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BACKGROUND: Pyroglutamic acidosis is a rare cause of high anion gap metabolic acidosis. Most cases of paracetamol related pyroglutamic acidosis are described in malnourished women and patients with kidney/liver failure, alcohol use or severe sepsis. In this report, we describe how pyroglutamic acidosis could be related to the use of chronic therapeutic paracetamol with only malnutrition as an associated risk factor. CASE PRESENTATION: We report a case of a 67-year-old male patient developing a pyroglutamic acidosis. The patient was initially admitted to hospital for infectious osteoarthritis and developed a metabolic acidosis during his hospital stay. Analgesics included daily therapeutic doses of paracetamol. What makes our case unusual is that our malnourished male patient did not have renal or hepatic failure. The diagnosis of paracetamol related pyroglutamic acidosis was made after ruling out the main causes of metabolic acidosis. It was further confirmed by urine organic acids measurement showing a markedly elevated level of pyroglutamic aciduria. Paracetamol was discontinued allowing a prompt correction of the anion gap. CONCLUSION: This case is a representative of pyroglutamic acidosis related to chronic therapeutic paracetamol with only malnutrition as an associated risk factor. Physicians should be aware of such unusual cause of metabolic acidosis, which may be more common than expected in hospitalized patients. A high clinical suspicion is needed when urine organic acids analysis is not available.

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Background: Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death. Methods: In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2). Results: There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed. Conclusions: The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

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SARS-CoV-2 strains have made an appearance across the globe, causing over 757 million cases and over 6.85 million deaths at the time of writing. The emergence of these variants shows the amplitude of genetic variation to which the wild-type strains have been subjected. The rise of the different SARS-CoV-2 variants resulting from such genetic modification has significantly affected COVD-19's major impact on proliferation, virulence, and clinics. With the emergence of the variants of concern, the spike protein has been identified as a possible therapeutic target due to its critical role in binding to human cells and pathogenesis. These mutations could be linked to functional heterogeneity and use a different infection strategy. For example, the Omicron variant's multiple mutations should be carefully examined, as they represent one of the most widely spread strains and hint to us that there may be more genetic changes in the virus. As a result, we applied a common protocol where we reconstructed SARS-CoV-2 variants of concern and performed molecular dynamics simulations to study the stability of the ACE2-RBD complex in each variant. We also carried out free energy calculations to compare the binding and biophysical properties of the different SARS-CoV-2 variants when they interact with ACE2. Therefore, we were able to obtain consistent results and uncover new crucial residues that were essential for preserving a balance between maintaining a high affinity for ACE2 and the capacity to evade RBD-targeted antibodies. Our detailed structural analysis showed that SARS-CoV-2 variants of concern show a higher affinity for ACE2 compared to the Wuhan strain. Additionally, residues K417N and E484K/A might play a crucial role in antibody evasion, whereas Q498R and N501Y are specifically mutated to strengthen RBD affinity to ACE2 and, thereby, increase the viral effect of the COVID-19 virus.

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Bacillary angiomatosis is a disseminated vascular proliferative disease caused by aerobic gram-negative bacilli Bartonella henselae or Bartonella quintana. Bacillary angiomatosis is mostly described in immunosuppressed patients with HIV infection and organ transplant recipients. We describe the case of a female aged 75 years who is a kidney transplant recipient who was admitted for a 3-month history of intermittent fever, chills, vomiting, and a 12-kg weight loss. The maintenance immunosuppression was based on prednisone, mycophenolate, and monthly infusions of belatacept. Physical examination was unremarkable. Laboratory investigations revealed elevated blood acute phase proteins but all blood cultures were negative. Serological tests for Bartonella were negative. Thoracoabdominal computed tomography scan and transesophageal echocardiography were normal. A Positron Emission Tomography scan showed a hypermetabolic mass in the duodenopancreatic region, with multiple hepatic and splenic lesions. Histological findings of spleen and pancreatic biopsies were not conclusive. The histopathological examination of a celiac lymph node biopsy finally demonstrated bacillary angiomatosis. The diagnosis of bacillary angiomatosis in immunocompromised patients is most often delayed in the absence of skin involvement. A high index of clinical suspicion is needed when interpreting negative results.

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The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.

