Early over-expression of GRP receptors in prostatic carcinogenesis

BACKGROUND The GRP receptor shows high over-expression in prostatic adenocarcinoma and high grade PIN, but low expression in normal prostate glands. This represents the molecular basis for GRP receptor imaging of prostate cancer with radioactive compounds. However, a focal, high density GRP receptor expression can be observed in hitherto uncharacterized prostate glands. METHODS GRP receptors were quantitatively measured with in vitro receptor autoradiography using ¹²⁵I-Tyr⁴ -bombesin in samples from 115 prostates. On successive tissue sections, ¹²⁵I-Tyr⁴ -bombesin autoradiography was compared with H&E staining and MIB-1 and 34βE12 immunohistochemistry. RESULTS On one hand, it was confirmed that GRP receptors were expressed in adenocarcinoma and high grade PIN in high density and high incidence (77% and 73%, respectively), but in normal prostate glands in low density and low frequency (18%). On the other hand, a novel and intriguing observation was the existence of focal non-invasive prostate glands with high GRP receptor density, characterized by low grade nuclear atypia and increased proliferation, compatible with lower grade PIN. There was a significant GRP receptor density gradient (P ≤ 0.005), increasing from normal prostate glands (mean relative optical density, ROD, of ¹²⁵I-Tyr⁴ -bombesin binding: 0.17) over atypical glands without increased MIB-1 labeling (0.28) and atypical glands with increased MIB-1 expression (0.44) to high grade PIN and adenocarcinoma (0.64 and 0.58, respectively). CONCLUSIONS GRP receptor over-expression may be a novel, specific marker of early prostatic neoplastic transformation, arising in low grade PIN, and progressively increasing during malignant progression. This should be considered when interpreting in vivo GRP receptor imaging in males.

A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms

Objective The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires. Methods Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration. Results SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the ‘get-up-and-go test’ with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem-walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects. Conclusions 4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

Criminal Solicitation, Entrapment, and the Enforcement of Law

This paper examines the optimal use of criminal solicitation as a law enforcement strategy. The benefits are greater deterrence of crime (due to the greater likelihood of apprehension), and the savings in social harm as some offenders are diverted away from committing actual crimes through solicitation. The costs are the expense of hiring undercover cops and the greater likelihood of punishment. The optimal use of solicitation balances these factors. The paper also examines the justification for the entrapment defense, which exonerates those caught in a criminal solicitation but who otherwise had no predisposition to commit a crime.

Criminal Solicitation, Entrapment, and the Enforcement of Law

This paper examines the optimal use of criminal solicitation as a law enforcement strategy. The benefits are greater deterrence of crime (due to the greater likelihood of apprehension), and the savings in social harm and apprehension costs as some offenders are diverted away from committing actual crimes through solicitation. The costs are the expense of hiring undercover cops and the greater likelihood of punishment. The optimal use of solicitation balances these factors. The paper also examines the justification for, and impact of, the entrapment defense, which exonerates those caught in a solicitation but otherwise not predisposed to commit a crime.

The Role of Patents in the Advent of Web 2.0

Given the significant impact of Web 2.0-related innovations on new Internet-based initiatives, this paper seeks to identify to what extent the main developments are protected by patents and whether patents have had a leading role in the advent of Web 2.0. The article shows that the number of patent applications filed is not that important for many of the Web 2.0 technologies in frequent use and that, of those filed, those granted are even less. The conclusion is that patents do not seem to be a relevant factor in the development of the Web 2.0 (and more generally in dynamic markets) where there is a high degree of innovation and low entry barriers for newcomers.

Evolution over time of heavy vehicle volume in toll roads: A dynamic panel data to identify key explanatory variables in Spain

Improving the knowledge of demand evolution over time is a key aspect in the evaluation of transport policies and in forecasting future investment needs. It becomes even more critical for the case of toll roads, which in recent decades has become an increasingly common device to fund road projects. However, literature regarding demand elasticity estimates in toll roads is sparse and leaves some important aspects to be analyzed in greater detail. In particular, previous research on traffic analysis does not often disaggregate heavy vehicle demand from the total volume, so that the specific behavioral patternsof this traffic segment are not taken into account. Furthermore, GDP is the main socioeconomic variable most commonly chosen to explain road freight traffic growth over time. This paper seeks to determine the variables that better explain the evolution of heavy vehicle demand in toll roads over time. To that end, we present a dynamic panel data methodology aimed at identifying the key socioeconomic variables that explain the behavior of road freight traffic throughout the years. The results show that, despite the usual practice, GDP may not constitute a suitable explanatory variable for heavy vehicle demand. Rather, considering only the GDP of those sectors with a high impact on transport demand, such as construction or industry, leads to more consistent results. The methodology is applied to Spanish toll roads for the 1990?2011 period. This is an interesting case in the international context, as road freight demand has experienced an even greater reduction in Spain than elsewhere, since the beginning of the economic crisis in 2008.

Anterior axis duplication in Xenopus induced by the over-expression of the cadherin-binding protein plakoglobin.

Plakoglobin interacts with both classical and desmosomal cadherins. It is closely related to Drosophila aramadillo (arm) gene product; arm acts in the wingless (wg)-signaling pathway to establish segment polarity. In Xenopus, homologs of wg--i.e., wnts, can produce anterior axis duplications by inducing dorsal mesoderm. Studies in Drosophila suggest that wnt acts by increasing the level of cytoplasmic armadillo protein (arm). To test whether simply increasing the level of plakoglobin mimics the effects of exogenous wnts in Xenopus, we injected fertilized eggs with RNA encoding an epitope-tagged form of plakoglobin; this induced both early radial gastrulation and anterior axis duplication. Exogenous plakoglobin accumulates in the nuclei of embryonic cells. Plakoglobin binds to the tail domain of the desmosomal cadherin desmoglein 1. When RNA encoding the tail domain of desmoglein was coinjected with plakoglobin RNA, both the dorsalizing effect and nuclear accumulation of plakoglobin were suppressed. Mutational analysis indicates that the central arm repeat region of plakoglobin is sufficient to induce axis duplication and that this polypeptide accumulates in the nuclei of embryonic cells. These data show that increased plakoglobin levels can, by themselves, generate the intracellular signals involved in the specification of dorsal mesoderm.

Disclosure of Leniency Materials: A Bridge between Public and Private Enforcement of Antitrust Law. Research Paper in Law 08/2013, December

The disclosure of leniency materials held by competition authorities has recently been under the spot. On the one hand, these documents could greatly help cartel victims to prove the damage and the causation link when filing damage actions against cartelists. On the other hand, future cartelists could be deterred from applying for leniency since damage actions could be brought as a result of the information submitted by themselves. Neither the current legislation nor the case law have attained yet to sufficiently clarify how to deal with this clash of interests. Our approach obviously attempts to strike a balance between both interests. But not only that. We see the current debate as a great opportunity to boost the private enforcement of antitrust law through the positive spillovers of leniency programmes. We hence propose to build a bridge between the public and the private enforcement by enabling a partial disclosure of the documents.