Evaluation of Point-of-Care-Directed Coagulation Management in Pediatric Cardiac Surgery.

BACKGROUND: Coagulatory alterations are common after pediatric cardiac surgery and can be addressed with point-of-care (POC) coagulation analysis. The aim of the present study is to evaluate a preventive POC-controlled coagulation algorithm in pediatric cardiac surgery. METHODS: This single-center, retrospective data analysis included patients younger than 18 years who underwent cardiac surgery with cardiopulmonary bypass (CPB) and received a coagulation therapy according to a predefined POC-controlled coagulation algorithm. Patients were divided into two groups (<10 and >10 kg body weight) because of different CPB priming strategies. RESULTS: In total, 173 surgeries with the use of the POC-guided hemostatic therapy were analyzed. In 71% of cases, target parameters were achieved and only in one case primary sternal closure was not possible. Children with a body weight ≤10 kg underwent surgical re-evaluation in 13.2% (15/113), and respectively 6.7% (4/60) in patients >10 kg. Hemorrhage in children ≤10 kg was associated with cyanotic heart defects, deeper intraoperative hypothermia, longer duration of CPB, more complex procedures (RACHS-1 score), and with more intraoperative platelets, and respectively red blood cell concentrate transfusions (all p-values < 0.05). In children ≤10 kg, fibrinogen levels were significantly lower over the 12-hour postoperative period (without revision: 3.1 [2.9-3.3] vs. with revision 2.8 [2.3-3.4]). Hemorrhage in children >10 kg was associated with a longer duration of CPB (p = 0.042), lower preoperative platelets (p = 0.026), and over the 12-hour postoperative period lower platelets (p = 0.002) and fibrinogen (p = 0.05). CONCLUSION: The use of a preventive, algorithm-based coagulation therapy with factor concentrates after CPB followed by POC created intraoperative clinical stable coagulation status with a subsequent executable thorax closure, although the presented algorithm in its current form is not superior in the reduction of the re-exploration rate compared to equivalent collectives. Reduced fibrinogen concentrations 12 hours after surgery may be associated with an increased incidence of surgical revisions.

Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma.

We report a case of a long-term surviving patient with EML4/ALK translocated non-small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/ALK translocation could still be detected in this situation. Employing a 3D reconstruction of the ALK tertiary structure, considering its interaction with various ALK inhibitors at the molecular binding site, our analysis indicated the presence of a mutation associated with crizotinib resistance. To validate the biological relevance of this previously unknown mutation, we carried out an in vitro validation approach in cell culture in addition to the molecular diagnostics accompanied by the molecular tumor board. The tumor scenario was mimicked through retroviral transfection. Our comparative in vitro treatment regimen paired with the clinical trajectory of the patient, corroborated our initial clinical and biochemical suspicions. Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards.

A production platform for disulfide-bonded peptides in the periplasm of Escherichia coli.

BACKGROUND: Recombinant peptide production in Escherichia coli provides a sustainable alternative to environmentally harmful and size-limited chemical synthesis. However, in-vivo production of disulfide-bonded peptides at high yields remains challenging, due to degradation by host proteases/peptidases and the necessity of translocation into the periplasmic space for disulfide bond formation. RESULTS: In this study, we established an expression system for efficient and soluble production of disulfide-bonded peptides in the periplasm of E. coli. We chose model peptides with varying complexity (size, structure, number of disulfide bonds), namely parathyroid hormone 1-84, somatostatin 1-28, plectasin, and bovine pancreatic trypsin inhibitor (aprotinin). All peptides were expressed without and with the N-terminal, low molecular weight CASPON™ tag (4.1 kDa), with the expression cassette being integrated into the host genome. During BioLector™ cultivations at microliter scale, we found that most of our model peptides can only be sufficiently expressed in combination with the CASPON™ tag, otherwise expression was only weak or undetectable on SDS-PAGE. Undesired degradation by host proteases/peptidases was evident even with the CASPON™ tag. Therefore, we investigated whether degradation happened before or after translocation by expressing the peptides in combination with either a co- or post-translational signal sequence. Our results suggest that degradation predominantly happened after the translocation, as degradation fragments appeared to be identical independent of the signal sequence, and expression was not enhanced with the co-translational signal sequence. Lastly, we expressed all CASPON™-tagged peptides in two industry-relevant host strains during C-limited fed-batch cultivations in bioreactors. We found that the process performance was highly dependent on the peptide-host-combination. The titers that were reached varied between 0.6-2.6 g L-1, and exceeded previously published data in E. coli. Moreover, all peptides were shown by mass spectrometry to be expressed to completion, including full formation of disulfide bonds. CONCLUSION: In this work, we demonstrated the potential of the CASPON™ technology as a highly efficient platform for the production of soluble peptides in the periplasm of E. coli. The titers we show here are unprecedented whenever parathyroid hormone, somatostatin, plectasin or bovine pancreatic trypsin inhibitor were produced in E. coli, thus making our proposed upstream platform favorable over previously published approaches and chemical synthesis.

