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Many malignant cells release the NKG2D ligand ULBP2 from their cell surface to evade immunosurveillance by NK cells and CD8 T cells. Although the shedding mechanism remains unclear, various inhibitors of matrix metalloproteinases have been shown to efficiently block the release of soluble ULBP2. The clinical use of these inhibitors, however, is limited because of adverse side effects. Using high-throughput screening technique, we identified a specific inhibitor of phosphatase of regenerating liver 3 (PRL-3) that could reduce the level of soluble ULBP2 in the culture supernatant of various cancer cell lines. Inhibition or gene knockdown of PRL-3 did not reduce ULBP2 shedding, but rather suppressed posttranslational maturation of ULBP2, resulting in intracellular retention of immature ULBP2. We then found that ULBP2 was constitutively associated with heat shock protein HSP60. Complete maturation of ULBP2 required tyrosine phosphorylation of HSP60 which was mediated by PRL-3.

Background Neoplasm-related precocious puberty (PP) is a rare presenting feature of childhood cancer. Moreover, evaluation of suspected PP in a child is complex, and cancer is often not considered. We characterized the clinicopathologic features of patients presenting with PP at a large pediatric cancer center, reviewed the relevant literature, and developed an algorithm for the diagnostic work-up of these patients.

Purpose: To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II. Methods: Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg). Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline. Results: Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P = 0.0049 for weekly and P = 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P = 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P = 0.065), and a 160 mL increase in absolute forced vital capacity (P = 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients during the study. Conclusion: This study supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis II.

This study was made to elucidate the transmission of nematode infections in outdoor pigs at different stocking rates during two consecutive seasons. Five pigs (Group 1A) inoculated with low doses of Oesophagostomum dentatum, Ascaris suum, and Trichuris suis and five helminth-naïve pigs (Group 1B) were turned out together in June 1996 on each of four pastures at stocking rates of 100, 240 (two pastures) and 576m(2) per pig, respectively. The pigs were slaughtered in early October, and pasture infectivity was subsequently measured using helminth-naïve tracer pigs (Tracer). In 1997, 10 helminth-naïve pigs were turned out on each pasture in May (Group 2) and again in August (Group 3), and allowed to graze for 12 weeks. The percentage of grass cover was reduced considerably at the high stocking rate in comparison to the other stocking rates. Transmission of all three helminths was observed on all pastures. In 1996, the O. dentatum faecal egg counts and worm burdens were significantly higher in pigs at the high stocking rate compared to pigs at the other stocking rates. O. dentatum did not survive the winter and pigs of Group 2 were inoculated with 3000 larvae each to reintroduce this parasite. Ascaris suum ELISA values and worm counts were highest at the high stocking rate in 1997 (Group 3). Transmission of T. suis was not significantly influenced by stocking rate. The results indicate that transmission of O. dentatum, and to some extent A. suum is influenced by stocking rate. However, both A. suum and T. suis eggs are still expected to constitute a high risk of infection on intensively used pastures where eggs may accumulate for years. The relationship between host density and helminth transmission seems more complex for grazing/rooting pigs than for grazing ruminants. This may be due to the differences in behaviour of the animals and the resulting differences in microclimate of the developing eggs/larvae.

The ability of retinal Muller glial cells to perform phagocytosis in vivo is studied in a rabbit model of experimental retinal detachment where pigment epithelial cells are occasionally detached together with the neural retina. While macrophages and/or microglial cells phagocytoze most of the cellular debris at the sclerad surface of the detached retinae, some Muller cells accumulate melanin granules. The granules are virtually intact at the ultrastructural level, and are surrounded by a membrane. They are often located close to the sclerad end of the cells, but some are distributed throughout the outer stem process up to the soma. It is concluded that rabbit Muller cells in vivo are capable of phagocytosis and of transporting the phagocytozed material within their cytoplasm.

In dem voran gegangenen Kapitel wurden die Entwicklungen in den TIME-Branchen und die daraus resultierenden Herausforderungen fur etablierte Branchenunternehmen dargestellt. Es wurde aufgezeigt, dass die bestehenden Produkte, Geschaftsmodelle und Geschaftsfelder in diesen Branchen revolutionaren Veranderungen ausgesetzt sind, die zu einer Storung des Wertschopfungskreislaufs und zu erfolgswirtschaftlichen Destabilisierungen der Branchenunternehmen fuhren konnen. Um diesen Herausforderungen zu begegnen, mussen etablierte Unternehmen Handlungsstrategien fur die Sicherung, den Aufbau und die Gestaltung ihrer Produkt-Markt-Aktivitaten entwickeln, um auch zukunftig Erfolg und Stabilitat zu gewahrleisten. Dies ist eine Aufgabe des Portfoliomanagement, dass in der Literatur als Instrument des strategischen Management fur die Bewertung und Planung bestehender und zukunftiger Produkt-Markt- Aktivitaten genannt wird.283

