Selective tumor localization of radiolabeled anti-human melanoma monoclonal antibody fragment demonstrated in the nude mouse model.

Monoclonal antibodies (Mab) directed against distinct epitopes of the human 240 kD melanoma-associated antigen have been evaluated for their capacity to localize in human melanoma grafted into nude mice. A favorable tumor to normal tissue ratio of 13 was obtained with intact 131I-labeled MAb Me1-14. This ratio was further increased to 43 and 23 by the use of F(ab')2 and Fab fragments, respectively. The specificity of tumor localization was demonstrated by the simultaneous injection of F(ab')2 fragments from MAb Me1-14 and anti-CEA MAb 35, each labeled with a different iodine isotope, into nude mice grafted with a melanoma and colon carcinoma. The fragments from both MAb localized with perfect selectivity in their relevant tumor as shown by differential whole body scanning and by direct measurement of the two isotopes in tumors and normal tissues. These in vivo experimental results suggest that the F(ab')2 fragment from MAb Me1-14 is suitable for melanoma detection by immunoscintigraphy in patients.

Iowa Aviation Plan, 2004-2024

The Iowa Department of Transportation (DOT), working closely with the Federal Aviation Administration (FAA), strives to ensure that Iowa’s system of public airports is positioned to meet the needs of businesses, residents, and visitors to our state. Airports must be accessible and positioned to safely meet different levels of aviation activity. In partnership with the FAA and various cities, counties, and airport authorities, the Iowa DOT helps to direct the systematic development of public airports. This report is a summary of a more comprehensive technical report that outlines a strategic plan for improving the performance of airports in Iowa over the next 20 years. More information on the technical report and on individual reports prepared for each of the public airports can be obtained from the Iowa DOT, Office of Aviation website at www.iawings.com. The Iowa Aviation System Plan provides the Iowa DOT with an important tool to monitor the ability of airports to meet customer needs. The plan also provides a means to measure the effects of investment on the performance of the Iowa Aviation System. Over the next 20 years, federal, state, local, and private funding will be needed to ensure that the aviation system meets goals established in this study. It is estimated that at least $821 million will be needed over the next 20 years if airports in Iowa are to respond to objectives set by the system plan. In future years, the plan will enable the Iowa DOT to measure system performance. By tracking key indicators for the airport system, it will be possible for the Iowa DOT and the FAA to formulate strategies for responding to Iowa’s air transportation needs. The Iowa Aviation System Plan provides a guide for the state and its communities to ensure that the vision established for the Iowa Aviation System can be achieved.

Iowa Aviation Plan, 2004-2024

The Iowa Department of Transportation (DOT), working closely with the Federal Aviation Administration (FAA), strives to ensure that Iowa’s system of public airports is positioned to meet the needs of businesses, residents, and visitors to our state. Airports must be accessible and positioned to safely meet different levels of aviation activity. In partnership with the FAA and various cities, counties, and airport authorities, the Iowa DOT helps to direct the systematic development of public airports. This report is a summary of a more comprehensive technical report that outlines a strategic plan for improving the performance of airports in Iowa over the next 20 years. More information on the technical report and on individual reports prepared for each of the public airports can be obtained from the Iowa DOT, Office of Aviation website at www.iawings.com. The Iowa Aviation System Plan provides the Iowa DOT with an important tool to monitor the ability of airports to meet customer needs. The plan also provides a means to measure the effects of investment on the performance of the Iowa Aviation System. Over the next 20 years, federal, state, local, and private funding will be needed to ensure that the aviation system meets goals established in this study. It is estimated that at least $821 million will be needed over the next 20 years if airports in Iowa are to respond to objectives set by the system plan. In future years, the plan will enable the Iowa DOT to measure system performance. By tracking key indicators for the airport system, it will be possible for the Iowa DOT and the FAA to formulate strategies for responding to Iowa’s air transportation needs. The Iowa Aviation System Plan provides a guide for the state and its communities to ensure that the vision established for the Iowa Aviation System can be achieved.

