פרסומים

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.

There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. However, it is unclear what information about the prior distribution is acquired by the perceptual system over short periods of time and how this information is utilized in the process of perceptual decision making. Here we address this question using a simple two-tone discrimination task. We find that the contraction bias , in which small magnitudes are overestimated and large magnitudes are underestimated, dominates the pattern of responses of human participants. This contraction bias is consistent with the Bayesian hypothesis in which the true prior information is available to the decision-maker. However, a trial-by-trial analysis of the pattern of responses reveals that the contribution of most recent trials to performance is overweighted compared with the predictions of a standard Bayesian model. Moreover, we study participants performance in a-typical distributions of stimuli and demonstrate substantial deviations from the ideal Bayesian detector, suggesting that the brain utilizes a heuristic approximation of the Bayesian inference. We propose a biologically plausible model, in which decision in the two-tone discrimination task is based on a comparison between the second tone and an exponentially-decaying average of the first tone and past tones. We show that this model accounts for both the contraction bias and the deviations from the ideal Bayesian detector hypothesis. These findings demonstrate the power of Bayesian-like heuristics in the brain, as well as their limitations in their failure to fully adapt to novel environments.

There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. However, it is unclear what information about the prior distribution is acquired by the perceptual system over short periods of time and how this information is utilized in the process of perceptual decision making. Here we address this question using a simple two-tone discrimination task. We find that the “contraction bias”, in which small magnitudes are overestimated and large magnitudes are underestimated, dominates the pattern of responses of human participants. This contraction bias is consistent with the Bayesian hypothesis in which the true prior information is available to the decision-maker. However, a trial-by-trial analysis of the pattern of responses reveals that the contribution of most recent trials to performance is overweighted compared with the predictions of a standard Bayesian model. Moreover, we study participants' performance in a-typical distributions of stimuli and demonstrate substantial deviations from the ideal Bayesian detector, suggesting that the brain utilizes a heuristic approximation of the Bayesian inference. We propose a biologically plausible model, in which decision in the two-tone discrimination task is based on a comparison between the second tone and an exponentially-decaying average of the first tone and past tones. We show that this model accounts for both the contraction bias and the deviations from the ideal Bayesian detector hypothesis. These findings demonstrate the power of Bayesian-like heuristics in the brain, as well as their limitations in their failure to fully adapt to novel environments.

Background & Aims: Worldwide, about 180 million people are chronically infected with the hepatitis C virus (HCV). Current in vitro culture systems for HCV depend chiefly on human hepatoma cell lines. Although primary human hepatocytes support HCV infection in vitro, and immunodeficient mice repopulated with human hepatocytes support HCV infection in vivo, these models are limited because of shortage of human livers to isolate hepatocytes. Therefore, there is significant interest in the establishment from of a HCV culture system in human stem cell-derived hepatocyte-like cells. Methods: Human embryonic stem cell (hESC)-derived hepatocytes were infected with HCV in the presence or absence of direct acting antivirals. After inoculation, replication of HCV was analyzed extensively. Results: We demonstrate that hESC-derived hepatocytes can be infected with the HCV JFH1 genotype 2a, resulting in the production of viral RNA in the stem cell progeny. Viral replication is inhibited by a non-nucleoside HCV polymerase-inhibitor (HCV-796), a cyclophilin binding molecule (Debio 025-Alisporivir) and the protease inhibitor VX-950 (Telaprevir). Stem cell-derived hepatocytes produced, for more than 10 days, the HCV core protein as well as virions that were capable of re-infecting hepatoma cells. Conclusions: Hepatocytes derived from hESC support the complete HCV replication cycle (including the production of infectious virus), and viral replication in these cells is efficiently inhibited by selective inhibitors of HCV replication. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The present study investigated the expression and clinical role of hyaluronan synthases (HAS1-3) and hyaluronidases (Hyal1-3) in serous ovarian carcinoma. HAS and HYAL mRNA expression was analyzed in 97 tumors (61 effusions, 27 primary carcinomas, 9 solid metastases) using PCR and further studied for association with clinicopathologic parameters, including survival. HAS1 mRNA was overexpressed in effusions compared to primary carcinomas and solid metastases (p < 0.001), and an alternatively spliced HAS1 was expressed only in effusions. HAS2 mRNA was overexpressed in solid metastases and primary carcinomas compared to effusions (p = 0.043), and HAS3 mRNA was overexpressed in primary carcinomas and effusions compared to solid metastases (p = 0.008). HYAL1 mRNA was absent in all specimens, whereas HYAL2 was expressed as two splice variants, of which HYAL2-var2 was overexpressed in solid metastases compared to effusions and primary carcinomas (p < 0.001). HYAL3 mRNA was expressed as wild-type and variant 1-3 form, the latter more highly in primary carcinomas and effusions compared to solid metastases (p = 0.006). HAS1 mRNA was overexpressed in pre- compared to post-chemotherapy effusions (p < 0.001), with opposite finding for HYAL2-var1 and HYAL3-WT (p = 0.016 and p = 0.024, respectively). Higher HYAL2-var1 and HAS1 splice variant mRNA expression in effusions was associated with longer (p = 0.033) and shorter (p = 0.047) overall survival, respectively. These data are the first to document a role for HAS and Hyal members in tumor progression in ovarian carcinoma, as evidenced by their differential expression as function of anatomic site and chemotherapy exposure, with a possible prognostic role for patients with malignant effusions.