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Zebrafish is broadly used as a model organism in gene loss-of-function studies in vivo, but its employment in vitro is greatly limited by the lack of efficient gene knockdown approaches in zebrafish cell lines such as ZF4. In this article, we attempted to induce silencing of telomere associated genes in ZF4 by applying the frequently-used siRNA transfection technology and a novel moiety-linked morpholino (vivo-MO). By proceeding with integrated optimization of siRNAs transfection and vivo-MOs treatment, we compared five transfection reagents and vivo-MOs simultaneously to evaluate the efficiency of terfa silencing in ZF4. 48 h after siRNAs transfection, Lipofectamine™ 3000 and X-tremeGENE™ HP leaded to knockdown in 35% and 43% of terfa transcription, respectively, while vivo-MO-terfa modulated 58% down-expression of zfTRF2 in contrast to vivo-MO-ctrl 72 h after treatment. Further siRNAs transfection targeting telomere associated genes by X-tremeGENE™ HP showed silencing in 40-68% of these genes without significant cytotoxicity and off-target effect. Our results confirmed the feasibility of gene loss-of-function studies in a zebrafish cell line, offered a systematic optimizing strategy to employ gene silencing experiments, and presented Lipofectamine™ 3000, X-tremeGENE™ HP and vivo-morpholinos as candidate gene silencing approaches for zebrafish in vitro gene loss-of-function studies. Successfully knockdown of shelterin genes further opened a new field for telomeric study in zebrafish.

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AIM: To evaluate the fracture resistance and failure pattern of endodontically treated teeth with post and cores made of different CAD/CAM materials in comparison with cast post and cores. MATERIALS AND METHODS: A total of 40 maxillary central incisors were divided into four groups. Post and cores were fabricated using the following materials: fiber-reinforced composite, high-density polymer, polymer-infiltrated ceramic network, and nonprecious metal alloy as a control group. Specimens were covered with lithium disilicate crowns and subjected to thermomechanical cyclic loading followed by fracture resistance testing until failure. One-way ANOVA followed by Bonferroni multiple comparison tests were used to determine significant differences between the four groups. The significance level was set at 0.05. 3D finite element analysis was then performed, and results were analyzed based on the von Mises stress distribution criteria and the maximum principal stress for the possible failure areas. RESULTS: No statistically significant differences were found in the fracture resistance between the four groups. In terms of unrestorable failures, no significant differences were found among the tested groups. CONCLUSION: The tested post and cores have comparable fracture resistance to that of metallic cast post and cores in the anterior region. CLINICAL SIGNIFICANCE: Post and cores made of CAD/CAM materials offer an acceptable alternative for the restoration of anterior teeth.

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AIM: To evaluate the fracture resistance of three-unit fixed dental prosthesis (FDP) made of composite, high-density polymers (HDP), fiber-reinforced composite (FRC), and metal-ceramic (MC) using different fabrication methods. MATERIALS AND METHODS: A typodont model was prepared to receive a three-unit FDP replacing a missing second maxillary premolar. The prepared model was digitally scanned using an intraoral scanner (Trios3, 3Shape, Denmark). In total, 60 FDPs were fabricated and divided into four groups (n = 15) according to the materials and fabrication method: the subtractive method was used for the FRC (Trilor, Bioloren, Italy) and the HDP (Ambarino, Creamed, Germany) groups; the HDP group was monolithic, whereas the FRC group was layered with a nanocomposite (G-aenial Sculpt, GC). The additive method was used for the 3D printed (3DP) nanocomposite (Irix Max, DWS, Italy) and the Cr-Co (Starbond CoS powder 30) infrastructure of the MC groups. The FDPs were adhesively seated on stereolithography (SLA) fabricated dies. All samples were subjected to thermomechanical loading and fracture testing. The data for maximum load (N) to fracture was statistically analyzed with one-way analysis of variance (ANOVA) followed by Games-Howell post hoc test (α = 0.05). RESULTS: The MC group reported the highest fracture resistance with a statistically significant difference (2390.87 ± 166.28 N) compared to other groups. No significance was noted between 3DP and HDP groups (1360.20 ± 148.15 N and 1312.27 ± 64.40 N, respectively), while the FRC group displayed the lowest value (839.07 ± 54.30 N). The higher frequency of nonrepairable failures was observed in the MC and FRC groups, while HDP and 3DP groups reported a high frequency of repairable failures. CONCLUSION: Significant differences were found in fracture resistance between the tested groups. The load-bearing capacity of the composite-based FPDs exceeded the range of maximum chewing forces. CLINICAL SIGNIFICANCE: 3D printed and milled composite-based materials might offer a suitable solution for the fabrication of FPDs.