Die Restrukturierung der als TIME bezeichneten Branchen Telekommunikation, Informationstechnologie sowie Medien- und Entertainment ist ein von Praktikern und Wissenschaftlern viel diskutiertes Phanomen. Wissenschaftliche Arbeiten zur Untersuchung der Entwicklungen sowie Management-Literatur mit Empfehlungen zum Umgang mit dem Wandel wurden vor allem in der Grundungs-Phase der so genannten „New Economy“62 veroffentlicht.63 Mit dem Platzen der „Dot.com-Blase“64 nahmen auch die Untersuchungen dieser Branchenveranderungen ab, insbesondere Praktiker sahen die Entwicklungen als vernachlassigbar an.65

Die Branchen Telekommunikation, Informationstechnologie sowie Medien und Entertainment (kurz: TIME)1 haben sowohl weltweit als auch in Deutschland eine hohe wirtschaftliche Bedeutung. Im Jahr 2008 generierten die drei Branchen zusammengenommen einen Umsatz von rund 180 Mrd. €2 und beschaftigten ca. 1,3 Mio. Erwerbstatige in Deutschland.3 Ihre Bedeutung geht jedoch daruber hinaus. Die technologischen Weiterentwicklungen in Telekommunikation, Informationstechnologien und neuen Medien beeinflussen andere Wirtschaftszweige und pragen das Konsumentenverhalten nachhaltig. So hat der Ausbau breitbandiger Internetzugangstechnologien, die Durchdringung des Mobilfunks, die Verbreitung von Personal Computern sowie die Penetration des Internets in den letzten Jahrzehnten sowohl wirtschaftliche Prozesse und Arbeitswelten aber auch das private Umfeld und Konsumverhalten von Menschen nachhaltig verandert.4

Trotz der umfangreichen Literatur zum Thema Portfoliomanagement existieren nur wenige empirische Studien zur Anwendung des Portfoliomanagement als Instrument des strategischen Management in der Praxis und nahezu keine Studien speziell zum Portfoliomanagement in TIME-Unternehmen. Uber Desk Research oder Meta- Analysen konnen aus diesem Grund kaum Erkenntnisse zur Anwendung und Bedeutung des Portfoliomanagement in den TIME-Branchen gewonnen werden. Um dem in Kapitel 1 dargelegten Anspruch einer Forschung im Gegenstrom gerecht zu werden, ist es jedoch wesentlich, neben theoretischen Uberlegungen auch Erkenntnisse aus der Praxis zu generieren.527 Daher erfolgt die Untersuchung des Portfoliomanagement in TIME-Unternehmen mittels einer eigenen empirischen Studie. Die Ergebnisse dieser Studie bilden zusammen mit den Erkenntnissen aus den Kapiteln 2 und 3 die Basis fur die in Kapitel 5 zu entwickelnde Portfoliomanagement-Konzeption.

Im Verlauf dieses Kapitels erfolgt die Entwicklung einer Portfoliomanagement- Konzeption fur TIME-Unternehmen auf Basis der Erkenntnisse aus den vorangegangenen Betrachtungen. Hierbei werden sowohl die Strukturen und Veranderungen der TIME-Branchen, als auch die in der Theorie bestehenden Portfoliomanagement- Konzepte und die Anwendung des Portfoliomanagement in der Praxis von TIMEUnternehmen berucksichtigt. Die Arbeit auf den Erkenntnissen aus Theorie und Praxis aufzubauen, entspricht dem der vorliegenden Arbeit zugrunde liegenden Gedanken der Forschung im Gegenstrom.653 Zielsetzung dieses Vorgehen ist es, mit der Portfoliomanagement- Konzeption nicht nur ein theoretisches Konstrukt bereitzuste

Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. Conclusions: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

The comparison of a clinical Acinetobacter baumanii isolate (strain No. 4852/88) and its selected imipenem-resistant (IMR) clone exhibited a complex reorganization of the penicillin-binding proteins (PBPs) with diminished labelling of all PBPs except the 24-kD PBP which showed an increased binding of 14C-penicillin. This protein could not be saturated by preincubation of membranes with imipenem at 8-fold the MIC of imipenem, thus indicating PBP alterations responsible for imipenem resistance. In A. baumanii 4852/88 seven PBPs with the apparent molecular weights of 94, 84, 65, 61, 48, 40 and 24 kD could be detected. beta-Lactamase production was barely detectable in any case and could not be enhanced in the presence of various beta-lactams as the inducer. The outer membrane proteins were found identical in both the wild-type strain and the Im clone. So far, imipenem-resistant A. baumanii isolates have been isolated twice in our diagnostic laboratory; however, no implications on the future relevance of the above findings can be made.

