Prolonged administration of secretin to normal rats increases biliary proliferation and secretin-induced ductal secretory activity

Background and aim

Cholangiocyte proliferation is coordinately regulated by a number of gastrointestinal hormones/peptides, some of which display stimulatory effects and some have inhibitory actions on cholangiocyte proliferation. Enhanced biliary proliferation [for example after bile duct ligation (BDL) and partial hepatectomy] is associated with increased expression of secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR) and Cl^–/HCO₃^– anion exchanger 2 and secretin-stimulated ductal secretion, whereas loss/damage of bile ducts [for example after acute carbon tetrachloride (CCl₄) administration] is associated with reduced secretin-stimulated ductal secretory activity. There is growing information regarding the role of gastrointestinal hormones the regulation of biliary growth. For example, while gastrin, somatostatin and serotonin inhibit bile duct hyperplasia of cholestatic rats by downregulation of cAMP signaling, secretin has been shown to stimulate the proliferation of normal mice by activation of cyclic adenosine 3'',5''-monophosphate (cAMP)-dependent signaling. However, no information exists regarding the stimulatory effects of secretin on biliary proliferation of normal rats. Thus, we evaluated the in vivo and in vitro effect of secretin on biliary proliferation, the expression of markers key of ductal secretion and secretin-stimulated ductal secretion.

Methods

Normal male rats were treated with saline or secretin (2.5 nmoles/kg BW/day by osmotic minipumps for one week). We evaluated: (I) intrahepatic bile duct mass (IBDM) in liver sections and PCNA expression in purified cholangiocytes; (II) SR and CFTR mRNA expression and secretin-stimulated cAMP levels in purified cholangiocytes; and (III) secretin-stimulated bile and bicarbonate secretion in bile fistula rats. In vitro, normal rat intrahepatic cholangiocyte lines (NRIC) were treated with BSA (basal) or secretin (100 nM) for 24 to 72 hours in the absence/presence of a PKA or a MEK inhibitor before evaluating proliferation by MTS assays.

Results

Prolonged administration of secretin to normal rats increased IBDM and PCNA expression in purified cholangiocytes compared to saline-treated normal rats. Also, secretin increased the expression of proteins (SR and CFTR) that are key in the regulating ductal secretion and enhanced secretin-stimulated cAMP levels and bile and bicarbonate secretion. In vitro, secretin increased the proliferation of NRIC, increase that was prevented by PKA and MAPK inhibitors.

Conclusions

We have demonstrated that secretin stimulates both in vivo and in vitro biliary proliferation and secretin-stimulated ductal secretory activity in normal rats. We suggest that the stimulatory effect of secretin on biliary proliferation and secretion may be important for preventing biliary dysfunction during ductopenic disorders.     

Melatonin regulation of biliary functions

The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions.     

Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes

Background and aims

Reduction of biliary serotonin N-acetyltransferase (AANAT) expression and melatonin administration/secretion in cholangiocytes increases biliary proliferation and the expression of SR, CFTR and Cl^–/HCO₃^– AE2. The balance between biliary proliferation/damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor-A/C (VEGF-A/C). VEGFs are secreted by several epithelia, where they modulate cell growth by autocrine and paracrine mechanisms. No data exists regarding the effect of AANAT modulation on the expressions of VEGFs by cholangiocytes.

Methods

In this study, we evaluated the effect of local modulation of biliary AANAT expression on the cholangiocytes synthesis of VEGF-A/C.

Results

The decrease in AANAT expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of VEGF-A/C. Overexpression of AANAT in cholangiocyte lines decreased the expression of VEGF-A/C.

Conclusions

Modulation of melatonin synthesis may affect the expression of VEGF-A/C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of VEGF-A/C expression regulating biliary functions.     

Linking novelty seeking and harm avoidance personality traits to cerebellar volumes

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions, and neuroimaging studies showed structural or functional abnormalities of cerebellum in subjects with personality disorders, suggesting a cerebellar role in affective processing and an effect on personality characteristics. To test the hypothesis that cerebellar [white matter (WM) and cortex] volumes are correlated with scores obtained in the four temperamental scales of the Temperament and Character Inventory (TCI) by Cloninger, a total of 125 healthy participants aged 18–67 years of both genders (males = 52) completed the TCI and underwent magnetic resonance imaging. The scores obtained in each temperamental scale were associated with the volumes of cerebellar WM and cortex of right and left hemispheres separately by using linear regression analyses. In line with our hypothesis, novelty seeking (NS) scores were positively associated with WM and cortex cerebellar volumes. Harm avoidance (HA) scores were negatively associated with WM and cortex cerebellar volumes. The range of individual differences in NS and HA scores reflects the range of variances of cerebellar volumes. The present data indicating a cerebellar substrate for some personality traits extend the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. Hum Brain Mapp 35:285–296, 2014. © 2012 Wiley Periodicals, Inc.     

Endoscopic Internal Drainage with Enteral Nutrition (EDEN) for Treatment of Leaks Following Sleeve Gastrectomy

Background

Endoscopic treatment of gastric leaks (GL) following sleeve gastrectomy (SG) involves different techniques; however, standard management is not yet established. We report our experience about endoscopic internal drainage of leaks using pigtail stents coupled with enteral nutrition (EDEN) for 4 to 6 weeks until healing is achieved.

