Aganirsen Antisense Oligonucleotide Eye Drops Inhibit Keratitis-Induced Corneal Neovascularization and Reduce Need for Transplantation: The I-CAN Study.

OBJECTIVE: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. MAIN OUTCOME MEASURES: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. RESULTS: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. CONCLUSIONS: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

Risky single occasion drinking frequency and alcohol-related consequences: can abstinence during early adulthood lead to alcohol problems?

QUESTIONS UNDER STUDY: the main purpose of this longitudinal study was to determine the impact of risky single occasion drinking (RSOD) frequency on alcohol dependence and drinking consequences reported 15 months later. METHODS: As a baseline sample, 5,990 young men were assessed on their drinking habits including the frequency of RSOD. Of them, 5,196 were reassessed at follow-up 15 months later on RSOD frequency, alcohol dependence and alcohol related consequences in thze interceding year. Drop out biases were investigated. RESULTS: Around 45% of the baseline participants reported regular RSOD (every month or more frequently). Despite the fact that RSOD distribution was generally stable during the initial sample, 47.4% reported a variation of their RSOD frequency 15 months later. Around 25% of the sample reported reduced RSOD frequency. Nonetheless, occasional RS drinkers were more likely to become regular (monthly) RSO drinkers at follow up. Daily and weekly RSOD were associated with high proportions of alcohol dependence and detrimental consequences of drinking. Surprisingly, abstainers at baseline were more likely to be at risk of alcohol dependence and consequences at follow up than non-RSO drinkers. CONCLUSIONS: Despite the fact that alcohol abstinence is logically the best way to avoid the detrimental consequences of alcohol drinking, abstainers at baseline reported as many problems due to alcohol use at follow up as occasional or monthly RSO drinkers. The few participants who had become RSO drinkers during the follow up period were indeed likely to engage in detrimental behaviour. Non-RSO drinkers had the fewest problems due to alcohol use. This substantiates the early occurrence of drinking consequences among inexperienced RSO drinkers.

Human thymus exports naive CD8 T cells that can home to nonlymphoid tissues.

Functionally naive CD8 T cells in peripheral blood from adult humans can be fully described by their CD45RA(bright)CCR7(+)CD62L(+) cell surface phenotype. Cord blood lymphocytes, from healthy newborns, are homogenously functionally naive. Accordingly, the majority of cord blood CD8 T cells express the same pattern of cell surface molecules. Unexpectedly, however, a significant fraction of cord blood CD8 T cells express neither CCR7 nor CD62L. Yet these cells remain functionally naive as they contain high levels of TCR excision circles, have long telomeres, display highly polyclonal TCRs, and do not exhibit immediate effector functions. In addition, these CD8 T cells already represent a significant fraction of the mature naive CD8 single-positive thymocyte repertoire and may selectively express the cutaneous lymphocyte Ag. We suggest that CD8 single-positive thymocytes comprise two pools of naive precursors that exhibit distinct homing properties. Once seeded in the periphery, naive CCR7(+)CD62L(+) CD8 T cells patrol secondary lymphoid organs, whereas naive CCR7(-)CD62L(-) CD8 T cells selectively migrate to peripheral tissues such as skin.

Can Families Resist Managerial and Financial Revolutions? Swiss Family Firms in the Twentieth Century

The aim of this contribution is to highlight the long-term evolution of family capitalism in Switzerland during the twentieth century. We focus on 22 large companies of the machine, electrotechnical and metallurgy (MEM) sector whose boards of directors and general managers have been identified in five benchmark years across the twentieth century, which allows us to distinguish between family-owned and family-controlled firms. Our results show that family firms prevailed until the 1980s and thus contradict the dominance of 'managerial capitalism'. Although we observe a decline of family capitalism during the last decade of the century, the significant remaining presence of family firms in 2000 allows us to relativise the advent of investor capitalism.

Can Science of Religion Render Service to Islamic Studies?