Aim: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease. Methods: Safety and efficacy of ERT with agalsidase alfa, 0.2 mg/kg infused over 40 minutes every 2 weeks for 23 weeks, were studied in a multicentre open-label trial in nine boys and four girls. Median age at the start of the study was 11.0 years (range 3.5–18 years). Results: Fifty-four adverse events were reported in 11 patients. No serious adverse events related to ERT were reported. Twelve of the 54 adverse events were considered possibly or probably related to ERT. Infusion reactions (8 mild, 3 moderate) occurred in four boys, in seven infusions. One boy developed IgG antibodies, although he continued to make good clinical progress. At the end of the study, two of the four boys and the one girl on regular pain medication at baseline had stopped taking analgesics. Brief Pain Inventory (BPI) scores decreased in most patients by week 12 and were sustained until the end of the study. This change was greater in the boys, who had higher (worse) BPI scores at baseline. Pain-related quality of life (QoL) scores also decreased during the study. Plasma globotriaosylceramide concentrations and urinary globotriaosylceramide:sphingomyelin ratios decreased after 12 and 23 weeks of therapy, particularly in the boys. Increases in sweat volume were recorded in three out of five of the boys and in one of two girls tested after 23 weeks of treatment. Conclusion: ERT with agalsidase alfa in children with Fabry disease is well tolerated and, in the short term, appears to decrease pain and to improve pain-related QoL.

Fabry disease is an inherited lysosomal storage disease caused by deficiency of alpha-galactosidase A. Enzyme replacement therapy for this multisystem progressive disease has been available only since 2001. We here report the first known successful pregnancy of a female patient receiving such therapy.

Mejer H, Wendt S, Thomsen LE, Roepstorff A, Hindsbo O: Nose-rings and transmission of helminth parasites in outdoor pigs. Acta vet. scand. 2000, 41, 153–165. – Five growing pigs experimentally infected with low doses of Oesophagostomum dentation, Ascaris suum, and Trichuris suis were turned out with 5 helminth-naive pigs on each of 3 pastures in June 1996 (Group 1). On one pasture all pigs received nose-rings. After slaughter of Group 1 in October, pasture infectivity was monitored using helminth-naive, unringed tracer pigs. In 1997, helminth-naive young pigs were turned out on the contaminated pastures in May (Group 2) and again in August (Group 3). Again all pigs on one pasture received nose-rings. All pigs and pastures were followed parasitologically and reduction in grass cover was monitored. Based on the acquisition of infection by the naive pigs in Group 1, the estimated minimal embryonation times for eggs deposited on pasture were 23–25 days for O. dentatum, 5–6 weeks for A. suum and 9–10 weeks for T. suis. Results from tracer pigs and grass/soil samples indicated that pasture infectivity was light both years. Free-living stages of O. dentatum did not survive the winter. The nose-rings reduced rooting considerably, resulting in three-fold more grass cover on the nose-ring pasture compared to the control pastures by the end of the experiment. Nevertheless, the nose-rings did not significantly influence parasite transmission.

CORRIGENDUM: Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome

Abstract 3292 Previous studies have demonstrated that many T cell subsets possess NK-like features, including the CD56+ and KIR+ populations. Collectively, these studies showed that these NK-like T cells are predominantly αβ+ CD8+ with memory phenotype and could recognize HLA-E associated viral peptides after expansion upon TCR engagement. However, their clonality, transcriptome, regulation, specificity, and memory response in human have not been fully elucidated. We hypothesize that these NK-like T cells are phenotypically and functionally distinct from conventional T and NK cells and they play unique roles in virus and cancer control. Herein, we extensively characterized the CD56+ T cells and the KIR+ T subset by analysis of TREC, TCRVβ spectrum, telomere length, surface biomarkers, genome-wide transcriptome, multi-analyte cytokine profiling, cancer cell susceptibility, tetramer staining, and real-time response to CMV reactivation in stem cell transplant recipients. In contrast to CD56– T cells, CD56+ T cells are limited in TREC, TCRVβ, telomere length, cytokine secretion, transcription of metabolic genes stx6, nnt, galnt2, hvcn1, tyms, rpa1 tmf1, ecop, and tspan3, and are mostly KIR+, CD8+, DNAM1+, NKG2D+, CD44+, NKp46– and CD25–. Compared to KIR– CD56+ T cells, KIR+ CD56+ T cells are even more limited in TREC, TCRVβ, telomere length, and cytokine secretion, but have elevated transcription of NK cytotoxicity-related genes arrb1, ppp3cc, and lamc3, higher degranulation after activation by IL-2/IL-15 and CD3/CD28 antibodies, better killing of cancer cells after cytokine priming, and are mostly KIR2DL2/3+, NKG2D+, NKp46+, CD16+, NKG2C+, CD57+, and 2B4+. Importantly during CMV reactivation after stem cell transplantation, the percentage of KIR+ CD56+ T cells in the patient's blood increased dramatically and was significantly higher (p=0.0021) than in those without viral reactivation. Ex vivo, KIR+ CD56+ T cells demonstrate CMVpp65 tetramer staining, memory response to CMV peptides, and potent lysis of CMVpp65-pulsed target cells dependent on both KIR and TCR specificity. Furthermore, we identified for the first time that KIR– CD56+ T cells are Rorc+ IL-13-secretor. In conclusion, both CD56+ and KIR+ NK-like T-cell subsets are unique in biological and clinical properties and have distinct roles in cancer and infection control. Disclosures: No relevant conflicts of interest to declare.