Accounting Problems Under the Excess Profits Tax

DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.Funding Agencies|Research Council of Norway; Odd Fellow</p

A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial

BACKGROUND: Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period. METHODOLOGY/PRINCIPAL FINDINGS: 229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qbeta (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012). CONCLUSIONS: Whereas Nicotine-Qbeta did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction. TRIAL REGISTRATION: Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616

Antithrombotic therapy and survival in patients with malignant disease

A broad range of studies suggest a two-way relationship between cancer and venous thromboembolism (VTE). Patients with cancer have consistently been shown to be at elevated risk for VTE; this risk is partly driven by an intrinsic hypercoagulable state elicited by the tumour itself. Conversely, thromboembolic events in patients without obvious risk factors are often the first clinical manifestation of an undiagnosed malignancy. The relationship between VTE and cancer is further supported by a number of trials and meta-analyses which, when taken together, strongly suggest that antithrombotic therapy can extend survival in patients with cancer by a mechanism that extends beyond its effect in preventing VTE. Moreover, accumulating evidence from in vitro and in vivo studies has shown that tumour growth, invasion, and metastasis are governed, in part, by elements of the coagulation system. On 22 May 2009, a group of health-care providers based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees evaluated evidence for and against an effect of antithrombotic therapy on survival in cancer. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents might exert antitumour effects. The summary is followed by a consensus statement developed by the group

Global Patterns of City Size Distributions and Their Fundamental Drivers

Urban areas and their voracious appetites are increasingly dominating the flows of energy and materials around the globe. Understanding the size distribution and dynamics of urban areas is vital if we are to manage their growth and mitigate their negative impacts on global ecosystems. For over 50 years, city size distributions have been assumed to universally follow a power function, and many theories have been put forth to explain what has become known as Zipf's law (the instance where the exponent of the power function equals unity). Most previous studies, however, only include the largest cities that comprise the tail of the distribution. Here we show that national, regional and continental city size distributions, whether based on census data or inferred from cluster areas of remotely-sensed nighttime lights, are in fact lognormally distributed through the majority of cities and only approach power functions for the largest cities in the distribution tails. To explore generating processes, we use a simple model incorporating only two basic human dynamics, migration and reproduction, that nonetheless generates distributions very similar to those found empirically. Our results suggest that macroscopic patterns of human settlements may be far more constrained by fundamental ecological principles than more fine-scale socioeconomic factors

Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy

Between 1984 and 2006, 12 959 people with HIV/AIDS (PWHA) in the Swiss HIV Cohort Study contributed a total of 73 412 person-years (py) of follow-up, 35 551 of which derived from PWHA treated with highly active antiretroviral therapy (HAART). Five hundred and ninety-seven incident Kaposi sarcoma (KS) cases were identified of whom 52 were among HAART users. Cox regression was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Kaposi sarcoma incidence fell abruptly in 1996–1998 to reach a plateau at 1.4 per 1000 py afterwards. Men having sex with men and birth in Africa or the Middle East were associated with KS in both non-users and users of HAART but the risk pattern by CD4 cell count differed. Only very low CD4 cell count (<50 cells μl−1) at enrolment or at HAART initiation were significantly associated with KS among HAART users. The HR for KS declined steeply in the first months after HAART initiation and continued to be low 7–10 years afterwards (HR, 0.06; 95% CI, 0.02–0.17). Thirty-three out of 52 (63.5%) KS cases among HAART users arose among PWHA who had stopped treatment or used HAART for less than 6 months

A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy

Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 andCD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.Fil: Daniels-Wells, Tracy R. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Helguera, Gustavo Fernando. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Tecnologia Farmaceutica; Argentina; University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Leuchter, Richard K. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Quintero, Rafael. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Kozman, Maggie. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Rodríguez, José A.. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América;Fil: Ortiz-Sánchez, E. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; Biomedical Research in Cancer. Basic Research Division. National Institute of Cancerology; Mexico.;Fil: Martínez-Maza, Otonel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Schultes, Brigit C.. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Nicodemus Christopher. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Penichet, Manuel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América

Information in small neuronal ensemble activity in the hippocampal CA1 during delayed non-matching to sample performance in rats

<p>Abstract</p> <p>Background</p> <p>The matrix-like organization of the hippocampus, with its several inputs and outputs, has given rise to several theories related to hippocampal information processing. Single-cell electrophysiological studies and studies of lesions or genetically altered animals using recognition memory tasks such as delayed non-matching-to-sample (DNMS) tasks support the theories. However, a complete understanding of hippocampal function necessitates knowledge of the encoding of information by multiple neurons in a single trial. The role of neuronal ensembles in the hippocampal CA1 for a DNMS task was assessed quantitatively in this study using multi-neuronal recordings and an artificial neural network classifier as a decoder.</p> <p>Results</p> <p>The activity of small neuronal ensembles (6-18 cells) over brief time intervals (2-50 ms) contains accurate information specifically related to the matching/non-matching of continuously presented stimuli (stimulus comparison). The accuracy of the combination of neurons pooled over all the ensembles was markedly lower than those of the ensembles over all examined time intervals.</p> <p>Conclusion</p> <p>The results show that the spatiotemporal patterns of spiking activity among cells in the small neuronal ensemble contain much information that is specifically useful for the stimulus comparison. Small neuronal networks in the hippocampal CA1 might therefore act as a comparator during recognition memory tasks.</p

Entomopathogenic Fungi on Hemiberlesia pitysophila

Hemiberlesia pitysophila Takagi is an extremely harmful exotic insect in forest to Pinus species, including Pinus massoniana. Using both morphological taxonomy and molecular phylogenetics, we identified 15 strains of entomogenous fungi, which belong to 9 genera with high diversities. Surprisingly, we found that five strains that were classified as species of Pestalotiopsis, which has been considered plant pathogens and endophytes, were the dominant entomopathogenic fungus of H. pitysophila. Molecular phylogenetic tree established by analyzing sequences of ribosomal DNA internal transcribed spacer showed that entomopathogenic Pestalotiopsis spp. were similar to plant Pestalotiopsis, but not to other pathogens and endophytes of its host plant P. massoniana. We were the first to isolate entomopathogenic Pestalotiopsis spp. from H. pitysophila. Our findings suggest a potential and promising method of H. pitysophila bio-control

Climate change and the long-term viability of the World’s busiest heavy haul ice road

Climate models project that the northern high latitudes will warm at a rate in excess of the global mean. This will pose severe problems for Arctic and sub-Arctic infrastructure dependent on maintaining low temperatures for structural integrity. This is the case for the economically important Tibbitt to Contwoyto Winter Road (TCWR)—the world’s busiest heavy haul ice road, spanning 400 km across mostly frozen lakes within the Northwest Territories of Canada. In this study, future climate scenarios are developed for the region using statistical downscaling methods. In addition, changes in lake ice thickness are projected based on historical relationships between measured ice thickness and air temperatures. These projections are used to infer the theoretical operational dates of the TCWR based on weight limits for trucks on the ice. Results across three climate models driven by four RCPs reveal a considerable warming trend over the coming decades. Projected changes in ice thickness reveal a trend towards thinner lake ice and a reduced time window when lake ice is at sufficient thickness to support trucks on the ice road, driven by increasing future temperatures. Given the uncertainties inherent in climate modelling and the resultant projections, caution should be exercised in interpreting the magnitude of these scenarios. More certain is the direction of change, with a clear trend towards winter warming that will reduce the operation time window of the TCWR. This illustrates the need for planners and policymakers to consider future changes in climate when planning annual haulage along the TCWR