiving pentolinium. These results are compatible with circulating NPY arising from the sympathetic nervous system, with release being controlled by the mechanisms already established for catecholamines.

The History of the Establishment of the Division of Child Welfare of the Social Welfare Department of the State of Iowa, 1938

History of Child Welfare Legislation in the State of Iowa 1838-1898; Establishment of the Iowa State board of Control in 1898 and its influence on Child Welfare Legislation until 1925; Immediate background, organizing and the administration functions of the Child Welfare Division of the Social Welfare Department of the State of Iowa. NOTE: This document has pagination errors.

A methodology for the classification of convective structures using meteorological radar: Application to heavy rainfall events on the Mediterranean coast of the Iberian Peninsula

During the period 1996-2000, forty-three heavy rainfall events have been detected in the Internal Basins of Catalonia (Northeastern of Spain). Most of these events caused floods and serious damage. This high number leads to the need for a methodology to classify them, on the basis of their surface rainfall distribution, their internal organization and their physical features. The aim of this paper is to show a methodology to analyze systematically the convective structures responsible of those heavy rainfall events on the basis of the information supplied by the meteorological radar. The proposed methodology is as follows. Firstly, the rainfall intensity and the surface rainfall pattern are analyzed on the basis of the raingauge data. Secondly, the convective structures at the lowest level are identified and characterized by using a 2-D algorithm, and the convective cells are identified by using a 3-D procedure that looks for the reflectivity cores in every radar volume. Thirdly, the convective cells (3-D) are associated with the 2-D structures (convective rainfall areas). This methodology has been applied to the 43 heavy rainfall events using the meteorological radar located near Barcelona and the SAIH automatic raingauge network.

The costs of crossing paths and switching tasks between audition and vision.

Switching from one functional or cognitive operation to another is thought to rely on executive/control processes. The efficacy of these processes may depend on the extent of overlap between neural circuitry mediating the different tasks; more effective task preparation (and by extension smaller switch costs) is achieved when this overlap is small. We investigated the performance costs associated with switching tasks and/or switching sensory modalities. Participants discriminated either the identity or spatial location of objects that were presented either visually or acoustically. Switch costs between tasks were significantly smaller when the sensory modality of the task switched versus when it repeated. This was the case irrespective of whether the pre-trial cue informed participants only of the upcoming task, but not sensory modality (Experiment 1) or whether the pre-trial cue was informative about both the upcoming task and sensory modality (Experiment 2). In addition, in both experiments switch costs between the senses were positively correlated when the sensory modality of the task repeated across trials and not when it switched. The collective evidence supports the independence of control processes mediating task switching and modality switching and also the hypothesis that switch costs reflect competitive interference between neural circuits.

Localization and characterization of an active fault in an urbanized area in central Guatemala by means of geoelectrical imaging

The Polochic and Motagua faults define the active plate boundary between the North American and Caribbean plates in central Guatemala. A splay of the Polochic Fault traverses the rapidly growing city of San Miguel Uspantan that is periodically affected by destructive earthquakes. This fault splay was located using a 2D electrical resistivity tomography (ERT) survey that also characterized the fault damage zone and evaluated the thickness and nature of recent deposits upon which most of the city is built. ERT images show the fault as a similar to 50 m wide, near-vertical low-resistivity anomaly, bounded within a few meters by high resistivity anomalies. Forward modeling reproduces the key aspects of the observed electrical resistivity data with remarkable fidelity thus defining the overall location, geometry, and internal structure of the fault zone as well as the affected lithologies. Our results indicate that the city is constructed on a similar to 20 m thick surficial layer consisting of poorly consolidated, highly porous, water-logged pumice. This soft layer is likely to amplify seismic waves and to liquefy upon moderate to strong ground shaking. The electrical conductivity as well as the major element chemistry of the groundwater provides evidence to suggest that the local aquifer might, at least in part, be fed by water rising along the fault. Therefore, the potential threat posed by this fault splay may not be limited to its seismic activity per se, but could be compounded its potential propensity to enhance seismic site effects by injecting water into the soft surficial sediments. The results of this study provide the basis for a rigorous analysis of seismic hazard and sustainable development of San Miguel Uspantan and illustrate the potential of ERT surveying for paleoseismic studies.

