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Αλέξανδρος Γ. Σφακιανάκης

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Sunday, September 11, 2022

Aβ plaques do not protect against HSV‐1 infection in a mouse model of familial Alzheimer's disease, and HSV‐1 does not induce Aβ pathology in a model of late onset Alzheimer's disease

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Abstract

The possibility that the etiology of late onset Alzheimer's disease is linked to viral infections of the CNS has been actively debated in recent years. According to the antiviral protection hypothesis, viral pathogens trigger aggregation of Aβ peptides that are produced as a defense mechanism in response to infection to entrap and neutralize pathogens. To test the causative relationship between viral infection and Aβ aggregation, the current study examined whether Aβ plaques protect the mouse brain against Herpes Simplex Virus 1 (HSV-1) infection introduced via a physiological route and whether HSV-1 infection triggers formation of Aβ plaques in a mouse model of late-onset AD that does not develop Aβ pathology spontaneously. In aged 5XFAD mice infected via eye scarification, high density of Aβ aggregates did not improve survival time or rate when compared with wild type controls. In 5XFADs, viral replication sites were found in brain areas with a high density of extracellula r Aβ deposits, however, no association between HSV-1 and Aβ aggregates could be found. To test whether HSV-1 triggers Aβ aggregation in a mouse model that lacks spontaneous Aβ pathology, 13-month-old hAβ/APOE4/Trem2*R47H mice were infected with HSV-1 via eye scarification with the McKrae HSV-1 strain, intracranial inoculation with McKrae, intracranial inoculation after priming with LPS for 6 weeks, or intracranial inoculation with high doses of McKrae or 17syn + strains that represent different degrees of neurovirulence. No signs of Aβ aggregation were found in any of the experimental groups. Instead, extensive infiltration of peripheral leukocytes was observed during the acute stage of HSV-1 infection, and phagocytic activity of myeloid cells was identified as the primary defense mechanism against HSV-1. The current results argue against a direct causative relationship between HSV-1 infection and Aβ pathology.
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Improving causal inference of mediation analysis with multiple mediators using interventional indirect effects

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Mediation analysis is indispensable for investigating how a treatment causally affects an outcome via intervening variables. Existing discussions on the validity of causal inference drawn from mediation analysis have prioritized single mediator settings. In this article, we focus on improving causal inference when investigating multiple mediators. We pay particular attention to the prevalent practice of exploring mediated effects along various paths linking several mediators. Such approaches are fraught with stringent—yet often overlooked—causal assumptions that predicate valid inference of indirect or mediated effects. To mitigate the risk of incorrect inference, we introduce a conceptually and substantively novel approach from the causal inference literature: interventional indirect effects. Interventional indirect effects focus on the contributions of each distinct mediator to the treatment effect on the outcome. An appealing feature of this approach is that valid causal in ference of mediation analysis with multiple mediators can be attained without assuming a (correct) causal structure among the mediators. Using a social psychology experiment as a running example, we illustrate how researchers can readily estimate and interpret the proposed interventional effects in practice. We hope this article will encourage explaining and substantiating the causal assumptions underpinning mediation analysis with multiple mediators to fortify causal inference in psychology research.
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Preclinical feasibility of robot‐assisted sentinel lymph node biopsy using multi‐modality magnetic and fluorescence guidance in the head and neck

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Abstract

Background

Sentinel lymph node biopsy (SLNB) is a staging procedure dependent on accurate mapping of draining lymphatics via tracers. Robot-assisted SLNB enables access to multiple neck levels with a single incision and intraoperative fluorescence guidance to the SLN.

Methods

Lymphatic mapping in swine was done using a magnetic tracer and fluorescent dye, injected into the tongue. MRI preoperatively mapped lymphatic spread of the magnetic tracer. Dissection was performed using a da Vinci Xi robot guided by fluorescence-imaging of the dye.

Results

Robot-assisted SLNB was successfully performed in all animals (n = 5). A novel MRI protocol differentiated SLNs (n = 6) from lower echelon nodes (n = 11) based on flow progression. Fluorescence imaging provided valuable intraoperative guidance and correlated with magnetic-positive nodes.

Conclusions

This study demonstrates preclinical feasibility of a robot-assisted approach to SLNB using magnetic and fluorescent tracers in the head and neck, enabling both preoperative mapping and intraoperative guidance.
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Quantification of Patient-Reported Pain Locations: Development of an Automated Measurement Method

alexandrossfakianakis shared this article with you from Inoreader
imagePatient-reported pain locations are critical for comprehensive pain assessment. Our study aim was to introduce an automated process for measuring the location and distribution of pain collected during a routine outpatient clinic visit. In a cross-sectional study, 116 adults with sickle cell disease–associated pain completed PAINReportItⓇ. This computer-based instrument includes a two-dimensional, digital body outline on which patients mark their pain location. Using the ImageJ software, we calculated the percentage of the body surface area marked as painful and summarized data with descriptive statistics and a pain frequency map. The painful body areas most frequently marked were the left leg-front (73%), right leg-front (72%), upper back (72%), and lower back (70%). The frequency of pain marks in each of the 48 body segments ranged from 3 to 79 (mean, 33.2 ± 21.9). The mean percentage of painful body surface area per segment was 10.8% ± 7.5% (ranging from 1.3% to 33.1%). Patient-reported pain locations can be easily analyzed from digital drawings using an algorithm created via the free ImageJ software. This method may enhance comprehensive pain assessment, facilitating research and personalized care over time for patients with various pain conditions.
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Potential associations between alterations in gut microbiome and obesity‐related traits after the bariatric surgery