The title of Henriette Frölich's Virginia oder die Kolonie von Kentucky (1820) voices the nineteenthcentury imagination of America as the locus of a new civilization in the wake of post-Revolutionary disillusionment. The novel's subtitle, Mehr Wahrheit als Dichtung, echoes the title of the autobiography of Goethe, author of the German Bildungsroman par excellence, Wilhelm Meister. Frölich's title establishes a correlation between new concepts of community and the individual's "Bildung" as the basis for novel forms of communal living in the early nineteenth century. This paper explores the ambivalent legacy of Frölich's text. On the one hand, Virginia has been described as a socialist utopia modeled on thinkers such as François-Noël Babeuf, Gabriel Bonnot de Mably, and Étienne-Gabriel Morelly. On the other hand, however, this new community does not extend equality to women, Native Americans, Blacks, and non-French European immigrants such as Germans. Ethnic, racial, and gender inequalities persist in the North American colony. Frölich's utopia is, therefore, also a dystopia, which is shaped by the same social injustice that provided the impetus for its creation. © 2012 Project MUSE.

BACKGROUND: Pressure ulcers are an important source of morbidity and suffering for patients and a formidable burden on caregivers. OBJECTIVES: To assess the impact of a feeding formula enriched with fish oil on healing of preexisting pressure ulcers and serum levels of C-reactive protein in critical care patients. METHODS: Adult patients with pressure ulcers grade II or higher were randomly allocated to receive either a formula enriched with fish oil or an isocaloric control formula. Wound healing was assessed by using the Pressure Ulcer Scale for Healing tool on days 7, 14, and 28. Blood levels of C-reactive protein were measured on days 0, 7, and 14. RESULTS: Baseline demographics did not differ between the study (n = 20) and the control (n = 20) groups. The mean score on the ulcer healing tool increased significantly (P = .02) from day 0 to day 28 in the control group (from 9.25 [SD, 2.12] to 10.75 [SD, 3.41]) compared with the study group (from 9.10 [SD, 2.84] to 9.40 [SD, 3.72]). Mean levels of C-reactive protein decreased significantly (P= .02) from day 0 to day 14 in the study group (from 191 [SD, 104.4] mg/L to 111.7 [SD, 97.8] mg/L) compared with the control group (from 145 [SD, 90] mg/L to 139 [SD, 62] mg/L). CONCLUSION: Administration of a feeding formula enriched with fish oil was associated with decreased progression of pressure ulcers and a decrease in blood concentrations of C-reactive protein.

A large number of studies show that war and terrorism have a significant effect on individuals’ political attitudes.  Yet, this extensive literature does not inspect the mechanisms behind this effect.  This paper concentrates on one possible mechanism, by differentiating between the human toll of terror and war and the economic costs they cause.  For these purposes we focus on the Israeli-Palestinian conflict, and use variation in the level of violence across time and space together with localities’ different exposure to the tourism sector to estimate their respective effects on political attitudes.  Our results suggest that whereas fatalities from the conflict make Israelis more willing to grant territorial concessions to the Palestinians, the associated economic costs of conflict do not have a consistent significant effect on individuals’ political attitudes. 

We extend implementation theory by allowing the social choice function to depend on more than just the profile of preferences of the agents and by allowing agents to support their statements with hard evidence. We show that a simple condition on the evidence structure which is necessary for the implementation of a social choice function f when the preferences of the agents are state independent is also sufficient for implementation for any preferences (including state dependent) if the social planner can perform small monetary transfers beyond those called for by f and there are at least three players. If transfers can be large, f can be implemented in a game with perfect information when there are at least two players under an additional boundedness assumption. In both cases, transfers only occur off the equilibrium path. In the special but important case of allocation problems, under weak conditions, f can be implemented in a perfect information game with at least two players and no transfers. In all cases, the use of evidence enables implementation which is robust in the sense that the social planner needs very little information about the preferences, beliefs, and evidence of the agents and the agents need little information about each others’ preferences. Furthermore, our results still hold if evidence can be forged at an arbitrarily small but strictly positive cost. Finally, we relate our results to the classical work of Maskin (1977) and Moore and Repullo (1988) on implementation without evidence.