Methods

In 21 pts (18 F, 41 years), one or two plastic pigtail stents were delivered across the leak 25.6 days (4–98) post-surgery. In all patients, nasojejunal tube was inserted. Check endoscopy was done at 4 to 6 weeks with either restenting if persistent leak, or removal if no extravasation of contrast in peritoneal cavity, or closure with an Over-the-Scope Clip® (OTSC®) if contrast opacifying the crossing stent without concomitant peritoneal extravasation.

Results

Twenty-one out of 21 (100 %) patients underwent check endoscopy at average of 30.15 days (26–45) from stenting. In 7/21 (33.3 %) patients leak sealed, 2/7 needed OTSC®. Second check endoscopy, 26.7 days (25–42) later, showed sealed leak in 10 out 14; 6/10 had OTSC®. Four required restenting. One patient, 28 days later, needed OTSC®. One healed at 135 days and another 180 days after four and seven changes, respectively. One patient is currently under treatment. In 20/21 (95.2 %), GL have healed with EID treatment of 55.5 days (26–?180); all are asymptomatic on a normal diet at average follow-up of 150.3 days (20–276).

Conclusions

EDEN is a promising therapeutic approach for treating leaks following SG. Multiple endoscopic sessions may be required.     

Novel N-terminal domain mutation in prion protein detected in 2 patients diagnosed with frontotemporal lobar degeneration syndrome

Prion protein gene mutations have been associated with clinical pictures mimicking neurodegenerative diseases different from inherited prion diseases (IPD). We report a novel missense P39L mutation in the N-terminal domain of prion protein in 2 patients affected by frontotemporal lobar degeneration syndrome, negative for mutations in genes causative of dementia. Neither the first carrier, a 67-year-old male in which the onset was a progressive non-fluent aphasia, nor the second carrier, a 78-year-old male affected by frontotemporal dementia and parkinsonism, showed any clinical or instrumental findings suggestive of IPD. Genetic screening of healthy controls and in silico analysis provide support for the potential pathogenicity of this variant. Patient phenotypes, unclassifiable as prion disease, may depend on the location of the mutation in the N-terminal domain, outside the amyloid core of pathologic prion protein, although further functional studies are required to determine whether and how this mutation exerts its pathogenic effect. However, genetic screening of prion protein gene becomes relevant in familial degenerative dementia, particularly in geographical areas with high IPD prevalence.     

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.     

Linking novelty seeking and harm avoidance personality traits to basal ganglia: volumetry and mean diffusivity

Novelty Seeking (NS) and Harm Avoidance (HA) temperamental traits are related to approaching or avoiding motivational circuits relying on the integrity and functionality of distributed brain areas implicated in arousal and action. The present study verified whether and how macro- and micro-structural variations of basal ganglia are correlated with scores obtained in the NS and HA temperamental scales of the Temperament and Character Inventory by Cloninger. To this aim, 125 healthy adults aged 18–67 years of both sexes completed the Temperament and Character Inventory and underwent a high-resolution T1-weighted magnetic resonance imaging and a diffusion tensor imaging using a 3T scanner. The scores obtained in the temperamental scales were associated with volumes, mean diffusivity and fractional anisotropy measures of basal ganglia of both hemispheres separately, by using linear regression analyses. We found increased bilateral caudate and pallidum volumes associated with higher NS scores, as well as increased mean diffusivity in the bilateral putamen associated with higher HA scores. Macro- and micro-structural variations of basal ganglia regions contribute to explain the biological variance associated with NS or HA personality phenotype. The present findings evidencing some brain-temperament relationships highlight the importance of obtaining macro- and micro-structural measures in relation to individual differences.     

Excess total mortality in 2021 in Italy was about one third of that observed in 2020

Background:Italy was severely hit by the Covid-19 pandemic with an excess of around 90,000 total deaths in 2020. Comparable data in 2021 are needed for monitoring the effects of the interventions adopted to control its spread and reduce the burden. This study estimates the excess mortality in Italy in the first eight months of 2021, with a focus on the working age population.Methods:Excess mortality was estimated as difference between the number of registered deaths and the expected deaths. Expected deaths in March-December 2020 and January-August 2021 were estimated separately by sex, through an over-dispersed Poisson regression model using mortality and population data for the period 2011-2019 (before the Covid-19 outbreak). The models included terms for calendar year, age group, a smooth function of week of the year and the natural logarithm of the population as offset term.Results:In the first eight months of 2021, we estimated 34,599 excess deaths (+7.9% of the expected deaths), of these 3667 were among individuals of working age (25-64 years). In this age group, mortality was 8.2% higher than expected with higher excesses among men (2972 deaths, +10.7%) than women (695 deaths, +4.1%).Conclusions:The excess deaths in the first eight months of 2021 account for about one third of that registered in 2020. Current data indicate that around 5000 excess deaths are expected by the end of the year, leading to a total excess for 2021 of around 40 thousand deaths. Despite the absence of influenza in January-March 2021, a relevant excess was also observed among the working age population.