Hepatitis C virus glycoproteins E1 and E2 do not reach the plasma membrane of the cell but accumulate intracellularly, mostly in the endoplasmic reticulum. Previous studies based on transient expression assays have shown that the transmembrane domains of both glycoproteins are sufficient to localize reporter proteins in the endoplasmic reticulum and that other localization signals may be contained in the ectodomain of E1 protein.To identify such signals we generated chimeric proteins between E1 and two reporter proteins, the human CD8 glycoprotein and the human alkaline phosphatase, and analyzed their subcellular localization in stable as well as transient transfectants. Our results showed that (i) an independent localization determinant for the endoplasmic reticulum is present in the juxtamembrane region of the ectodomain of E1 protein and (ii) the localization dictated by this determinant is either due to direct retention or to a recycling mechanism from the intermediate compartment/cis-Golgi complex region, which is clearly different from those previously described for other retrieval signals. These results show for the first time in mammalian cells that the localization in the endoplasmic reticulum of transmembrane protein can be determined by specific targeting signals acting in the lumen of the compartment. HCV1 is a major agent of chronic hepatitis and liver diseases in humans throughout the world. It is classified in the Flaviviridae family because of its similarity in genomic organization to flavivirus and pestivirus. The genome, a single positivestrand RNA, is translated into a polyprotein of about 3,000 amino acid residues, which is processed by host and viral proteases to generate at least 10 polypeptides (reviewed in Ref. 1). Little is known on HCV replication and assembly because the virus does not infect laboratory animals and tissue-cultured cells. Only recently Lohmann et al. (2) succeeded in designing a self-replicating subgenomic viral RNA, and to date biogenesis of HCV proteins has been studied only by cell-free transcription/translation and transfection assays. These experiments show that co-translational cleavages in the N-terminal region of HCV nascent chain release the two putative envelope viral glycoproteins, E1 and E2 (3). E1 and E2 are intrinsic membrane proteins with an N-terminal ectodomain that is heavily N-glycosylated and a C-terminal hydrophobic TMD, whose precise length has not been established. When expressed in tissue culture cells, E1 and E2 interact with each other and with resident chaperones forming two types of complexes: heterogeneous aggregates containing E1 and E2, possibly associated by intermolecular disulfide bonds, as well as calreticulin and calnexin and a non-covalent heterodimer presumably representing the correct folding state that precedes the formation of the viral envelope (4 -6). Independently of their oligomeric status, E1 and E2 localize predominantly in the ER and are not transported to the cell surface (4, 6 -8). This localization suggests that HCV bud...

Abstract. Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer's disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A-and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy. The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-Aon frontal tasks. The AD-A+ had poorer performance than AD-A-on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales. The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an 'apathetic syndrome', characterized by specific cognitive and psychological symptoms.

The aim of this study was to evaluate the effectiveness of a new technical variant applied to the Gufoni's manoeuvre, in the treatment of horizontal canal benign paroxysmal positional vertigo (HSC-BPPV). 87 patients with BPPV of HSC (55 women and 32 men), aged between 21 and 80 years, were randomized either to modified Gufoni's manoeuvre or to the Gufoni's manoeuvre. 93% of patients treated with modified Gufoni's manoeuvre was cured after the first treatment session, of which only 2% had a conversion into PSC-BPPV, while the Gufoni's manoeuvre led to a symptoms resolution in 88% of cases, of which 16% had a conversion into PSC-BPPV. Therefore, the modified Gufoni's manoeuvre shows the same effectiveness in the resolution of symptoms of Gufoni's manoeuvre, but it appears more effective than the latter to reduce the percentage of conversion of the HSC-BPPV into PSC-BPPV (χ2=6.13,P=0.047).

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