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Diseases, Volume 6, Issue 3 (September 2018)

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Open AccessFeature PaperArticle Host Protein BAG3 is a Negative Regulator of Lassa VLP Egress
Received: 25 June 2018 / Revised: 10 July 2018 / Accepted: 12 July 2018 / Published: 13 July 2018
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Abstract
Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like
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Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins. Full article
(This article belongs to the Special Issue Host-pathogen Interactions in Ebola, Chikungunya, and Zika Viruses)
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Open AccessReview Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia
Received: 29 June 2018 / Revised: 11 July 2018 / Accepted: 11 July 2018 / Published: 13 July 2018
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Abstract
The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic
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The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia. Full article
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Open AccessFeature PaperArticle Underutilization of Hepatitis C Virus Seropositive Donor Kidneys in the United States in the Current Opioid Epidemic and Direct-Acting Antiviral Era
Received: 14 June 2018 / Revised: 5 July 2018 / Accepted: 9 July 2018 / Published: 10 July 2018
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Abstract
In recent years, the opioid epidemic and new hepatitis C virus (HCV) treatments have changed the landscape of organ procurement and allocation. We studied national trends in solid organ transplantation (2000–2016), focusing on graft utilization from HCV seropositive deceased donors in the pre-2014
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In recent years, the opioid epidemic and new hepatitis C virus (HCV) treatments have changed the landscape of organ procurement and allocation. We studied national trends in solid organ transplantation (2000–2016), focusing on graft utilization from HCV seropositive deceased donors in the pre-2014 (2000–2013) versus current (2014–2016) eras with a retrospective analysis of the United Network for Organ Sharing database. During the study period, HCV seropositive donors increased from 181 to 661 donors/year. The rate of HCV seropositive donor transplants doubled from 2014 to 2016. Heart and lung transplantation data were too few to analyze. A higher number of HCV seropositive livers were transplanted into HCV seropositive recipients during the current era: 374 versus 124 liver transplants/year. Utilization rates for liver transplantation reached parity between HCV seropositive and non-HCV donors. While the number of HCV seropositive kidneys transplanted to HCV seropositive recipients increased from 165.4 to 334.7 kidneys/year from the pre-2014 era to the current era, utilization rates for kidneys remained lower in HCV seropositive than in non-HCV donors. In conclusion, relative underutilization of kidneys from HCV seropositive versus non-HCV donors has persisted, in contrast to trends in liver transplantation. Full article
(This article belongs to the Special Issue Hepatitis and Treatment)
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Open AccessCorrection Correction: Sugiyama, K.; et al. Management of Dyslipidemia in Type 2 Diabetes: Recent Advances in Nonstatin Treatment. Diseases 2018, 6, 44
Received: 6 July 2018 / Revised: 6 July 2018 / Accepted: 6 July 2018 / Published: 7 July 2018
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Open AccessArticle Grape Pomace: Antioxidant Activity, Potential Effect Against Hypertension and Metabolites Characterization after Intake
Received: 13 June 2018 / Revised: 4 July 2018 / Accepted: 6 July 2018 / Published: 6 July 2018
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Abstract
Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension and cardiovascular disease (CVD). Therefore, the aim of this study was to analyse the remained potential of grape by-products from important Rhône Valley red
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Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension and cardiovascular disease (CVD). Therefore, the aim of this study was to analyse the remained potential of grape by-products from important Rhône Valley red wine cultivars: Grenache, Syrah, Carignan, Mourvèdre and Alicante. For that, six different extracts from grape pomaces, selected by their antioxidant activity, were studied in vivo during six weeks with spontaneously hypertensive rats (SHR). Extracts used in SHR1, SHR2 and SHR6 groups presented a « rebound effect » on systolic blood pressure, whereas the other extracts do not change it significantly. The bioavailability of Grenache (GRE1) (EA70) seed pomace extract (SHR1 group), Mouvendre (MOU) (EA70) skin pomace extract (SHR5 group) and Alicante (ALI) (EA70) skin pomace extract (SHR6 group) was studied by High Performance Liquid Chromatography with Photodiode Array detector and Electrospray Ionization Mass Spectrometer (HPLC-PDA-ESI-MSn) in urine, plasma and tissues to search differences on the metabolism of the different extracts intake. Full article
(This article belongs to the Special Issue Wine and Vine Components and Health)
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Open AccessArticle Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus
Received: 7 May 2018 / Revised: 25 June 2018 / Accepted: 5 July 2018 / Published: 6 July 2018
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Abstract
Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease-specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs)
