Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based ...on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin‐producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub‐classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho‐molecular groups can currently be discriminated. Large‐duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2‐fusions are typically seen in small‐duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.
Idiopathic non-cirrhotic portal hypertension is an under-recognized vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension in the absence of cirrhosis. By ...definition, any disorder known to cause portal hypertension in the absence of cirrhosis and any cause of chronic liver disease must be excluded to make a diagnosis of idiopathic non-cirrhotic portal hypertension. However, the diagnosis is often difficult because the disease resembles cirrhosis and there is no gold standard test. Liver biopsy is an essential tool: it is able to exclude cirrhosis and other causes of portal hypertension and it allows the identification of the characteristic lesions. Nonetheless, the histological diagnosis of idiopathic non-cirrhotic portal hypertension is not always straightforward, in particular by needle biopsy samples, because there is no pathognomonic lesion, but rather a variety of vascular changes which are unevenly distributed, very subtle, and not all necessarily identified in a single specimen. Pathologists should be able to recognize several patterns of injury, involving portal/periportal areas as well as parenchymal structures.The histological features of idiopathic non-cirrhotic portal hypertension are described in this review, focusing on their interpretation in needle biopsy specimens.
CSF Neurofilament light chain(NfL) is a promising biomarker of neurodegeneration, but its utility in discriminating between Alzheimer's disease(AD) and frontotemporal dementia(FTD) is limited.
105 ...patients with clinical-biological diagnosis of mild cognitive impairment(MCI) due to AD (N = 72) or clinical diagnosis of FTD (N = 33) underwent neuropsychological assessment and CSF Aβ42/40, p-tau181, total-tau and NfL quantification. Group comparisons, correlations between continuous variables and ROC curve analysis were carried out to assess NfL role in discriminating between MCI due to AD and FTD, exploring the associations between NfL, ATN biomarkers and neuropsychological measures.
NfL levels were significantly lower in the AD group, while levels of total-tau were higher. In the FTD group, significant correlations were found between NfL, p-tau181 and total-tau, and between NfL and cognitive performances. In the AD group, NfL levels were directly correlated with total-tau and p-tau181; Aβ42/40 ratio was inversely correlated with total-tau and p-tau181, but not with NfL. Moreover, p-tau181 and t-tau levels were found to be associated with episodic memory and lexical-semantic impairment. Total-tau/NfL ratio differentiated prodromal-AD from FTD with an AUC of 0.951, higher than the individual measures.
The results support that NfL and total-tau levels reflect distinct pathophysiological neurodegeneration mechanisms, independent and dependent of Aβ pathology, respectively, Combining them may enhance both markers reliability, their ratio showing high accuracy in distinguishing MCI due to AD from FTD. Moreover, our results revealed associations between NfL and disease severity in FTD and between tauopathy and episodic memory and lexical-semantic impairment in prodromal-AD.
•NfL and t-tau reflect different pathophysiological mechanism of neurodegeneration.•The t-tau/NfL ratio distinguish MCI due to AD from FTD with high accuracy.•Episodic and semantic memory decline are related with p-tau and t-tau in prodromal AD.
Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic ...system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of α-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.
We read with great interest the recent article by Meneghini et al. on the assessment of the effects of different alimentary regimens, included Mediterranean diet (MD), on polycystic ovary syndrome ...(PCOS) patients prior to in vitro fertilization cycles ....
Background/Aims: In chronic viral hepatitis, liver biopsy is performed for assessing disease activity and fibrosis. In this study, we evaluated the impact of the size of liver biopsy on the grading ...and staging.
Methods: We selected 161 liver biopsies from patients with chronic types B and C hepatitis on the basis of their length (≥3 cm) and width (1.4 mm). Ishak scoring system was used for grading and staging. The score was blindly repeated reducing the length of the specimen from ≥3 to 1.5 cm and to 1 cm long and width from 1.4 to 1 mm.
