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

A prospective outcome study of membranous and solid distal common canalicular obstructions

To prospectively evaluate the surgical outcomes of membranous and solid distal common canalicular obstructions (CCOs) following endoscopic dacryocystorhinostomy (EnDCR) and lacrimal intubation combined with either membranotomy or trephination.This was a prospective, non-randomized, consecutive interventional case series. Inclusion criteria included patients undergoing EnDCR with evidence of a membranous block or more solid obstruction of the distal common canaliculus, treated with membranotomy or canalicular trephination. Complete CCO was confirmed pre-operatively using dacryocystography and dacryoscintigraphy. All patients received bicanalicular intubation for 3 months with a minimum follow-up of 12 months. Functional and anatomical success was assessed at 4 weeks, 3 months, and 12 months following surgery. Functional success was defined as subjective improvement of epiphora and anatomical success as the presence of a patent ostium and a positive dye test on nasal endoscopy.Twenty-nine patients were included in the study with a mean age of 58 years. Twenty-one patients (72%) received a membranotomy and eight (28%) required trephination. At 12 months, the functional and anatomical success rate in the membranotomy group was 90% (19/21) and 100% (21/21), respectively, and in trephination group the functional and anatomical success rate was 63% (5/8). There were no intra-operative or lacrimal stent-related complications.Identifying and excising distal CCOs in association with EnDCR and lacrimal intubation is associated with a high degree of functional (83%) and anatomical (90%) success. The success of membranous obstructions appear be superior to outcomes for solid obstructions of the distal common canaliculus that require trephination.P. N. Shams, A. Pirbhai and D. Selv