Emergency cerclage using double-level versus single-level suture in the management of cervical insufficiency (Cervical Occlusion double-level Stitch Application, COSA): study protocol for a multicentre, non-blinded, randomised controlled trial.

INTRODUCTION: Cervical insufficiency accounts for 15% of recurrent pregnancy losses between 16 and 28 weeks of gestation. The aim of the study is to verify the effectiveness of emergency double-level cerclage with vaginal progesterone in cervical insufficiency treatment in terms of the prevention of preterm delivery before 34 weeks of gestation. METHODS AND ANALYSIS: This trial is a multicentre, non-blinded, randomised study with 1:1 allocation ratio. The study is conducted at tertiary perinatal care departments in Poland. It will include patients with cervical insufficiency with the fetal membranes visible in the open cervical canal or protruding into the vagina between 16+0 and 23+6 weeks of pregnancy. They will be randomised into two arms: emergency single-level cerclage with vaginal progesterone or double-level cerclage with vaginal progesterone. All will be administered antibiotics and indomethacin. The primary outcome is the rate of deliveries below 34+0 weeks of gestation, while secondary outcomes include gestational age at delivery, neonatal outcomes, maternal outcomes according to the Core Outcome Set for Evaluation of Interventions to Prevent Preterm Birth and cerclage procedure complications. The planned number of participants according to the power analysis is 78. ETHICS AND DISSEMINATION: The study protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials statement. It was created according to the requirements of the Declaration of Helsinki for Medical Research involving Human Subject. Ethical approval was obtained from the Ethics Committee of the Centre of Postgraduate Medical Education (no. 1/2022). The study protocol was approved and published by ClinicalTrials.gov (posted on 24 February 2022). All participants gave a written informed consent. After completion of the study its results will be published in a peer-reviewed English language journal. TRIAL REGISTRATION: NCT05268640.

[The neuroprotective effect of PACAP, VIP, and derivatives in brain ischemia]. / Dzialanie neuroprotekcyjne PACAP, VIP oraz pochodnych w niedokrwieniu mózgu.

Nowadays, stroke is the most frequent cause of adult disability and death of the elderly. In most cases, the etiology of stroke involves cerebral ischemia. Ischemia-induced changes in the brain tissue lead not only to its degeneration, but also to significant activation of cellular mechanisms which protect the affected cells from damage. One such mechanism is the expression of endogenous neuroprotective substances, for example pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intenstinal peptide (VIP), whose properties were investigated recently. PACAP and VIP are neuropeptides widely distributed in both the central nervous system and peripheral organs of various vertebrates. They display pleiotropic biological activity. An extremely strong neuroprotective potential of these peptides has been observed and confirmed in numerous animal models. The protective mechanism of PACAP and VIP involves many intracellular pathways, which can be generally classified into four categories of action: antiapoptotic, anti-inflammatory, metabolic, and modulation of gene expression. Numerous data provided by many research centers suggest that endo- and exogenous PACAP and VIP, as well as their synthetic derivatives, reveal considerable neuroprotective and anti-inflammatory potential, suggesting a possibility of their use as new therapeutic strategies in stroke treatment.

Effects of PEDF and VEGF on PACAP-/VIP-induced cAMP formation in rat brain derived astrocyte cultures.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related peptides acting on their specific receptors. Both were shown to concentration-dependently (0.001 nM - 1 muM) stimulate cyclic 3',5' adenosinomonophosphate (cAMP) formation in rat primary glial cell (astrocyte) cultures, with PACAP being distinctly more potent than VIP. The acute effects of the peptides were significantly suppressed (25% and 36% for PACAP and VIP, respectively) when tested in cell cultures preincubated for 24 h (but not 2 h) in the presence of pigment epithelium-derived factor (PEDF, 50 ng/ml). Both 24 h and 2 h preincubation of cells with vascular endothelial growth factor (VEGF, 50 ng/ml) had no influence on PACAP or VIP actions. The addition of PEDF and VEGF together for 24 h preincubation, produced suppression of the PACAP- or VIP-evoked cAMP responses similar to that seen with PEDF alone. Neither PEDF nor VEGF significantly affected cAMP generation in an assay with a 15-min incubation, which is a standard incubation period for PACAP and VIP. The findings show that PEDF, displaying by itself no effect on cAMP generating system in rat astrocytes, significantly affected biological activity of both PACAP and VIP. The reported observation may be of significance, considering the neurotrophic and/or neuroprotective activity of the tested polypeptides.

Effects of PACAP and VIP on cyclic AMP formation in rat neuronal and astrocyte cultures under normoxic and hypoxic condition.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) concentration (0.001-1000 nM)-dependently stimulated cyclic AMP production in rat primary neuronal and glial cell (astrocyte) cultures. The actions of both peptides were much more pronounced in astrocytes than in neuronal cultures. Stimulatory effects of PACAP and VIP on cyclic AMP formation were significantly smaller in cell cultures subjected to 24h lasting hypoxic conditions, induced either chemically (100 microM cobalt chloride) or by low 3% oxygen hypoxia, compared to the normoxic condition (95% air and 5% CO(2)). This picture contrasted with the effects of forskolin that were similar under normoxic and hypoxic conditions. It is suggested that hypoxia leads to changes in PACAP- and VIP-driven cyclic AMP-dependent signaling in the rat brain by influencing molecular processes likely occurring at the level of receptor protein or receptor-Gs protein coupling.