C-Terminal Decarboxylation of Proline-Derived Building Blocks for Protein-Binding Peptides.

Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permeability need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis. For late-stage decarboxylation of ProM-like systems, a method for reductive halo decarboxylation was optimized and applied to several proline-derived substrates. In this way, a series of new decarboxy ProMs suitable as building blocks for decarboxy EVH1 inhibitors were obtained. In addition, we incorporated decarboxy-ProM-1 into the pentapeptide-like compound Ac[2ClF][ProM-2][Decarb-ProM-1], which showed similar affinity towards EVH1 as the methyl ester derivative (Ac[2Cl-F][ProM-2][ProM1]OMe). However, despite better calculated drug-like properties, this compound did not inhibit chemotaxis in a cellular assay.

Targeting KRAS Diversity: Covalent Modulation of G12X and Beyond in Cancer Therapy.

The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this balance, favoring the active form and promoting proliferative signaling, thus rendering KRAS an appealing target for precision medicine in oncology. In 2013, Shokat and co-workers achieved a groundbreaking feat by covalently targeting a previously undiscovered allosteric pocket (switch II pocket (SWIIP)) of KRASG12C. This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Recent achievements in targeting various KRASG12X mutants, using SWIIP as a key binding pocket, are discussed. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but in most cases life-threatening immune-mediated disease of the hematopoietic system frequently associated with hematologic neoplasms. Here, we report on a case in which we detected a novel constellation of two missense variants affecting the PRF1 gene, leading to de novo primary HLH. Diagnostics included a comprehensive clinical work-up and standard methods of hematopathology as well as extended molecular genomics based on polymerase chain reaction (PCR) reactions and the calculation of three-dimensional molecule reconstructions of PRF1. Subsequently, a comprehensive review of the literature was performed, which showed that this compound heterozygosity has not been previously described. The patient was a 20-year-old female. Molecular diagnostics revealed two heterozygous missense variants in the PRF1 gene (A91V and R104C) on exon 2. Apart from the finding of two inconclusive genetic variants, all clinical criteria defined by the HLH study group of Histiocyte Society were met at initial presentation. The final diagnosis was made in cooperation with the Consortium of German HLH-reference centers. Here, chemotherapy did not lead to sufficient sustained disease control. Therefore, the decision for allogenic hematopoietic stem cell transplantation (alloHSCT) was made. Hitherto, the duration of response was 6 months. Due to severe and unmanageable hepatic graft-versus-host disease (GvHD), the patient died. We report on a novel constellation of a compound heterozygosity containing two missense variants on exon 2 of the PRF1 gene. To the authors' best knowledge, this is the first presentation of a primary HLH case harboring this genomic constellation with late-onset clinical manifestation.

Synthesis and Derivatives of Beryllium Triflate.

Various pathways for the synthesis of beryllium triflate were investigated. The reaction of triflic acid or trimethylsilyl triflate with beryllium metal in liquid ammonia led to the formation of mono-, di-, and tetra-nuclear beryllium ammine complexes. Utilization of SMe2 as a solvent gave homoleptic Be(OTf)2. Various beryllium triflate complexes with N- and O-donor ligands as well as the complex anions [Be(OTf)4]2- and [Be2(OTf)6]2- were synthesized to evaluate the reactivity and solution properties of beryllium triflate. This showed that OTf- is not a weakly coordinating anion for Be2+ cations and that it exhibits good bridging properties.

