Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of much needed specific antiviral therapies and an effective vaccine has been hampered by the lack of a convenient small animal model. The determinants restricting HCV tropism to human and chimpanzee hosts are unknown. Replication of the viral RNA has been demonstrated in mouse cells1,2, but these cells are not infectable with either lentiviral particles bearing HCV glycoproteins (HCVpp)3 or HCV produced in cell culture (HCVcc)(unpublished data), suggesting a block at the level of entry. Through an iterative cDNA library screening approach we have identified human occludin (OCLN) as an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for HCV-susceptibility of human cells, since its overexpression in uninfectable cells specifically enhanced HCVpp uptake while its silencing in permissive cells impaired both HCVpp and HCVcc infection. In addition to OCLN, HCVpp infection of murine cells required expression of the previously identified HCV entry factors, CD814, scavenger receptor class B type I (SR-BI)5, and claudin-1 (CLDN1)6. While the mouse versions of SR-BI and CLDN1 function at least as well as the human proteins for promoting HCV entry; both OCLN and CD81, however, must be of human origin to allow efficient infection. The species-specific determinants of OCLN were mapped to its second extracellular loop. The identification of OCLN as a new HCV entry factor further highlights the importance of the tight junction complex in the viral entry process and provides a major advance towards efforts to develop small animal models for HCV.

NCT01564992.

Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson’s disease (PD), a recent meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores at baseline and 6–12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation.

There is currently no cure for Parkinson's disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson's disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.