Protective effect of divalent cations against aluminum toxicity in soybean

A large proportion of soybean fields in Brazil are currently cultivated in the Cerrado region, where the area planted with this crop is growing considerably every year. Soybean cultivation in acid soils is also increasing worldwide. Since the levels of toxic aluminum (Al) in these acid soils is usually high it is important to understand how cations can reduce Al rhizotoxicity in soybean. In the present study we evaluated the ameliorative effect of nine divalent cations (Ca, Mg, Mn, Sr, Sn, Cu, Zn, Co and Ba) in solution culture on Al rhizotoxicity in soybean. The growth benefit of Ca and Mg to plants in an acid Inceptisol was also evaluated. In this experiment soil exchangeable Ca:Mg ratios were adjusted to reach 10 and 60 % base saturation, controlled by different amounts of CaCl2 or MgCl2 (at proportions from 100:0 up to 0:100), without altering the soil pH level. The low (10 %) and adequate (60 %) base saturation were used to examine how plant roots respond to Al at distinct (Ca + Mg)/Al ratios, as if they were growing in soils with distinct acidity levels. Negative and positive control treatments consisted of absence (under native soil or undisturbed conditions) or presence of lime (CaCO3) to reach 10 and 60 % base saturation, respectively. It was observed that in the absence of Aluminum, Cu, Zn, Co and Sn were toxic even at a low concentration (25 µmol L-1), while the effect of Mn, Ba, Sr and Mg was positive or absent on soybean root elongation when used in concentrations up to 100 µmol L-1. At a level of 10 µmol L-1 Al, root growth was only reverted to the level of control plants by the Mg treatment. Higher Tin doses led to a small alleviation of Al rhizotoxicity, while the other cations reduced root growth or had no effect. This is an indication that the Mg effect is ion-specific and not associated to an electrostatic protection mechanism only, since all ions were divalent and used at low concentrations. An increased exchangeable Ca:Mg ratio (at constant soil pH) in the acid soil almost doubled the soybean shoot and root dry matter even though treatments did not modify soil pH and exchangeable Al3+. This indicates a more efficient alleviation of Al toxicity by Mg2+ than by Ca2+. The reason for the positive response to Mg2+ was not the supply of a deficient nutrient because CaCO3 increased soybean growth by increasing soil pH without inducing Mg2+ deficiency. Both in hydroponics and acid soil, the reduction in Al toxicity was accompanied by a lower Al accumulation in plant tissue, suggesting a competitive cation absorption and/or exclusion of Al from plant tissue stimulated by an Mg-induced physiological mechanism.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Covalent homodimers of murine secretory component induced by epitope substitution unravel the capacity of the polymeric Ig receptor to dimerize noncovalently in the absence of IgA ligand.

Recombinant secretory immunoglobulin A containing a bacterial epitope in domain I of the secretory component (SC) moiety can serve as a mucosal delivery vehicle triggering both mucosal and systemic responses (Corthésy, B., Kaufmann, M., Phalipon, A., Peitsch, M., Neutra, M. R., and Kraehenbuhl, J.-P. (1996) J. Biol. Chem. 271, 33670-33677). To load recombinant secretory IgA with multiple B and T epitopes and extend its biological functions, we selected, based on molecular modeling, five surface-exposed sites in domains II and III of murine SC. Loops predicted to be exposed at the surface of SC domains were replaced with the DYKDDDDK octapeptide (FLAG). Another two mutants were obtained with the FLAG inserted in between domains II and III or at the carboxyl terminus of SC. As shown by mass spectrometry, internal substitution of the FLAG into four of the mutants induced the formation of disulfide-linked homodimers. Three of the dimers and two of the monomers from SC mutants could be affinity-purified using an antibody to the FLAG, mapping them as candidates for insertion. FLAG-induced dimerization also occurred with the polymeric immunoglobulin receptor (pIgR) and might reflect the so-far nondemonstrated capacity of the receptor to oligomerize. By co-expressing in COS-7 cells and epithelial Caco-2 cells two pIgR constructs tagged at the carboxyl terminus with hexahistidine or FLAG, we provide the strongest evidence reported to date that the pIgR dimerizes noncovalently in the plasma membrane in the absence of polymeric IgA ligand. The implication of this finding is discussed in terms of IgA transport and specific antibody response at mucosal surfaces.

Do PES Improve the Governance of Forest Restoration?

Payments for Environmental Services (PES) are praised as innovative policy instruments and they influence the governance of forest restoration efforts in two major ways. The first is the establishment of multi-stakeholder agencies as intermediary bodies between funders and planters to manage the funds and to distribute incentives to planters. The second implication is that specific contracts assign objectives to land users in the form of conditions for payments that are believed to increase the chances for sustained impacts on the ground. These implications are important in the assessment of the potential of PES to operate as new and effective funding schemes for forest restoration. They are analyzed by looking at two prominent payments for watershed service programs in Indonesia-Cidanau (Banten province in Java) and West Lombok (Eastern Indonesia)-with combined economic and political science approaches. We derive lessons for the governance of funding efforts (e.g., multi-stakeholder agencies are not a guarantee of success; mixed results are obtained from a reliance on mandatory funding with ad hoc regulations, as opposed to voluntary contributions by the service beneficiary) and for the governance of financial expenditure (e.g., absolute need for evaluation procedures for the internal governance of farmer groups). Furthermore, we observe that these governance features provide no guarantee that restoration plots with the highest relevance for ecosystem services are targeted by the PES

The Island of Drive. Representations, somatic states and the origin of drive

Freud defined the drive as "a concept on the frontier between the mental and the somatic". Today this view that was based on clinical observations interpreted within the psychoanalytical framework, can be revisited in light of the current neuroscientific notions of neuronal plasticity and somatic states. Indeed, through the mechanisms of plasticity experience leaves a trace that forms the neural basis of a representation of the experience. Such a representation R is associated with a somatic state S in the sense taken from the "somatic marker" model of Damasio. Thus, the internal reality of the subject, particularly the unconscious one, is constituted by such connected R's and S's. In the model that we discuss, the posterior insula represents the primary interoceptive cortex where information about somatic states S converges, while in the anterior insula the connection between R and S can take place and establish a neurobiological correlate for the notion of drive. We posit that the re-representations of S associated with R in the anterior insula may correspond to the Vorstellungsrepräsentanz postulated by Freud. We further propose that the tension between R and S established in the anterior insula is discharged according to the notion of drive through the motor arm of the limbic system, namely the anterior cingulate cortex which is heavily connected with the anterior insula.