Thulium fiber laser vs. holmium laser enucleation of the prostate: results of a prospective randomized non-inferiority trial.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) represents the current standard procedure for size-independent surgical therapy of benign prostatic obstruction (BPO). With advent of the novel laser technology thulium fiber laser (TFL), we hypothesized that the functional outcome of TFL enucleation of the prostate (ThuFLEP) is non-inferior compared to HoLEP. METHODS: From October 2021 to October 2022, 150 patients with BPO were recruited for the prospective randomized trial in accordance with CONSORT. Stratified randomization into the arms ThuFLEP (n = 74) or HoLEP (n = 76) was carried out. The primary endpoint was non-inferior international prostate symptom score (IPSS) and quality of life (QoL) at three months after treatment. Secondary endpoints were rates of complications, peak flow, residual urine and operation times. RESULTS: Preoperative characteristics showed no significant differences. Overall IPSS and QoL improved from 21 to 8 and 4 to 1.5, respectively, after three months of follow-up. No statistically significant differences between ThuFLEP and HoLEP were observed regarding median postoperative IPSS (8.5 vs. 7, p > 0.9), QoL (1 vs. 2, p = 0.6), residual urine (48 vs. 30ml, p = 0.065) and peak flow (19 vs. 17ml/s, p > 0.9). Similarly, safety profile was comparable with no statistically significant differences regarding rate of major complications (5.3 vs. 5.4%, p = 0.5), laser hemostasis time (3 vs. 2min, p = 0.2), use of additive electric coagulation (74 vs. 87%, p = 0.06) or electric coagulation time (8 vs. 8min, p = 0.4). CONCLUSIONS: In this prospective, randomized trial ThuFLEP showed non-inferior results compared to HoLEP in terms of functional outcomes measured by IPSS and QoL as primary endpoint. TRIAL REGISTRATION NUMBER: DRKS00032699 (18.09.2023, retrospectively registered).

Induced pluripotent stem cell-derived human macrophages as an infection model for Leishmania donovani.

The parasite Leishmania donovani is one of the species causing visceral leishmaniasis in humans, a deadly infection claiming up to 40,000 lives each year. The current drugs for leishmaniasis treatment have severe drawbacks and there is an urgent need to find new anti-leishmanial compounds. However, the search for drug candidates is complicated by the intracellular lifestyle of Leishmania. Here, we investigate the use of human induced pluripotent stem cell (iPS)-derived macrophages (iMACs) as host cells for L. donovani. iMACs obtained through embryoid body differentiation were infected with L. donovani promastigotes, and high-content imaging techniques were used to optimize the iMACs seeding density and multiplicity of infection, allowing us to reach infection rates up to 70% five days after infection. IC50 values obtained for miltefosine and amphotericin B using the infected iMACs or mouse peritoneal macrophages as host cells were comparable and in agreement with the literature, showing the potential of iMACs as an infection model for drug screening.

Distinct patterns of spatial attentional modulation of steady-state visual evoked magnetic fields (SSVEFs) in subdivisions of the human early visual cortex.

In recent years, steady-state visual evoked potentials (SSVEPs) became an increasingly valuable tool to investigate neural dynamics of competitive attentional interactions and brain-computer interfaces. This is due to their good signal-to-noise ratio, allowing for single-trial analysis, and their ongoing oscillating nature that enables to analyze temporal dynamics of facilitation and suppression. Given the popularity of SSVEPs, it is surprising that only a few studies looked at the cortical sources of these responses. This is in particular the case when searching for studies that assessed the cortical sources of attentional SSVEP amplitude modulations. To address this issue, we used a typical spatial attention task and recorded neuromagnetic fields (MEG) while presenting frequency-tagged stimuli in the left and right visual fields, respectively. Importantly, we controlled for attentional deployment in a baseline period before the shifting cue. Subjects either attended to a central fixation cross or to two peripheral stimuli simultaneously. Results clearly showed that signal sources and attention effects were restricted to the early visual cortex: V1, V2, hMT+, precuneus, occipital-parietal, and inferior-temporal cortex. When subjects attended to central fixation first, shifting attention to one of the peripheral stimuli resulted in a significant activation increase for the to-be-attended stimulus with no activation decrease for the to-be-ignored stimulus in hMT+ and inferio-temporal cortex, but significant SSVEF decreases from V1 to occipito-parietal cortex. When attention was first deployed to both rings, shifting attention away from one ring basically resulted in a significant activation decrease in all areas for the then-to-be-ignored stimulus.

[Urinary diversion with or without simple cystectomy as a salvage option for benign diseases of the lower urinary tract]. / Harnableitungen mit oder ohne simple Zystektomie in der Salvage-Therapie benigner Erkrankungen des unteren Harntraktes.

