Diagnostic biomarkers for Parkinson's disease at a glance : where are we?

Parkinson's disease (PD) is a neurodegenerative disorder whose aetiology remains unclear: degeneration involves several neurotransmission systems, resulting in a heterogeneous disease characterized by motor and non-motor symptoms. PD causes progressive disability that responds only to symptomatic therapies. Future advances include neuroprotective strategies for use in at-risk populations before the clinical onset of disease, hence the continuing need to identify reliable biomarkers that can facilitate the clinical diagnosis of PD. In this evaluative review, we summarize information on potential diagnostic biomarkers for use in the clinical and preclinical stages of PD

Imaging review of the lung parenchymal complications in patients with IPF

Idiopathic pulmonary fibrosis (IPF) is a chronic, pulmonary-limited, interstitial lung disease with a poor prognosis. This condition is characterized by different clinical scenarios, ranging from the most typical slow and progressive deterioration of symptoms to a rapid and abrupt decline of lung function. Rapid worsening of clinical course is due to superimposed complications and comorbidities that can develop in IPF patients, with a higher incidence rate compared to the general population. These conditions may require a different management of the patient and a therapy adjustment, and thus it is fundamental to recognize them. High Resolution Computed Tomography (HRCT) is sensitive, but not specific, in detecting these complications, and can evaluate the presence of radiological variations when previous examinations are available; it recognizes ground glass opacities or consolidation that can be related to a large spectrum of comorbidities, such as infection, lung cancer, or acute exacerbation. To reach the final diagnosis, a multidisciplinary discussion is required, particularly when the clinical context is related to imaging findings

Reduced Deadtime and Higher Rate Photon-Counting Detection using a Multiplexed Detector Array

We present a scheme for a photon-counting detection system that can be operated at incident photon rates higher than otherwise possible by suppressing the effects of detector deadtime. The method uses an array of N detectors and a 1-by-N optical switch with a control circuit to direct input light to live detectors. Our calculations and models highlight the advantages of the technique. In particular, using this scheme, a group of N detectors provides an improvement in operation rate that can exceed the improvement that would be obtained by a single detector with deadtime reduced by 1/N, even if it were feasible to produce a single detector with such a large improvement in deadtime. We model the system for continuous and pulsed light sources, both of which are important for quantum metrology and quantum key distribution applications.Comment: 6 figure

GHz QKD at telecom wavelengths using up-conversion detectors

We have developed a hybrid single photon detection scheme for telecom wavelengths based on nonlinear sum-frequency generation and silicon single-photon avalanche diodes (SPADs). The SPAD devices employed have been designed to have very narrow temporal response, i.e. low jitter, which we can exploit for increasing the allowable bit rate for quantum key distribution. The wavelength conversion is obtained using periodically poled Lithium niobate waveguides (W/Gs). The inherently high efficiency of these W/Gs allows us to use a continuous wave laser to seed the nonlinear conversion so as to have a continuous detection scheme. We also present a 1.27GHz qubit repetition rate, one-way phase encoding, quantum key distribution experiment operating at telecom wavelengths that takes advantage of this detection scheme. The proof of principle experiment shows a system capable of MHz raw count rates with a QBER less than 2% and estimated secure key rates greater than 100 kbit/s over 25 km.Comment: 12 pages, 7 figure

Case Identification and Characterization of Migrants with Dementia in the Lazio Region Using Health Administrative Data

Background: A crucial step for planning effective public health policies for migrants with dementia is the collection of data on the local dimensions of the phenomenon and patients' characteristics.Objective: This study aimed to identify and characterize migrants with dementia in the Lazio region using health administrative databases.Methods: Residents with dementia aged 50 years or older, living in the Lazio region as of December 31, 2018, were identified using a validated algorithm based on hospital discharge(s), claims for antidementia drugs, and co-payment exemption for dementia. Migrants were defined as people born abroad and grouped in migrants from High Migratory Pressure Countries (HMPCs) and Highly Developed Countries (HDCs). Overall and age-specific prevalence rates were estimated in native- and foreign-born patients.Results: Dementia was ascertained in 38,460 residents. Among them, 37,280 (96.9%) were born in Italy, 337 (0.9%) were migrants from HDCs, and 843 (2.2%) from HMPCs. Dementia prevalence was higher among natives (1.15%, 95%CI 1.14-1.16) relative to migrants from HDCs (0.60%, 95%CI 0.54-0.67) and HMPCs (0.29%, 95%CI 0.27-0.31). The prevalence of comorbidities did not differ between groups. Migrants with dementia had a lower likelihood of receiving antidementia treatments compared with natives (51.6% in migrants from HDCs, 49.3% in migrants from HMPCs, and 53.5% among Italians).Conclusion: Routinely collected data in healthcare administrative databases can support the identification of migrants with dementia. Migrants exhibited a lower age-standardized prevalence of registered dementia and lower access to dedicated treatments than Italians. These findings are suggestive of underdiagnosis and undertreatment of dementia in migrants