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Aim

This study aimed to examine the effects of both obesity and bariatric surgery on gut microbiome, dietary intake, as well as metabolic and inflammatory parameters.

Methods

All participants (15 with morbid obesity who had bariatric surgery, 8 with morbid obesity and 11 non-obese) were followed-up for a 6-month period with the interviews at baseline (M0), at the end of 3 (M3) and 6 months (M6). Dietary assessment was done, and blood and faecal samples were collected.

Results

Dietary energy and nutrient intakes as well as serum levels glucose, total cholesterol, LDL-cholesterol, and hs-CRP levels decreased by surgery (p<0.05, for each). Participants with morbid obesity had higher levels of Firmicutes and lower levels of Bacteroidetes at M0 compared to non-obese participants. The abundances of Bacteroidetes increased (p=0.02) while Firmicutes decreased (p>0.05) by the surgery, leading a significant decrease in Firmicutes/Bacteroidetes ratio (p=0.01). At sub-phylum level, the abundances of Lactobacillus and Bifidobacterium decreased while Akkermansia increased by the surgery (p<0.01, for each). Although participants who are morbidly obese had a distinct profile according to ß-diversity indices at M0, it became similar with the profile of non-obese participants (p>0.05) at M3 and M6. Similarly, α-diversity indices were lower in subjects with morbid obesity at M0, but became similar to levels in non-obese controls at M6.

Conclusion

This study confirmed that bariatric surgery has substantial impacts on gut microbiome composition and diversity, as well as anthropometrical measurements and biochemical parameters, which were associated with the alterations in dietary intake patterns.

This article is protected by copyright. All rights reserved.
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Cost‐effectiveness analysis of silver diamine fluoride to divert dental general anaesthesia compared to standard care

alexandrossfakianakis shared this article with you from Inoreader

ABSTRACT

Background

The aim is to perform a model-based cost-effectiveness analysis of a silver diamine fluoride (SDF) protocol intervention to divert dental general anaesthesia (DGA) among Victorian children aged 2- 10 years.

Methods

Data inputs was based on an Australian single-cohort 2017/18 study. Intervention costs for standard care were derived from two subgroups of children: 1) children who received standard care without DGA, and 2) children who received standard care with DGA. Two scenarios were modelled due to limited post-follow-up data: 1) children receiving SDF had standard care without DGA (base-case scenario), and 2) children receiving SDF did not receive standard care without DGA (alternative scenario). A simple decision-tree model with probabilistic sensitivity analysis (PSA) estimated the incremental costs per diverted DGA.

Results

The probability of children requiring specialist referral and offered SDF, but the primary carer opted for DGA is 0.124 (SD 0.034), and the probability of children requiring DGA in standard care is 0.346 (SD 0.036). For both the base-case and alternative scenario, the incremental cost-effectiveness ratio outcome is dominant and their cost-effectiveness being either 74.8% or 100%, respectively.

Conclusions

The SDF protocol intervention is cost-effective dental caries management option for young children where referral for DGA is considered. © 2022 Australian Dental Association.
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SARS‐CoV‐2‐encoded Inhibitors of Human LINE‐1 Retrotransposition

alexandrossfakianakis shared this article with you from Inoreader

Abstract

The ongoing pandemic of severe acute respiratory coronavirus 2 (SARS-CoV-2) is causing a devastating impact on public health worldwide. However, details concerning the profound impact of SARS-CoV-2 on host cells remain elusive. Here, we investigated the effects of SARS-CoV-2-encoded viral proteins on the intracellular activity of long interspersed element 1 (L1) retrotransposons using well-established reporter systems. Several non-structural or accessory proteins (Nsps) of SARS-CoV-2 (i.e., Nsp1, Nsp3, Nsp5, and Nsp14) significantly suppress human L1 mobility, and these viral L1 inhibitors generate a complex network that modulates L1 transposition. Specifically, Nsp1 and Nsp14 inhibit the intracellular accumulation of L1 open reading frame proteins (ORF1p), whereas Nsp3, Nsp5, and Nsp14 repress the reverse transcriptase activity of L1 ORF2p. Given recent findings concerning the roles of L1 in antiviral immune activation and host genome instability, the anti- L1 activities mediated by SARS-CoV-2-encoded inhibitors suggest that SARS-CoV-2 employs different strategies to optimize the host genetic environment.