Benign diseases of the lower urinary tract can occur as a result of oncological or neurological diseases or their respective therapies (e.g., surgery or radiation treatment) and can significantly reduce the quality of life for affected patients. Urinary diversion serves as a salvage option when all other therapeutic regimens have been carried out and proven unsuccessful. When selecting the suitable urinary diversion, a comprehensive clinical assessment of the patients is required in order to ensure long-term success. In some cases, a cutaneous, catheterizable pouch offers the last and only option for a long-term and definitive treatment of a patient's condition. Overall, a decreasing trend in the establishment of a continent urinary diversion is observed in Germany. Current data on benign indications for urinary diversion are limited. Therefore, further data collection and research are needed.

Differences in Androgen Receptor Expression in Human Heart Tissue in Various Types of Cardiomyopathy and in Aortic Valve Stenosis.

Background: Sex-specific differences in heart disease outcomes are influenced by the levels of the steroid hormones, estrogen and testosterone. While the roles of estrogen receptors in cardiac disease are well-studied in animals and humans, respective research on androgen receptors (AR) is limited. Here we investigate AR protein and mRNA expression in human myocardium of various cardiac diseases. Methods: AR expression was analyzed by western blotting in myocardium from human non-failing hearts (NF, n = 6) and patients with aortic stenosis (AS, n = 6), hypertrophic cardiomyopathy (HCM, n = 7), dilated cardiomyopathy (DCM, n = 7), and ischemic cardiomyopathy (ICM, n = 7). Using an AR45-specific antibody, a subsequent western blot assessed samples from male and female patients with HCM (n = 10) and DCM (n = 10). The same sample set was probed for full-length AR and AR45 mRNA expression. Immunohistochemistry (IHC) localized AR in myocardium from HCM and AS hearts. Results: Full-length AR was notably enriched in AS and HCM hearts compared to ICM, DCM, and NF. Similarly, AR45 was more abundant in HCM than in DCM. In contrast to the pattern observed for AR protein, full-length AR mRNA levels were lower in HCM compared to DCM, with no discernible difference for the AR45 isoform. Although gender differences in AR expression were not detected in western blots or qRT-PCR, IHC showed stronger nuclear AR signals in males than in females. Conclusions: Our findings indicate disease-specific regulation of AR mRNA and/or AR protein in cardiac hypertrophy, underscoring a potential role in this cardiac pathology.

Gauging ambiphilicity of pseudo-halides via beryllium-trispyrazolylborato compounds.

The ambiphilicity of pseudo-halides has been the object of extensive debate. Herein, we use a series of trispyrazolylborato beryllium pseudo-halido complexes [TpBe(X')] with X' = CN-, N3-, NCO- and NCS- to explore the origins of the preferred isomers. Thus, we have synthesised and characterised through NMR and IR spectroscopy as well as single crystal X-ray diffraction these complexes. A combination with quantum chemical calculations within the DFT framework enabled an in-depth understanding of the bonding modes and preferences of the investigated pseudo-halido ligands.

Beryllium-Mediated Halide and Aryl Transfer onto Silicon.

The reactivity of hexamethylcyclotrisiloxane (D3 ) towards BeCl2 , BeBr2 , BeI2 and [Be3 Ph6 ]3 was investigated. While BeCl2 only showed unselective reactivity, BeBr2 , BeI2 and [Be3 Ph6 ] cleanly react to the trinuclear complexes [Be3 Br2 (OSiMe2 Br)4 ], [Be3 I2 (OSiMe2 I)4 ] and [Be3 Ph2 (OSiMe2 Ph)4 ]. These unprecedented bromide, iodide and phenyl transfer reactions from a group II metal onto silicon offer a versatile access to previously unknown diorgano bromo and iodo silanolates.

Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.

Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.

Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors.

Mutations within Ras proteins represent major drivers in human cancer. In this study, we report the structure-based design, synthesis, as well as biochemical and cellular evaluation of nucleotide-based covalent inhibitors for KRasG13C, an important oncogenic mutant of Ras that has not been successfully addressed in the past. Mass spectrometry experiments and kinetic studies reveal promising molecular properties of these covalent inhibitors, and X-ray crystallographic analysis has yielded the first reported crystal structures of KRasG13C covalently locked with these GDP analogues. Importantly, KRasG13C covalently modified with these inhibitors can no longer undergo SOS-catalysed nucleotide exchange. As a final proof-of-concept, we show that in contrast to KRasG13C, the covalently locked protein is unable to induce oncogenic signalling in cells, further highlighting the possibility of using nucleotide-based inhibitors with covalent warheads in KRasG13C-driven cancer.

Ligand exchange at tetra-coordinated beryllium centres.