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Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease-specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs) regulates the immune response in several inflammatory disease models. The aim of the current study was to evaluate the effect of HDAC inhibition in the production of inflammatory cytokines in human monocyte-derived macrophages infected with DENV serotype 2 (DENV-2). To this end, human monocyte-derived macrophages (MDMs) were treated with valproic acid (VPA) before or after infection and the inflammatory cytokine concentration was quantified by flow cytometry. We found that infected MDMs secreted IL-8, IL-1b, IL-6, TNF-alpha, and IL-10, but not IL-12. Strikingly, treatment of infected cells with VPA had a differential and concentration-dependent effect on the production of specific cytokines without eliciting significant changes in cell viability. Using the highest concentration of VPA, a significant reduction in the production of all cytokines was observed. These results suggest that HDAC inhibition during DENV-2 infection could exert an important regulatory effect in the production of inflammatory cytokines, representing a significant advance in the design of novel therapeutic dengue treatments. Full article
(This article belongs to the Section Infectious Disease)
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Open AccessFeature PaperShort Note Action Observation in People with Parkinson’s Disease. A Motor–Cognitive Combined Approach for Motor Rehabilitation. A Preliminary Report
Received: 19 May 2018 / Revised: 29 June 2018 / Accepted: 1 July 2018 / Published: 4 July 2018
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Abstract
The aim of this study was to assess the role of Action Observation (AO) to improve balance, gait, reduce falls, and to investigate the changes in P300 pattern. Five cognitively intact People with Parkinson’s disease (PwP) were enrolled in this prospective, quasi-experimental study
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The aim of this study was to assess the role of Action Observation (AO) to improve balance, gait, reduce falls, and to investigate the changes in P300 pattern. Five cognitively intact People with Parkinson’s disease (PwP) were enrolled in this prospective, quasi-experimental study to undergo a rehabilitation program of AO for gait and balance recovery of 60 min, three times a week for four weeks. The statistical analysis showed significant improvements for Unified Parkinson’s Disease Rating Scale (UPDRS) motor section III p = 0.0082, Short form 12-items Healthy Survey (SF-12) Mental Composite Score (MCS) p = 0.0007, Freezing of gait Questionnaire (FOG-Q) p = 0.0030, The 39-items Parkinson’s Disease Questionnaire (PDQ-39) p = 0.100, and for P300ld p = 0.0077. In conclusion, AO reveals to be a safe and feasible paradigm of rehabilitative exercise in cognitively preserved PwP. Full article
(This article belongs to the Special Issue Neuro-psychiatric Disorders - from Diagnosis to Care)
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Open AccessFeature PaperReview Nonviral Gene Therapy for Cancer: A Review
Received: 27 April 2018 / Revised: 29 June 2018 / Accepted: 1 July 2018 / Published: 3 July 2018
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Abstract
Although the development of effective viral vectors put gene therapy on the road to commercialization, nonviral vectors show promise for practical use because of their relative safety and lower cost. A significant barrier to the use of nonviral vectors, however, is that they
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Although the development of effective viral vectors put gene therapy on the road to commercialization, nonviral vectors show promise for practical use because of their relative safety and lower cost. A significant barrier to the use of nonviral vectors, however, is that they have not yet proven effective. This apparent lack of interest can be attributed to the problem of the low gene transfer efficiency associated with nonviral vectors. The efficiency of gene transfer via nonviral vectors has been reported to be 1/10th to 1/1000th that of viral vectors. Despite the fact that new gene transfer methods and nonviral vectors have been developed, no significant improvements in gene transfer efficiency have been achieved. Nevertheless, some notable progress has been made. In this review, we discuss studies that report good results using nonviral vectors in vivo in animal models, with a particular focus on studies aimed at in vivo gene therapy to treat cancer, as this disease has attracted the interest of researchers developing nonviral vectors. We describe the conditions in which nonviral vectors work more efficiently for gene therapy and discuss how the goals might differ for nonviral versus viral vector development and use. Full article
(This article belongs to the Section Oncology)
Open AccessFeature PaperReview Gut Microbiome and Cardiovascular Diseases
Received: 8 June 2018 / Revised: 27 June 2018 / Accepted: 29 June 2018 / Published: 29 June 2018
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Abstract
Recent evidence has suggested that the gut microbiome is involved in human health and diseases, such as inflammatory bowel disease, liver cirrhosis, rheumatoid arthritis, and type 2 diabetes. Cardiovascular diseases, which are associated with high morbidity and mortality across the world, are no
