Expression Analysis of PAC1-R and PACAP Genes in Zebrafish Embryos

This study describes the expression of the pituitary adenylate cyclase-activating polypeptide (PACAP1 and PACAP2) and PAC1 receptor genes (PAC1a-R and PAC1b-R) in the brain of zebrafish (Danio rerio) during development. In situ hybridization of the 24- and 48-hpf embryos revealed that PACAP genes were expressed in the telencephalon, the diencephalon, the rhombencephalon, and the neurons in the dorsal part of the spinal cord. PACAP2 mRNA appears to be the most abundant form during brain development. The two PAC1-R subtypes showed a similar expression pattern: mRNAs were detected in the forebrain, the thalamus, and the rhombencephalon. However, in the tectum, only PAC1b-R gene was detected. These results suggest that, in fish, PACAP may play a role in brain development

The Expression of Vasoactive Intestinal Peptide Receptor 1 Is Negatively Modulated by MicroRNA 525-5p

Background: The human Vasoactive Intestinal Peptide (VIP) is a neurokine with effects on the immune system where it is involved in promoting tolerance. In this context, one of its receptors, VPAC1, has been found to be down-modulated in cells of the immune network in response to activating stimuli. In particular, the bacterial liposaccaride (LPS), a strong activator of the innate immune system, induces a rapid decrease of VPAC1 expression in monocytes and this event correlates with polymorphisms in the 3'-UTR of the gene. Methodology/Principal Findings: MicroRNA 525-5p, having as putative target the 3'-UTR region of VPAC1, has been analysed for its expression in monocytes and for its role in down-modulating VPAC1 expression. We report here that miR-525-5p is promptly up-regulated in LPS-treated monocytes. This microRNA, when co-transfected in 293T cells together with a construct containing the 3'-UTR of the VPAC1 gene, significantly reduced the luciferase activity in a standard expression assay. The U937 cell line as well as primary monocytes enforced to express miR-525-5p, both down-modulate VPAC1 expression at similar extent. Conclusions/Significance: Our results show that the response to an inflammatory stimulus elicits in monocytes a rapid increase of miR-525-5p that targets a signaling pathway involved in the control of the immune homeostasis

Occurrence and Functions of PACAP in the Placenta

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide with a widespread distribution both in the nervous system and peripheral organs. The peptide is also present in the female gonadal system, indicating its role in reproductive functions. While a lot of data are known on PACAP-induced effects in oogenesis and in the regulation of gonadotropin secretion at pituitary level, its placental effects are somewhat neglected in spite of the documented implantation deficit in mice lacking endogenous PACAP. The aim of the present review is to give a brief summary on the occurrence and actions of PACAP and its receptors in the placenta. Radioimmunoassay (RIA) measurements revealed increased serum PACAP levels during the third trimester and several changes in placental PACAP content in obstetrical pathological conditions, further supporting the function of PACAP during pregnancy. Both the peptide and its receptors have been shown in different parts of the placenta and the umbilical cord. PACAP influences blood vessel and smooth muscle contractility of the uteroplacental unit and is involved in regulation of local hormone secretion. The effects of PACAP on trophoblast cells have been mainly studied in vitro. Effects of PACAP on cell survival, angiogenesis and invasion/proliferation have been described in different trophoblast cell lines. PACAP increases proliferation and decreases invasion in proliferative extravillous trophoblast cells, but not in primary trophoblast cells, where PACAP decreased the secretion of various angiogenic markers. PACAP pretreatment enhances survival of non-tumorous primary trophoblast cells exposed to oxidative stress, but it does not influence the cell death-inducing effects of methotrexate in proliferative extravillous cytotrophoblast cells. Interestingly, PACAP has pro-apoptotic effect in choriocarcinoma cells suggesting that the effect of PACAP depends on the type of trophoblast cells. These data strongly support that PACAP plays a role in normal and pathological pregnancies and our review provides an overview of currently available experimental data worth to be further investigated to elucidate the exact role of this peptide in the placenta

Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted pvalue 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74±0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51±0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone