Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA’s neuroprotective action derives from animal models of Alzheimer’s disease, Parkinson’s disease, Huntington’s diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.

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Endoscopic management for difficult common bile duct (CBD) stones still presents a challenge for several reasons, including anatomic anomalies, patients’ individual conditions and stone features. In recent years, variable methods have emerged that have attributed to higher stone removal success rates, reduced cost and lower adverse events. In this review, we outline a stepwise approach in CBD stone management. As first line therapy, endoscopic sphincterotomy and large balloon dilation are recommended, due to a 30%-50% reduction of the use of mechanical lithotripsy. On the other hand, cholangioscopy-assisted lithotripsy has been increasingly reported as an effective and safe alternative technique to mechanical lithotripsy but remains to be reserved in special settings due to limited large-scale evidence. As discussed, findings suggest that management needs to be tailored to the patient’s characteristics and anatomical conditions. Furthermore, we evaluate the management of CBD stones in various surgical altered anatomy (Billroth II, Roux-en-Y and Roux-en-Y gastric bypass). Moreover, we could conclude that cholangioscopy-assisted lithotripsy needs to be evaluated for primary use, rather than following a failed management option. In addition, we discuss the importance of dissecting other techniques, such as the primary use of interventional endoscopic ultrasound for the management of CBD stones when other techniques have failed. In conclusion, we recognize that endoscopic sphincterotomy and large balloon dilation, mechanical lithotripsy and intraductal lithotripsy substantiate an indication to the management of difficult CBD stones, but emerging techniques are in rapid evolution with encouraging results.

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