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Recent evidence has suggested that the gut microbiome is involved in human health and diseases, such as inflammatory bowel disease, liver cirrhosis, rheumatoid arthritis, and type 2 diabetes. Cardiovascular diseases, which are associated with high morbidity and mortality across the world, are no exception. Increasing evidence has suggested a strong relationship between the gut microbiome and the progression of cardiovascular diseases. We first reported such a relationship with coronary artery disease two years ago. Next-generation sequencing techniques, together with bioinformatics technology, constantly and dramatically expand our knowledge of the complex human gut bacterial ecosystem and reveal the exact role of this bacterial ecosystem in cardiovascular diseases via the functional analysis of the gut microbiome. Such knowledge may pave the way for the development of further diagnostics and therapeutics for prevention and management of cardiovascular diseases. The aim of the current review is to highlight the relationship between the gut microbiome and their metabolites, and the development of cardiovascular diseases by fostering an understanding of recent studies. Full article
(This article belongs to the Special Issue Gut Microbiome and Human Diseases)
Open AccessCase Report Role of Handheld In Vivo Reflectance Confocal Microscopy for the Diagnosis of Fabry Disease: A Case Report
Received: 6 June 2018 / Revised: 21 June 2018 / Accepted: 25 June 2018 / Published: 27 June 2018
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Abstract
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase that leads to a systemic accumulation of globotriaosylceramide. Handheld in vivo reflectance confocal microscopy (HH-RCM) is a useful modern technique in diagnosis and
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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase that leads to a systemic accumulation of globotriaosylceramide. Handheld in vivo reflectance confocal microscopy (HH-RCM) is a useful modern technique in diagnosis and follow-ups of many skin diseases. This noninvasive device provides high-resolution and high-contrast real-time images to study both the skin and the ocular surface structures that can help clinicians to confirm the diagnosis of FD. HH-RCM could be helpful even for the follow-ups of these patients, enabling us to monitor the effect of enzyme replacement therapy on corneal cells and keratinocytes. Full article
(This article belongs to the collection Lysosomal Storage Diseases)
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Open AccessFeature PaperInteresting Images Solitary Brain Mass in a Patient with Seizures: An Unexpected Infectious Etiology
Received: 9 June 2018 / Revised: 22 June 2018 / Accepted: 22 June 2018 / Published: 22 June 2018
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Abstract
Neurocysticercosis is a parasitosis caused by the larval stage of the pork tapeworm Taenia solium. The diagnosis is challenging as morphology on neuroimaging can be inconclusive and serology is frequently negative. We describe the case of a 24-year old Hispanic man who presented
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Neurocysticercosis is a parasitosis caused by the larval stage of the pork tapeworm Taenia solium. The diagnosis is challenging as morphology on neuroimaging can be inconclusive and serology is frequently negative. We describe the case of a 24-year old Hispanic man who presented with seizures and loss of consciousness. Magnetic resonance imaging (MRI) showed a cystic mass in right frontal lobe. Work-up that included body computed tomography (CT) scan and Western blot serology for Echinococcus and cysticercosis was unrevealing. He underwent craniotomy with resection of the mass. Histopathology showed fragments of Taenia solium. He was treated with albendazole for 14 days. No further seizures were noted at 6-month follow-up. Full article
(This article belongs to the Section Infectious Disease)
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Open AccessFeature PaperCase Report Fatal Human Case of Zika and Chikungunya Virus Co-Infection with Prolonged Viremia and Viruria
Received: 17 May 2018 / Revised: 14 June 2018 / Accepted: 18 June 2018 / Published: 21 June 2018
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Abstract
Zika virus (ZIKV) infection usually presents as a mild and self-limited illness, but it may be associated with severe outcomes. We describe a case of a 30-year-old man with systemic erythematous lupus and common variable immunodeficiency who became infected with both Zika (ZIKV)
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Zika virus (ZIKV) infection usually presents as a mild and self-limited illness, but it may be associated with severe outcomes. We describe a case of a 30-year-old man with systemic erythematous lupus and common variable immunodeficiency who became infected with both Zika (ZIKV) and Chikungunya (CHIKV) virus during the 2016 outbreak in Rio de Janeiro, Brazil. The patient presented with intense wrist and right ankle arthritis, and ZIKV RNA and virus particles were detected in synovial tissue, blood and urine, and CHIKV RNA in serum sample, at the time of the diagnosis. During the follow up, ZIKV RNA persisted for 275 days post symptoms onset. The patient evolved with severe arthralgia/arthritis and progressive deterioration of renal function. Fatal outcome occurred after 310 days post ZIKV and CHIKV co-infection onset. The results show the development of severe disease and fatal outcome of ZIKV infection in an immunosuppressed adult. The data suggests a correlation between immunodeficiency and prolonged ZIKV RNA shedding in both blood and urine with progressive disease. The results also indicate a possible role for arbovirus co-infections as risk factors for severe and fatal outcomes from ZIKV infection. Full article
(This article belongs to the Special Issue Host-pathogen Interactions in Ebola, Chikungunya, and Zika Viruses)
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