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Aging is a multifactorial process that results in progressive loss of regenerative capacity and tissue function while simultaneously favoring the development of a large array of age-related diseases. Evidence suggests that the accumulation of senescent cells in tissue promotes both normal and pathological aging. Oxic stress is a key driver of cellular senescence. Because symbiotic long-lived reef corals experience daily hyperoxic and hypoxic transitions, we hypothesized that these long-lived animals have developed specific longevity strategies in response to light. We analyzed transcriptome variation in the reef coral Stylophora pistillata during the day-night cycle and revealed a signature of the FoxO longevity pathway. We confirmed this pathway by immunofluorescence using antibodies against coral FoxO to demonstrate its nuclear translocation. Through qPCR analysis of nycthemeral variations of candidate genes under different light regimens, we found that, among genes that were specifically up- or downregulated upon exposure to light, human orthologs of two "light-up" genes (HEY1 and LONF3) exhibited anti-senescence properties in primary human fibroblasts. Therefore, these genes are interesting candidates for counteracting skin aging. We propose a large screen for other light-up genes and an investigation of the biological response of reef corals to light (e.g., metabolic switching) to elucidate these processes and identify effective interventions for promoting healthy aging in humans.

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AIM: The study aimed to assess the effect of friction and adhesion on the pushout bond strength of CAD/CAM fiber-reinforced composite (FRC) post and cores in comparison to prefabricated fiber posts. MATERIALS AND METHODS: Thirty extracted single-rooted premolars were divided into three groups (N = 10): CP: CAD/CAM FRC posts (Trilor, Bioloren) cemented with self-adhesive resin cement (Rely X U200, 3M) as control group. CPL: CAD/CAM FRC composite posts cemented with the same self-adhesive resin cement after lubricating the root canal with petroleum jelly (Vaseline, Unilever) to prevent adhesion. RXP: prefabricated posts cemented with self-adhesive resin cement. Specimens were subjected to thermal cycling and then to pushout tests. The mode of failure was observed using a stereomicroscope. Results were analyzed by two-way ANOVA followed by a Tukey's post hoc test for comparison, p = 0.05. RESULTS: Push-out bond strength was significantly lower in the RXP group (8.54 ± 3.35 MPa) in comparison to CP (12.10 ± 1.38 MPa), while no significant differences were concluded between the other groups. Failure was mostly adhesive for CPL and RXP and adhesive and mixed for CP. CONCLUSION: Custom made CAD/CAM posts have a positive effect on the retention of FRC posts to root canal walls while adhesion between self-adhesive cement and root dentin did not influence significantly the pushout bond strength of CAD/CAM posts to root canal. CLINICAL SIGNIFICANCE: The friction of well-adapted CAD/CAM fiber post and cores plays a predominant role in the success of post restorations of endodontically treated teeth.

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PURPOSE: This study is to investigate the effect of milling custom fit anatomical post and cores from fiber reinforced composite and high-density polymer blocks using CAD/CAM technology on the bond strength to root canal dentin compared with prefabricated fiber posts, and to evaluate the influence of thermal cycling on the push out bond strength of the tested materials. MATERIALS AND METHODS: Eighty extracted single-rooted premolars, endodontically treated and prepared to receive the posts, were randomly divided into four groups (n = 20): BLC: Custom-milled fiber-reinforced composite posts and cores (Trilor, Bioloren), AMC: Custom-milled high-density polymer posts and cores (Ambarino, Creamed), BLP: Prefabricated fiber-reinforced composite posts and composite core buildups (Bioloren; Filtek Bulk Fill Posterior, 3M). The posts used have the same matrix and fiber composition as BLC, RXP: Prefabricated posts and composite core buildups (RelyX fiber post, 3M; Filtek Bulk Fill Posterior); used as a control group. All of the posts were cemented using a self-adhesive resin cement (RelyX U200, 3M). Half of the sample was randomly assigned to thermal cycling in distilled water for 6,000 cycles to simulate aging, while the other half was tested for bond strength without thermal cycling. A push-out test was conducted using a universal testing machine until failure. Bond strength values were calculated in megapascals (MPa). The mode of failure was observed using a stereo microscope. Results were analyzed by two-way ANOVA followed by a Bonferroni post hoc test for comparison. The level of significance was set at p < 0.05. RESULTS: Push-out bond strength was significantly higher (p <0.001) in the CAD/CAM post groups than in the groups with prefabricated posts regardless of the post material, while aging of the teeth did not significantly affect the push-out strength (p = 0.536). Failures were adhesive between cement and dentin for all groups except for AMC, where adhesive failure between the cement and the post was also observed. CONCLUSION: The CAD/CAM manufacturing technique was proved to ameliorate the retention of the post and cores in the root canal. Thermal cycling did not affect the bond strength of the tested groups.