(Résumé de l'ouvrage) Der international renommierte Religionswissenschaftler Michael Pye, seit 1982 Professor für Religionswissenschaft an der Philipps-Universität Marburg, hat die moderne, konfessionell unabhängige Religionsforschung maßgeblich mitgeprägt und dazu beigetragen, das Profil der Religionswissenschaft als einer autonomen akademischen Disziplin zu schärfen. In der vorliegenden Festschrift, die aus Anlaß des 65. Geburtstages Michael Pyes von zweien seiner Schüler bzw. Schülerinnen und einer ehemaligen Mitarbeiterin herausgegeben wurde, würdigen über 30 Religionswissenschaftler und Religionswissenschaftlerinnen aus Finnland, Großbritannien, Dänemark, Deutschland, Italien, Japan, Kanada, den Niederlanden, Norwegen, Schweden, der Schweiz, Tschechien und den USA mit ihren Beiträgen die Person und das Werk des Jubilars. Darüber hinaus enthält die Festschrift Porträts und eine Bibliographie der Arbeiten Michael Pyes. Die große thematische und methodische Bandbreite, die das Oevre dieses maßgebenden Religionswissenschaftlers kennzeichnet, spiegelt sich in der Vielfalt der Beiträge wider. So gibt dieses Buch zugleich einen guten Überblick über die Themen und Methoden der gegenwärtigen Religionswissenschaft.

Brain dysfunction in sepsis: what can we learn from cerebral perfusion studies?

Investigations on the relationship between sepsis, brain dysfunction, and cerebral perfusion are methodologically very difficult to perform. It is important to interpret the results of such studies in view of our limited ability to diagnose and quantify brain dysfunction and to consider our limited understanding of the mechanisms that lead to or are associated with brain dysfunction in sepsis.

Transgenic Arabidopsis plants can accumulate polyhydroxybutyrate to up to 4% of their fresh weight.

Transgenic Arabidopsis thaliana (L.) Heynh. plants expressing the three enzymes encoding the biosynthetic route to polyhydroxybutyrate (PHB) are described. These plants accumulated more than 4% of their fresh weight (approximately 40% of their dry weight) in the form of PHB in leaf chloroplasts. These very high producers were obtained and identified following a novel strategy consisting of a rapid GC-MS analysis of a large number of transgenic Arabidopsis plants generated using a triple construct, thus allowing the parallel transfer of all three genes necessary for PHB synthesis in a single transformation event. The level of PHB produced was 4-fold greater than previously published values, thus demonstrating the large potential of plants to produce this renewable resource. However, the high levels of the polymer produced had severe effects on both plant development and metabolism. Stunted growth and a loss of fertility were observed in the high-producing lines. Analysis of the metabolite composition of these lines using a GC-MS method that we have newly developed showed that the accumulation of high levels of PHB was not accompanied by an appreciable change in either the composition or the amount of fatty acids. Substantial changes were, however, observed in the levels of various organic acids, amino acids, sugars and sugar alcohols.

Can health beliefs help in explaining attendance to follow-up care? The Swiss childhood cancer survivor study.

Objective: Improved treatment has increased the survival of childhood cancer patients in recent decades, but follow-up care is recommended to detect and treat late effects. We investigated relationships between health beliefs and follow-up attendance in adult childhood cancer survivors.Methods: Childhood cancer survivors aged younger than 16 years when diagnosed between 1976 and 2003, who had survived for more than 5 years and were currently aged 20+ years, received a postal questionnaire. We asked survivors whether they attended follow-up in the past year. Concepts from the Health Belief Model (perceived susceptibility and severity of future late effects, potential benefits and barriers to follow-up, general health value and cues to action) were assessed. Medical information was extracted from the Swiss Childhood Cancer Registry.Results: Of 1075 survivors (response rate 72.3%), 250 (23.3%) still attended regular follow-up care. In unadjusted analyses, all health belief concepts were significantly associated with follow-up (p < 0.05). Adjusting for other health beliefs, demographic, and medical variables, only barriers (OR = 0.59; 95% CI: 0.43-0.82) remained significant. Younger survivors, those with lower educational background, diagnosed at an older age, treated with chemotherapy, radiotherapy, or bone marrow transplantation and with a relapse were more likely to attend follow-up care.Conclusions: Our study showed that more survivors at high risk of cancer-and treatment-related late effects attend follow-up care in Switzerland. Patient-perceived barriers hinder attendance even after accounting for medical variables. Information about the potential effectiveness and value of follow-up needs to be available to increase the attendance among childhood cancer survivors. Copyright (C) 2010 John Wiley & Sons, Ltd.

