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Influence of macrophage polarization on the effectiveness of surgical therapy of peri-implantitis
(2021)
Purpose: To evaluate the influence of macrophage expression and polarization on the effectiveness of surgical therapy of peri-implantitis over a 6 month follow-up.
Methods: A total of fourteen patients (n = 14 implants) diagnosed with peri-implantitis underwent access flap surgery, granulation tissue removal, implantoplasty, and augmentation at intra-bony components using a natural derived bone mineral and application of a native collagen membrane during a standardized surgical procedure. Granulation tissue biopsies were prepared for immunohistochemical characterization and macrophage polarization assessment. M1 and M2 phenotype expression was identified and quantified through immunohistochemical markers and histomorphometrical analyses. Clinical evaluation and data collection were performed initially and after a healing period of 6 months. Statistical analyses were performed to associate infiltrated area, macrophage, and M1/M2 phenotype influence on peri-implant tissue healing parameters after a 6-month follow-up.
Results: Mean infiltrated compartment (ICT) values occupied a total percentage of 70.3% ± 13.0 in the analyzed granulation tissue biopsies. Macrophages occupied a mean area of 15.3% ± 7.0. M1 and M2 phenotypes were present in 7.1 ± 4.1% and 5.5 ± 3.7%, respectively. No statistically significant difference was observed between M1 and M2% expression (p = 0.16). The mean M1/ M2 ratio amounted to 1.5 ± 0.8. Surgical therapy was associated with statistically significant reductions in mean bleeding on probing (BOP), probing depth (PD) and suppuration (SUPP) scores at 6 months (p < 0.05). Linear regression analyses revealed a significant correlation between macrophage expression (CD68%) and changes in PD scores and M1 (%) expression and changes in mucosal recession (MR) scores at 6 months.
Conclusions: The present data suggest that macrophages might influence peri-implant tissue healing mechanisms following surgical therapy of peri-implantitis over a short-term period. Particularly, changes in PD and MR scores were statistically significantly associated with macrophage expression and phenotype.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.
Background: During the current second wave of COVID-19, the radiologists are expected to face great challenges in differentiation between COVID-19 and other virulent influenza viruses, mainly H1N1. Accordingly, this study was performed in order to find any differentiating CT criteria that would help during the expected clinical overlap during the current Influenza season.
Results: This study was retrospectively conducted during the period from June till November 2020, on acute symptomatic 130 patients with no history of previous pulmonary diseases; 65 patients had positive PCR for COVID-19 including 50 mild patients and 15 critical or severe patients; meanwhile, the other 65 patients had positive PCR for H1N1 including 50 mild patients and 15 critical or severe patients. They included 74 males and 56 females (56.9%:43.1%). Their age ranged 14–90 years (mean age 38.9 ± 20.3 SD). HRCT findings were analyzed by four expert consultant radiologists in consensus. All patients with COVID-19 showed parenchymal or alveolar HRCT findings; only one of them had associated airway involvement. Among the 65 patients with H1N1; 56 patients (86.2%) had parenchymal or alveolar HRCT findings while six patients (9.2%) presented only by HRCT signs of airway involvement and three patients (4.6%) had mixed parenchymal and airway involvement. Regarding HRCT findings of airway involvement (namely tree in bud nodules, air trapping, bronchial wall thickening, traction bronchiectasis, and mucous plugging), all showed significant p value (ranging from 0.008 to 0.04). On the other hand, HRCT findings of parenchymal or alveolar involvement (mainly ground glass opacities) showed no significant relation.
Conclusion: HRCT can help in differentiation between non-severe COVID-19 and H1N1 based on signs of airway involvement.
Background/Objective: Evidence-based clinical pathways can be a useful tool for guideline implementation. However, there seem to be barriers to the use of clinical pathways. The aim of the present questionnaire survey was to assess the perceived usability of the clinical pathway “Overweight/obesity in children and adolescents at primary care level” and to identify factors promoting and hindering the use of the clinical pathway.
Methods: In January 2020, an online questionnaire survey was sent out to 3,916 general practitioners and 470 pediatricians in Austria. The data collected were analysed descriptively.
Results: A total of 148 people took part in the questionnaire survey (response rate 3.7 %). The majority of respondents indicated that they, in general, perceive evidence-based clinical pathways as helpful (90 %) and also make use of them (57 %). Few respondents (9 %) felt well-informed about new clinical pathways developed in Austria. Most of the respondents considered the clinical pathway “Overweight/obesity in children and adolescents at primary care level” as a useful support (60 %), as a reference work (72 %) or as a facilitator for justifying their approach to their patients (68 %). However, a large proportion of the respondents stated that the clinical pathway is not easily applicable in everyday practice. The three most frequently cited barriers to using the clinical pathway were lack of time resources, lack of structures and lack of financial incentives. Other display and access options (e. g., individualisation, integration into practice software) were most frequently cited as factors that might promote the use of the pathway.
Conclusion: Although the majority of the respondents had positive expectations regarding the use of the clinical pathway “Overweight/obesity in children and adolescents at primary care level”, many of them still perceived its usability in everyday clinical practice as difficult. The necessary next steps to improve the use of evidence-based clinical pathways seem to be: an economic and practicable design, easy accessibility of clinical pathways and the creation of framework conditions that facilitate their use in everyday practice.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium.
In recent decades, mass spectrometry has moved more than ever before into the front line of protein-centered research. After being established at the qualitative level, the more challenging question of quantification of proteins and peptides using mass spectrometry has become a focus for further development. In this chapter, we discuss and review actual strategies and problems of the methods for the quantitative analysis of peptides, proteins, and finally proteomes by mass spectrometry. The common themes, the differences, and the potential pitfalls of the main approaches are presented in order to provide a survey of the emerging field of quantitative, mass spectrometry-based proteomics.
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
Objective: To analyze the influence of biopsy Gleason score on the risk for lymph node invasion (LNI) during pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy (RP) for intermediate-risk prostate cancer (PCa).
Materials and Methods: We retrospectively analyzed 684 patients, who underwent RP between 2014 and June 2020 due to PCa. Univariable and multivariable logistic regression, as well as binary regression tree models were used to assess the risk of positive LNI and evaluate the need of PLND in men with intermediate-risk PCa.
Results: Of the 672 eligible patients with RP, 80 (11.9%) men harbored low-risk, 32 (4.8%) intermediate-risk with international society of urologic pathologists grade (ISUP) 1 (IR-ISUP1), 215 (32.0%) intermediate-risk with ISUP 2 (IR-ISUP2), 99 (14.7%) intermediate-risk with ISUP 3 (IR-ISUP3), and 246 (36.6%) high-risk PCa. Proportions of LNI were 0, 3.1, 3.7, 5.1, and 24.0% for low-risk, IR-ISUP1, IR-ISUP 2, IR-ISUP-3, and high-risk PCa, respectively (p < 0.001). In multivariable analyses, after adjustment for patient and surgical characteristics, IR-ISUP1 [hazard ratio (HR) 0.10, p = 0.03], IR-ISUP2 (HR 0.09, p < 0.001), and IR-ISUP3 (HR 0.18, p < 0.001) were independent predictors for lower risk of LNI, compared with men with high-risk PCa disease.
Conclusions: The international society of urologic pathologists grade significantly influence the risk of LNI in patients with intermediate- risk PCa. The risk of LNI only exceeds 5% in men with IR-ISUP3 PCa. In consequence, the need for PLND in selected patients with IR-ISUP 1 or IR-ISUP2 PCa should be critically discussed.