Dementia Among Migrants and Ethnic Minorities in Italy: Rationale and Study Protocol of the ImmiDem Project

Introduction: Due to the ongoing demographic and epidemiological transitions, estimating the phenomenon of dementia in migrants and minority groups, exploring its characteristics and challenges and implementing dedicated healthcare policies, constitute emerging and urgent matters for Western countries. In the present paper we describe the rationale and design of the 'Dementia in immigrants and ethnic minorities living in Italy: clinical-epidemiological aspects and public health perspectives" (ImmiDem) project. Methods and analysis: Three main aims will be pursued by the ImmiDem project. First, a survey of all Italian dementia services will be conducted with dedicated questionnaires in order to estimate and describe the proportion and characteristics of migrants seeking help for cognitive disturbances. The different clinical approaches for diagnosing dementia and the challenges encountered in the assessment of cognitive functioning and in the provision of care in these groups of individuals will also be investigated. Second, record linkage procedures of data routinely collected in regional Health Information Systems will be conducted in order to identify and monitor migrant individuals with dementia living in the Lazio region. Third, tailored national and local care-coordination pathways and/or good practices dedicated to migrants affected by dementia and cognitive disorders will be identified and promoted. Ethics and dissemination: The study protocol was approved by the Ethics Committee of the Italian National Institute of Health (protocol 10749; 5 April 2018). The project was launched in November 2018 and will end in November 2021. The findings of the project will be disseminated through scientific peer-reviewed journals as well as to the public via the Dementia Observatory website (https://demenze.iss.it)

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N-Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

UDP-N-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and N- and O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate N-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual Plasmodium falciparum parasites. Furthermore, we present the 1.95 A resolution structure of the GNA1 ortholog from Cryptosporidium parvum, an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for P. falciparum GNA1. The indepth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria. IMPORTANCE Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite''s ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate N-acetyltransferase (GNA1), required for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), is essential for P. falciparum asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite C. parvum, used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate <i>N</i>-Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development.

--- - i: - N - N - O - N - Plasmodium falciparum - Cryptosporidium parvum - P. falciparum - N - N - P. falciparum - C. parvum b: - IMPORTANCE content: - UDP- - "-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and " - "- and " - "-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate " - "-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual " - " parasites. Furthermore, we present the 1.95\xE2\x80\x89\xC3\x85 resolution structure of the GNA1 ortholog from " - ", an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for " - " GNA1. The in-depth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria." - " Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite's ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate " - -acetyltransferase (GNA1), required for the biosynthesis of UDP- - "-acetylglucosamine (UDP-GlcNAc), is essential for " - " asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite " - ", used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite.

Inhibition of hepadnaviral replication by polyethylenimine-based intravenous delivery of antisense phosphodiester oligodeoxynucleotides to the liver

Antisense oligodeoxynucleotides (ODNs) appear as attractive anti-hepatitis B virus (HBV) agents. We investigated in vivo, in the duck HBV (DHBV) infection model, whether linear polyethylenimine (lPEI)-based intravenous delivery of the natural antisense phosphodiester ODNs (O-ODNs) can prevent their degradation and allow viral replication inhibition in the liver. DHBV-infected Pekin ducklings were injected with antisense O-ODNs covering the initiation codon of the DHBV large envelope protein, either in free form (O-ODN-AS2) or coupled to lPEI (lPEI/O-ODN-AS2). Following optimization of lPEI/O-ODN complex formulation, complete O-ODN condensation into a homogenous population of small (20–60 nm) spherical particles was achieved. Flow cytometry analysis showed that lPEI-mediated transfer allowed the intrahepatic delivery of lPEI/O-ODN-AS2 to increase three-fold as compared with the O-ODN-AS2. Following 9-day therapy the intrahepatic levels of both DHBV DNA and RNA were significantly decreased in the lPEI/O-ODN-AS2-treated group as compared with the O-ODN-AS2-treated, control lPEI/O-ODN-treated, and untreated controls. In addition, inhibition of intrahepatic viral replication by lPEI/O-ODN-AS2 was not associated with toxicity and was comparable with that induced by the phosphorothioate S-ODN-AS2 at a five-fold higher dose. Taken together, our results demonstrate that phosphodiester antisense lPEI/O-ODN complexes specifically inhibit hepadnaviral replication. Therefore we provide here the first in vivo evidence that intravenous treatment with antisense phosphodiester ODNs coupled to lPEI can selectively block a viral disease-causing gene in the liver