Active antiviral T-lymphocyte response can be redirected against tumor cells by antitumor antibody x MHC/viral peptide conjugates.

PURPOSE: To redirect an ongoing antiviral T-cell response against tumor cells in vivo, we evaluated conjugates consisting of antitumor antibody fragments coupled to class I MHC molecules loaded with immunodominant viral peptides. EXPERIMENTAL DESIGN: First, lymphochoriomeningitis virus (LCMV)-infected C57BL/6 mice were s.c. grafted on the right flank with carcinoembryonic antigen (CEA)-transfected MC38 colon carcinoma cells precoated with anti-CEA x H-2D(b)/GP33 LCMV peptide conjugate and on the left flank with the same cells precoated with control anti-CEA F(ab')(2) fragments. Second, influenza virus-infected mice were injected i.v., to induce lung metastases, with HER2-transfected B16F10 cells, coated with either anti-HER2 x H-2D(b)/NP366 influenza peptide conjugates, or anti-HER2 F(ab')(2) fragments alone, or intact anti-HER2 monoclonal antibody. Third, systemic injections of anti-CEA x H-2D(b) conjugates with covalently cross-linked GP33 peptides were tested for the growth inhibition of MC38-CEA(+) cells, s.c. grafted in LCMV-infected mice. RESULTS: In the LCMV-infected mice, five of the six grafts with conjugate-precoated MC38-CEA(+) cells did not develop into tumors, whereas all grafts with F(ab')(2)-precoated MC38-CEA(+) cells did so (P = 0.0022). In influenza virus-infected mice, the group injected with cells precoated with specific conjugate had seven times less lung metastases than control groups (P = 0.0022 and P = 0.013). Most importantly, systemic injection in LCMV-infected mice of anti-CEA x H-2D(b)/cross-linked GP33 conjugates completely abolished tumor growth in four of five mice, whereas the same tumor grew in all five control mice (P = 0.016). CONCLUSION: The results show that a physiologic T-cell antiviral response in immunocompetent mice can be redirected against tumor cells by the use of antitumor antibody x MHC/viral peptide conjugates.

Can we measure accurately the prevalence of doping?

Questionnaires are used in the majority of the studies ondoping prevalence in sport. Nevertheless, prevalence is noteasy to evaluate and previous epidemiologic studies demonstrateda wide variance. This variance has mostly beenexplained by sample differences. The way to evaluate dopingprevalence in the survey is questioned in this paper. Aquestionnaire was administered to 1810 amateur athletes(993 males, 817 females). Doping use was ascertained invarious ways, using different definitions of doping and typesof question in the survey. Depending on the definition ofdoping and the type of question used, the prevalence ofdoping obtained can differ enormously, between 1.3 and39.2% of athletes. Marijuana and drugs for asthma were thetwo banned substances most used. The majority of athletesoften ignored the banned list and did not use prohibitedsubstances to dope. Using various ways to question athletes,observing the usage of substances, cross checking the data,taking into account the aim of substances uses and thevarious definitions of doping are necessary to give morereliable prevalence of doping. Moreover, doping at anamateur level seems to be less of a sport problem than asocial problem.