Mono and dinuclear phosphine complexes of beryllium halides [(PMe3)2BeX2], [(PMe3)BeX2]2 and [(PCy3)BeX2]2 (X = Cl, Br, I) were synthesised and characterised via NMR and IR spectroscopy as well as single crystal X-ray diffraction experiments. Dissociation and ligand exchange processes at these complexes were investigated through variable temperature NMR experiments in combination with line shape analysis and complemented by quantum chemical calculations. The PMe3 dissociation energy is smallest in [(PMe3)2BeCl2], while PMe3 exchange is similar in energy in all mononuclear [(PMe3)2BeX2] complexes and follows an interchange mechanism. While [(PMe3)BeX2]2 dissociates homolytically, [(PCy3)BeX2]2 cleaves one phosphine ligand. These distinctive dissociation processes account for the different chemical behaviour of these complexes.

Validation of an ICH Q2 Compliant Flow Cytometry-Based Assay for the Assessment of the Inhibitory Potential of Mesenchymal Stromal Cells on T Cell Proliferation.

Mesenchymal stromal cells (MSCs) have the potential to suppress pathological activation of immune cells and have therefore been considered for the treatment of Graft-versus-Host-Disease. The clinical application of MSCs requires a process validation to ensure consistent quality. A flow cytometry-based mixed lymphocyte reaction (MLR) was developed to analyse the inhibitory effect of MSCs on T cell proliferation. Monoclonal antibodies were used to stimulate T cell expansion and determine the effect of MSCs after four days of co-culture based on proliferation tracking with the violet proliferation dye VPD450. Following the guidelines of the International Council for Harmonisation (ICH) Q2 (R1), the performance of n = 30 peripheral blood mononuclear cell (PBMC) donor pairs was assessed. The specific inhibition of T cells by viable MSCs was determined and precision values of <10% variation for repeatability and <15% for intermediate precision were found. Compared to a non-compendial reference method, a linear correlation of r = 0.9021 was shown. Serial dilution experiments demonstrated a linear range for PBMC:MSC ratios from 1:1 to 1:0.01. The assay was unaffected by PBMC inter-donor variability. In conclusion, the presented MLR can be used as part of quality control tests for the validation of MSCs as a clinical product.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Do Titanium Dioxide Particles Stimulate Macrophages to Release Proinflammatory Cytokines and Increase the Risk for Peri-implantitis?

PURPOSE: Titanium dioxide (TiO2) particles detached from titanium dental implants by tribocorrosion can be phagocytosed by macrophages, releasing various proinflammatory cytokines at the implant sites that may trigger peri-implantitis. The study objective was to measure the association between peri-implantitis and the presence of non-allergy-related proinflammatory cytokines associated with TiO2 particles. METHODS: The investigators implemented a retrospective cross-sectional study and enrolled a sample of 60 subjects from a dental practice. Subjects were excluded if the plaque index was grade 3 (Silness and Löe). The predictor variable was a positive or negative TiO2 stimulation test, an in vitro macrophage proinflammatory response test. The outcome variable was peri-implantitis status defined as present or absent. Three groups were considered: control group with 20 patients without dental implants (group 1), 2 groups of patients with titanium dental implants, one without peri-implantitis (group 2), and the other with peri-implantitis (group 3) (n = 20 each). For patients with implants, depth of the gingival pockets of the implants were measured, and existing bleeding and suppuration were determined to assess peri-implantitis. Radiographs were taken if one or more factors applied to confirm the diagnosis of peri-implantitis. Further covariates were age, sex, duration of implant wear, and number of implants which were analyzed descriptively. Inferential analyses were undertaken using χ2 test, Kruskal-Wallis-, Wilcoxon-two-sample tests, and logistic regressions. RESULTS: The sample was composed of 35 female and 25 male patients with a mean age of 54.2 years (standard deviation = 14.76). The overall TiO2 stimulation test positivity frequency was 28.3% and were 30.0%, 5.0%, and 50.0% in the control, implants without peri-implantitis, and implants with peri-implantitis groups. No statistically significant differences could be seen in the frequencies of the TiO2 stimulation test results between control group and combined groups 2 and 3 (P-value = .84). The risk for positive TiO2 patients with a titanium implant of developing peri-implantitis was statistically significant and higher compared to negative TiO2 patients (odds ratio, 19.0 with 95% confidence interval [2.12,170.38]; P-value< .01). CONCLUSIONS: The data in this study showed a statistically significant relationship between a positive TiO2 stimulation test and peri-implantitis. Further studies with larger numbers of subjects are recommended to confirm this result.