Iowa Aviation System Plan, 2004-2024

The Iowa Department of Transportation (DOT), working closely with the Federal Aviation Administration (FAA), strives to ensure that Iowa’s system of public airports is positioned to meet the needs of businesses, residents, and visitors to our state. Airports must be accessible and positioned to safely meet different levels of aviation activity. In partnership with the FAA and various cities, counties, and airport authorities, the Iowa DOT helps to direct the systematic development of public airports. This report is a summary of a more comprehensive technical report that outlines a strategic plan for improving the performance of airports in Iowa over the next 20 years. More information on the technical report and on individual reports prepared for each of the public airports can be obtained from the Iowa DOT, Office of Aviation website at www.iawings.com. The Iowa Aviation System Plan provides the Iowa DOT with an important tool to monitor the ability of airports to meet customer needs. The plan also provides a means to measure the effects of investment on the performance of the Iowa Aviation System. Over the next 20 years, federal, state, local, and private funding will be needed to ensure that the aviation system meets goals established in this study. It is estimated that at least $821 million will be needed over the next 20 years if airports in Iowa are to respond to objectives set by the system plan. In future years, the plan will enable the Iowa DOT to measure system performance. By tracking key indicators for the airport system, it will be possible for the Iowa DOT and the FAA to formulate strategies for responding to Iowa’s air transportation needs. The Iowa Aviation System Plan provides a guide for the state and its communities to ensure that the vision established for the Iowa Aviation System can be achieved.

Synthesis of chemically functionalized superparamagnetic nanoparticles as delivery vectors for chemotherapeutic drugs.

Superparamagnetic iron oxide nanoparticles (SPIONs) are in clinical use for disease detection by MRI. A major advancement would be to link therapeutic drugs to SPIONs in order to achieve targeted drug delivery combined with detection. In the present work, we studied the possibility of developing a versatile synthesis protocol to hierarchically construct drug-functionalized-SPIONs as potential anti-cancer agents. Our model biocompatible SPIONs consisted of an iron oxide core (9-10 nm diameter) coated with polyvinylalcohols (PVA/aminoPVA), which can be internalized by cancer cells, depending on the positive charges at their surface. To develop drug-functionalized-aminoPVA-SPIONs as vectors for drug delivery, we first designed and synthesized bifunctional linkers of varied length and chemical composition to which the anti-cancer drugs 5-fluorouridine or doxorubicin were attached as biologically labile esters or peptides, respectively. These functionalized linkers were in turn coupled to aminoPVA by amide linkages before preparing the drug-functionalized-SPIONs that were characterized and evaluated as anti-cancer agents using human melanoma cells in culture. The 5-fluorouridine-SPIONs with an optimized ester linker were taken up by cells and proved to be efficient anti-tumor agents. While the doxorubicin-SPIONs linked with a Gly-Phe-Leu-Gly tetrapeptide were cleaved by lysosomal enzymes, they exhibited poor uptake by human melanoma cells in culture.

Different behaviour of mouse-human chimeric antibody F(ab')2 fragments of IgG1, IgG2 and IgG4 sub-class in vivo.

Mouse-human chimeric monoclonal antibodies (MAbs) of 3 different human IgG sub-classes directed against carcinoembryonic antigen (CEA) have been produced in SP-0 cells transfected with genomic chimeric DNA. F(ab')2 fragments were obtained by pepsin digestion of the purified chimeric MAbs of human IgG1, IgG2 and IgG4 sub-class and of parental mouse MAb IgG1. The 4 F(ab')2 fragments exhibit similar molecular weight by SDS-PAGE. They were labelled with 125I or 131I and high binding (80 to 87%) to purified unsolubilized CEA was observed. In vivo, double labelling experiments indicate that the longest biological half-life and the highest tumour-localization capacity is obtained with F(ab')2 from chimeric MAb of human IgG2 sub-class, whereas F(ab')2 from chimeric MAb IgG4 give very low values for these 2 parameters. F(ab')2 from chimeric MAb IgG1 and from parental mouse MAb yield intermediate results in vivo. Our findings should help to select the appropriate human IgG sub-class to produce chimeric or reshaped MAb F(ab')2 to be used for tumour detection by immunoscintigraphy and for radioimmunotherapy.

