cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions

Ship security challenges in high-risk areas : manageable or insurmountable?

Piracy can lead to risks so high that they, according to the International Maritime Organization, are tolerable only if risk reduction is not practicable or is disproportionate to the benefits achieved. Therefore, there is a need for reducing ship security risks in relation to antagonistic threats such as piracy. The aim of this study is to identify challenges for ship operators when developing their ship security management. Furthermore, this study also investigates two central aspects in the analysis: understanding the threat and understanding how a security threat affects the crew and operation of the ship. It is clear from the analysis that the importance of subjective aspects beyond a ship operators’ direct control is high. This seems to be the fact for all aspects of the risk management process. The situation is also dynamic as the security risk, as well as the risk perception, can change dramatically even though there are no actual operational changes. As a result, the ship security management process is highly iterative and depends on situations on board as well as conditions out of the ship operator’s control. In order to make ship security manageable, the risk management has to put particular focus on methodological understanding, relevant system understanding and well-defined risk acceptance criteria as well as on including all levels of the organization in the risk reduction implementation and on a continuous monitoring