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AIM: To evaluate the fracture resistance and failure pattern of custom made computer-aided design & computer-aided manufacturing (CAD/CAM) post and cores using a fiber reinforced composite material (FRC) and a high-density-polymer. MATERIALS AND METHODS: Thirty extracted mandibular second premolars were selected, endodontically treated and prepared to receive the posts. The specimens were randomly divided into three groups (n = 10) according to each material: group 1 (RXP) : fiber posts (Rely X, 3M-ESPE) with composite core build-up (Filtek Bulk Fill Posterior, 3M-ESPE) as a control group; group 2 (BLC): one-piece milled post and core from fiber reinforced composite blocks (Trilor, Bioloren); and group 3 (AMC): one-piece milled post and core from hybrid ceramic disks (Ambarino, Creamed). All the posts were cemented using a self-adhesive resin cement (Rely X U200, 3M ESPE). Fracture resistance was tested using a universal testing machine, failure patterns were then observed visually and radiographically then evaluated under SEM. Data was analyzed using One-way analysis of variance (ANOVA) followed by Tamhane post-hoc test in order to determine significant differences among groups (α = 0.05). RESULTS: The mean fracture resistance values were: 426.08 ± 128.26 N for group 1 (R X P), 367.06 ± 72.34N for group 2 (BLC), and 620.02 ± 54.29N for group 3 (AMC). Statistical analysis revealed that group 3 (AMC) had the highest mean load to fracture in comparison to the other groups (p = 0.000). failures were cohesive in group 2 and 3 and mixed in group 1 with no catastrophic failures reported in all groups. CONCLUSION: All systems evaluated presented sufficient mean load-to-failure values for endodontically treated teeth restorations. CAD/CAM post and cores made from high-density-polymer showed a better performance than prefabricated fiber posts.

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Mutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerase-positive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX.

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PURPOSE: The aim of this study was to compare all ceramic inlay/onlay survival rates in vital and nonvital teeth having the same cavity design. Filling the pulp chamber with ceramic materials or not was also discussed. MATERIALS AND METHODS: Ceramic class II inlays/onlays were made on 11 premolars and 30 molars: 14 vital, 27 endodontically treated. The same tooth preparation design was performed on vital and nonvital teeth: In nonvital teeth the pulp chambers were covered by a glass ionomer cement until the pulpal floor depths were between 2 and 2.5 mm, more likely similar to the vital teeth preparations. In vital teeth, glass ionomer was used as a liner to achieve pulpal floor depths between 2 and 2.5 mm when needed. The restorations were assessed (at baseline, 6 months, 1 and 2 years) according to three criteria: marginal discoloration, marginal integrity, and fracture of teeth/restorations, consistent with United States Public Health Service (USPHS) criteria. RESULTS: Eight teeth (19%) showed minor marginal discolorations, while three molars (7%) had loss of marginal integrity. These margins were adjusted using rubber polishing cups and were then judged clinically acceptable. From these three molars, one was vital and two were endodontically treated. No fracture of teeth or restorations was observed. Chi square and exact probability tests were used. There was no statistical difference between vital and nonvital teeth (p = 0.719 chi-squared and Fisher) or between premolars and molars (p = 0.564 chi-squared; 1.000, Fisher). CONCLUSION: Within the limitations of this study there was no difference for the same inlay/onlay cavity design between vital and nonvital teeth. In nonvital teeth, it seems that filling the pulp chamber with a ceramic core material is not important. Long-term observation periods are needed to reinforce the clinical behavior outcome.

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When fabricating indirect post and core, internal coronal walls are tapered to remove undercuts and allow a better adaptation. To evaluate the fracture strength of anterior tooth reconstructed with post and core and crowned, with two different taper of internal coronal walls, 6° and 30° to the long axis, two groups of 30 clear plastic analogues simulating endodontically treated maxillary central incisors were prepared. The analogues crowned were subjected to a compressive load with a 1-kN cell at a crosshead speed of 0.05 mm/min at 130° to the long axis until fracture occurred. Data were analyzed by Lillifors and Mann-Whitney tests. Mean failure loads for the groups were as follows: group I 1038.69 N (standard deviation ±243.52 N) and group II 1231.86 N (standard deviation ±368.76 N). Statistical tests showed significant difference between groups (p = 0.0010 < 0.01). Increasing the taper of internal coronal walls appears to enhance the fracture resistance of anterior maxillary teeth post and core reconstructed.