Surveillance of adenoviruses and noroviruses in European recreational waters

Exposure to human pathogenic viruses in recreational waters has been shown to cause disease outbreaks. In the context of Article 14 of the revised European Bathing Waters Directive 2006/7/EC (rBWD, CEU, 2006) a Europe-wide surveillance study was carried out to determine the frequency of occurrence of two human enteric viruses in recreational waters. Adenoviruses were selected based on their near-universal shedding and environmental survival, and noroviruses (NoV) selected as being the most prevalent gastroenteritis agent worldwide. Concentration of marine and freshwater samples was done by adsorption/elution followed by molecular detection by (RT)-PCR. Out of 1410 samples, 553 (39.2%) were positive for one or more of the target viruses. Adenoviruses, detected in 36.4% of samples, were more prevalent than noroviruses (9.4%), with 3.5% GI and 6.2% GII, some samples being positive for both GI and GII. Of 513 human adenovirus-positive samples, 63 (12.3%) were also norovirus-positive, whereas 69 (7.7%) norovirus-positive samples were adenovirus-negative. More freshwater samples than marine water samples were virus-positive. Out of a small selection of samples tested for adenovirus infectivity, approximately one-quarter were positive. Sixty percent of 132 nested-PCR adenovirus-positive samples analysed by quantitative PCR gave a mean value of over 3000 genome copies per L of water. The simultaneous detection of infectious adenovirus and of adenovirus and NoV by (RT)PCR suggests that the presence of infectious viruses in recreational waters may constitute a public health risk upon exposure. These studies support the case for considering adenoviruses as an indicator of bathing water quality.

Unusual association of diseases/symptoms: Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome?

We report on a 70-year-old woman with partial complex status epilepticus who was initially diagnosed with herpes simplex-2 (HSV-2) encephalitis, based on brain magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) lymphocytic pleocytosis and HSV-2 DNA detection by polymerase chain reaction (PCR) in the CSF, but without improvement on intravenous acyclovir. Anti-Ri antibodies were positive and computed tomography (CT) investigations revealed a small cell carcinoma at biopsy suggesting paraneoplastic encephalitis. The outcome was unfavourable and the autopsy showed typical features of paraneoplastic encephalitis but no evidence of viral inclusions. This case report is interesting because: (1) it is the first report of an autopsy proven paraneoplastic widespread encephalitis with anti-Ri antibodies; (2) despite a positive HSV-2 PCR in the CSF, there was no sign of herpetic infections of the nervous system; and (3) it illustrates the fact that if paraneoplastic antibodies are usually good markers of the underlying tumour, they are not always predictive of neurological deficits.

The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial.

The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.

Field data and prediction models of pesticide spray drift on coffee crop

The objective of this work was to generate drift curves from pesticide applications on coffee plants and to compare them with two European drift-prediction models. The used methodology is based on the ISO 22866 standard. The experimental design was a randomized complete block with ten replicates in a 2x20 split-plot arrangement. The evaluated factors were: two types of nozzles (hollow cone with and without air induction) and 20 parallel distances to the crop line outside of the target area, spaced at 2.5 m. Blotting papers were used as a target and placed in each of the evaluated distances. The spray solution was composed of water+rhodamine B fluorescent tracer at a concentration of 100 mg L-1, for detection by fluorimetry. A spray volume of 400 L ha-1 was applied using a hydropneumatic sprayer. The air-induction nozzle reduces the drift up to 20 m from the treated area. The application with the hollow cone nozzle results in 6.68% maximum drift in the nearest collector of the treated area. The German and Dutch models overestimate the drift at distances closest to the crop, although the Dutch model more closely approximates the drift curves generated by both spray nozzles.