Results: Reducing the length of the biopsy led to an increase of cases with mild grades: 49.7% in ≥3 cm, 60.2% in 1.5 cm and 86.6% in 1 cm long specimens (
P<0.001). Similarly, cases staged as having mild fibrosis significantly increased in the shorter specimens: 59% in ≥3 cm, 68.3% in 1.5 cm and 80.1% in 1 cm long specimens (
P<0.001). As for the width, both grade and stage were significantly underscored in the 1 mm samples, regardless of their length.
Conclusions: Liver biopsy size strongly influences the grading and staging of chronic viral hepatitis. The use of fine needles should be discouraged in this setting.
Induced seismicity represents a negative drawback during subsurface exploitation for geothermal energy production. Understanding the triggering mechanisms of induced earthquakes can help implement ...effective seismic hazard mitigation actions. Among the triggering mechanisms, the pore fluid pressure is of primary importance. Here we provide a static picture of the excess pore fluid pressure at the hypocenters of a seismic sequence induced at the deep geothermal field in St. Gallen, Switzerland, in July 2013. We find that in addition to the Coulomb static stress change, fluids play a key role in promoting the sequence. The estimated excess pore fluid pressure for approximately half of the earthquakes is higher than the injection pressure necessary during the well control phase to fight the unexpected gas kick, that accidently occurred during field operations when a trap of overpressured gas was broken.
Plain Language Summary
In July 2013, a sequence of more than 340 earthquakes was induced during the exploitation of the subsurface for energy production in St. Gallen geothermal field (Switzerland). To understand the mechanisms underlying the evolution of the sequence, we investigated the role of fluids and elastic stress transfer. The excess pore fluid pressure measurements suggest that the main triggering mechanism is related to high‐pressure fluids. The high values of the pore fluid pressure may be due to an already existing in situ overpressure condition from which a documented unexpected gas kick occurred.
Key Points
The main earthquake triggering mechanism is the effect of high‐pressure fluids
The high pore fluid pressure values may be due to an already existing in situ overpressure condition
Glucocorticoids (GCs) are currently used for the therapeutic management of cholestatic diseases, but their use and molecular mechanism remain controversial. The aims of this study were 1) to assess ...the therapeutic effect of a 2-week treatment with the GC dexamethasone on hepatic damage in bile duct-ligated rats; 2) to investigate its effect on the activation of the nuclear receptors (NRs) pregnane X receptor (PXR), constitutive androstane receptor (CAR) and GC receptor (GR), and NF-kB, as well as on oxidative stress and bile acid (BA) hepatic composition. Cholestasis was induced by ligation of bile duct (BDL animals) in 16 male Wistar-Kyoto rats, and eight of them were daily treated by oral gavage with 0.125 mg/ml/kg DEX for 14 days. Eight Sham-operated rats were used as controls. Severity of cholestasis was assessed histologically and on plasma biochemical parameters. The nuclear expression of NF-kB (p65), GR, PXR and CAR was measured in hepatic tissue by Western Blot. Oxidative stress was evaluated by measuring malondialdehyde, carbonylated proteins, GHS and ROS content in rat livers. LC-MS was used to measure the plasma and liver concentration of 7 BAs. Histological findings and a significant drop in several markers of inflammation (p65 nuclear translocation, mRNA expressions of TNF-α, IL-1β, IL-6) showed that DEX treatment reversed cholestasis-induced inflammation, and similar results have been obtained with oxidative stress markers. The nuclear expression of p65 and CAR were inversely correlated, with the latter increasing significantly after DEX treatment (p<0.01 vs vehicle). Hepatic BA levels tended to drop in the untreated cholestatic rats, whereas they were similar to those of healthy rats in DEX-treated animals. Plasma BAs decreased significantly in DEX-treated animals with respect to untreated cholestatic rats. In conclusion, DEX reduces inflammation and oxidative stress in BDL rats, and probably CAR is responsible for this effect. Therefore, this NR represents a promising pharmacological target for managing cholestatic and inflammatory liver diseases.
22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, ...most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol‐O‐methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.
PDF