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ADMET study, spectroscopic characterization and effect of synthetic nitro chalcone in combination with Norfloxacin, Ciprofloxacin and Ethidium Bromide against Staphylococcus aureus efflux pumps

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Chalcones are present in a wide variety of plants, having in their structure two aromatic rings that are linked together by a chain composed of three carbon atoms with α, β-unsaturated to carbonyl system. Bacteria have several drug resistance mechanisms, among them the Efflux Pump, this mechanism when active, is able to expel different compounds from inside bacterial cells. Several efflux pumps have already been identified for Staphylococcus aureus bacteria, including MepA and NorA. Many chalcones have been isolated and identified with various activities, such as antimicrobial. In view of this, this article aimed to evaluate the antibiotic modifying effect of chalcone (E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one against Staphylococcus aureus carrier of NorA and MepA efflux pump. Regarding the antibiotic, there was a synergism when associated with Ciprofloxacin in SA-K2068 strain, showing this chalcone as an alternative to reverse the resistance to this medicine. The physicochemical properties calculated were fundamental in the description of the predicted pharmacokinetic properties. Despite the mutagenic risk caused by the metabolic activation of nitrochalcone, it is possible to notice a pharmacological principle in a longer half-life for the performance of biological activities. The compound has a good bioavailability, as it is highly absorbed in the intestine and easily transported by plasma proteins, in addition to not presenting neurotoxic, hepatotoxic and cardiotoxic damage.
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Overexpression of NIMA related kinase 2 in multiple myeloma and its relevance with disease features and prognosis to bortezomib treatment

alexandrossfakianakis shared this article with you from Inoreader
Overexpression of NIMA related kinase 2 in multiple myeloma and its relevance with disease features and prognosis to bortezomib treatment

A total of 76 multiple myeloma (MM) patients and 30 health donors (HDs) were enrolled to collect bone marrow plasma cells for NIMA related kinase 2 (NEK2) detection using RT-qPCR. Meanwhile, NEK2 siRNA was transfected into the RPMI-8226 and KMS-11 cells (MM cell lines), subsequently their cell viability was evaluated using CCK8 reagent. NEK2 expression was higher in MM patients compared with HDs. Besides, elevated NEK2 expression associated with the occurrence of the bone lesion and t (4; 14). Additionally, elevated NEK2 expression correlated with declined objective response rate (ORR) and shorter progression-free survival (PFS). What is more, NEK2 silence decreased the cell viability under bortezomib treatment and the IC50 value of bortezomib in RPMI-8226 and KMS-11 cells (MM cell lines).


Abstract

What is Known and Objective

NIMA related kinase 2 (NEK2) promotes the malignant transformation and enhances the chemoresistance to proteasome inhibitor in multiple myeloma (MM) cell lines. The current study aimed to further investigate its correlation with clinical features and responsiveness to bortezomib treatment in MM patients.

Methods

Totally, 76 MM patients and 30 health donors (HDs) were enrolled to collect bone marrow plasma cells for NEK2 detection using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Meanwhile, NEK2 siRNA was transfected into the RPMI-8226 and KMS-11 cells, subsequently their cell viability was evaluated using Cell Counting Kit-8 reagent after treatment with different doses of bortezomib.

Results and Discussion

NEK2 expression was higher in MM patients compared with HDs (Z = −5.123, p < 0.001). Besides, elevated NEK2 expression was associated with the occurrence of the bone lesion (χ 2 = 4.610, p = 0.032) and t (4; 14) (χ 2 = 3.971, p = 0.046). Additionally, elevated NEK2 expression was correlated with declined objective response rate (ORR) (χ 2 = 4.808, p = 0.028), but not with complete response (CR) (χ 2 = 2.341, p = 0.126). More importantly, elevated NEK2 expression was correlated with shorter progression-free survival (PFS) (χ 2 = 8.352, p = 0.039), but not with overall survival (OS) (χ 2 = 5.624, p = 0.131), What is more, NEK2 silence decreased the cell viability under bortezomib treatment and the inhibitory concentration (IC50) value of bortezomib in RPMI-8226 and KMS-11 cell lines (all p < 0.05).

What is New and Conclusion

NEK2 overexpression links with occurrence of bone lesion, t (4; 14), and poor prognosis to bortezomib treatment in MM patients.
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Relationships between squamous cell carcinoma antigen and cytokeratin 19 fragment values and renal function in oral cancer patients

alexandrossfakianakis shared this article with you from Inoreader
Squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragment (CYFRA) are used to screen and monitor oral cancer patients. However, recent studies have reported that tumour markers become elevated as renal function decreases, regardless of tumour progression. A retrospective study was performed of 423 oral cancer patients who underwent blood testing for these tumour markers and other blood analytes during a 10-year period. The values of SCC-Ag and CYFRA increased significantly with decreasing renal function (P   (Source: International Journal of Oral and Maxillofacial Surgery)
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