Recognition of insect eggs in Arabidopsis modulates defense responses

Plants activate direct and indirect defenses in response to insect egg deposition. In Arabidopsis thaliana, oviposition by the butterfly Pieris brassicae triggers cellular and molecular changes that are similar to the changes caused by biotrophic pathogens. Even though this innate immune response did not affect egg survival in Arabidopsis, we could show that different insect eggs elicit specific gene expression changes. Additionally, egg- induced necrosis could be observed in a variety of plants from different families ranging from dicotyledonous plants to monocots, suggesting that insect-egg detection by plants is a widespread mechanism and that different insect species contain elicitors of immune responses. Extracts from caterpillars and eggs contain elicitors that co-purified over several extraction steps. Chemical fractionation of caterpillar extracts lead to the characterisation of an active compound that was determined to be a triglyceride by NMR analysis. The exact structure of the side chains as well as the elicitor's presence in insect eggs have yet to be confirmed.We also found that the plant defense signal salicylic acid (SA) accumulates at the site of oviposition. This is unexpected, as the SA pathway controls the defense against fungal and bacterial pathogens whereas it negatively interacts with the jasmonic acid (JA) pathway, which is crucial for the defense against herbivores. Application of P. brassicae or Spodoptera littoralis egg extract onto leaves reduced the induction of insect-responsive genes after challenge with caterpillars, suggesting that egg-derived elicitors suppress plant defense. Consequently, larval growth of the generalist herbivore S. littoralis, but not of the specialist P. brassicae, was significantly higher on plants treated with egg extract than on control plants. In contrast, suppression of gene induction and enhanced S. littoralis performance were not found in the SA-deficient mutant sid2-l, indicating that SA mediates this phenomenon. These data reveal an intriguing facet of the crosstalk between SA- and JA-signalling pathways and suggest that insects have evolved a way to suppress the induction of defense genes by laying eggs that release elicitors. Additionally, we demonstrated that mutants of known crosstalk regulators, including nprl-1, tga2356, ein2-l and wrky70-l, are not affected in egg-induced suppression of herbivore defenses. JA treatment was not able to alleviate this SA/JA negative crosstalk, suggesting that this suppression operates through a novel mechanism downstream of JA biosynthesis.

IRF-3 partners Bax in a viral-induced dance macabre.

In this issue of The EMBO Journal, Chattopadhyay et al (2010) describe a surprising new mechanism for how viral dsRNA detection by the RIG-I/MAVS signalling complex can initiate apoptosis. Independent of its transcriptional function, a pool of interferon regulatory factor (IRF)-3 activated downstream of MAVS can bind to and activate cytosolic Bax, resulting in Bax translocation to the mitochondria and initiation of the intrinsic apoptotic pathway.

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients.

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.

Perception of acceleration in motion-in-depth with only monocular and both monocular and binocular information

Observers are often required to adjust actions with objects that change their speed. However, no evidence for a direct sense of acceleration has been found so far. Instead, observers seem to detect changes in velocity within a temporal window when confronted with motion in the frontal plane (2D motion). Furthermore, recent studies suggest that motion-in-depth is detected by tracking changes of position in depth. Therefore, in order to sense acceleration in depth a kind of second-order computation would have to be carried out by the visual system. In two experiments, we show that observers misperceive acceleration of head-on approaches at least within the ranges we used [600-800 ms] resulting in an overestimation of arrival time. Regardless of the viewing condition (only monocular or monocular and binocular), the response pattern conformed to a constant velocity strategy. However, when binocular information was available, overestimation was highly reduced.

Fetal programming and epigenetic mechanisms in arterial hypertension.

PURPOSE OF REVIEW: To provide an overview of available evidence of the potential role of epigenetics in the pathogenesis of hypertension and vascular dysfunction. RECENT FINDINGS: Arterial hypertension is a highly heritable condition. Surprisingly, however, genetic variants only explain a tiny fraction of the phenotypic variation and the term 'missing heritability' has been coined to describe this phenomenon. Recent evidence suggests that phenotypic alteration that is unrelated to changes in DNA sequence (thereby escaping detection by classic genetic methodology) offers a potential explanation. Here, we present some basic information on epigenetics and review recent work consistent with the hypothesis of epigenetically induced arterial hypertension. SUMMARY: New technologies that enable the rigorous assessment of epigenetic changes and their phenotypic consequences may provide the basis for explaining the missing heritability of arterial hypertension and offer new possibilities for treatment and/or prevention.