Excess Mortality among Physicians and Dentists during COVID-19 in Italy: A Cross-Sectional Study Related to a High-Risk Territory.

BACKGROUND: Many studies previously reported epidemiological data on mortality due to COVID-19 among health workers. All these studies included a partial sample of the population with a substantial selection bias. The present study evaluates the trend of mortality among physicians and dentists operating in an area considered to be at high risk during the COVID-19 pandemic. METHODS: Data relating to all physicians and dentists registered in the province of Pavia (Italy), a sample consisting of 5454 doctors in 2020 was analyzed. The mortality rates obtained were compared with those related to the 5-year period preceding the pandemic and with those related to the general population. RESULTS: In the area considered, a mortality rate of 0.83% (+69% compared to 2015-2019) was observed in the entire sample in 2020 and 0.43% (-11% compared to 2015-2019) in 2021; among physicians, there was a mortality rate of 0.76% (+53% compared to 2015-2019) in 2020 and 0.35% (-29% compared to 2015-2019) in 2021; for dentists, there was a mortality rate of 1.27% (+185% compared to 2015-2019) in 2020 and 1.01% (+127% compared to 2015-2019) in 2021. CONCLUSIONS: These data report the global impact of the SARS-CoV-2 pandemic on physicians and dentists in a high-risk territory. In 2020, a significant increase in the mortality rate compared to the previous 5 years was observed for both physicians and dentists; in 2021, a significant increase in the mortality rate was observed only for dentists. These data are also significant in evaluating the impact of vaccination on physicians and dentists and indicate that dentists were among the professions most at risk during the pandemic.

Biochemical Modification of Titanium Oral Implants: Evidence from In Vivo Studies.

The discovery of osseointegration of titanium implants revolutionized the dental prosthesis field. Traditionally, implants have a surface that is processed by additive or subtractive techniques, which have positive effects on the osseointegration process by altering the topography. In the last decade, innovative implant surfaces have been developed, on which biologically active molecules have been immobilized with the aim of increasing stimulation at the implant-biological tissue interface, thus favoring the quality of osseointegration. Among these molecules, some are normally present in the human body, and the techniques for the immobilization of these molecules on the implant surface have been called Biochemical Modification of Titanium Surfaces (BMTiS). Different techniques have been described in order to immobilize those biomolecules on titanium implant surfaces. The aim of the present paper is to present evidence, available from in vivo studies, about the effects of biochemical modification of titanium oral implants on osseointegration.

Long-Term Effects of Acute Myeloid Leukemia Treatment on the Oral System in a Pediatric Patient.

INTRODUCTION: Acute Myeloid Leukemia (AML) in pediatric patients is a serious disease, although, for the subgroup of patients who receive proper treatment, a long-term survival rate above 50% is typical. The cycles of chemo- and radiotherapy used to treat AML can impair dental development. CASE REPORT: Herein, we describe the oral condition of a 25-year-old male patient treated for AML with chemo- and radiotherapy from 5 to 7 years of age; his AML has remained in remission for the past 18 years. He had lost only one permanent tooth, but the remaining teeth demonstrated serious deformations and radicular hypoplasia. Two teeth required immediate extraction and subsequent replacement by implant-supported crowns. We found that the decayed, missing, filled teeth (DMFT) index was not representative of the real oral condition. Here, we report the full case and provide a brief review of the literature. CONCLUSION: Antitumor treatment of pediatric leukemia can induce total impairment of dental development and function. These adverse effects may become clinically evident many years after the resolution of cancer, and can be significantly detrimental to the patient's quality of life.

Differences between panoramic and Cone Beam-CT in the surgical evaluation of lower third molars.

BACKGROUND: The aim of this study was to evaluate the ability to identify the contiguity between the root of the mandibular third molar and the mandibular canal (MC) in panoramic radiographs compared with Cone Beam-CT. MATERIAL AND METHODS: Panoramic radiographs of 326 third molars and CBCT radiographs of 86 cases indicated for surgery and considered at risk were evaluated. The following signs were assessed in panoramic radiographs as risk factors: radiolucent band, loss of MC border, change in MC direction, MC narrowing, root narrowing, root deviation, bifid apex, superimposition, and contact between the root third molar and the MC. RESULTS: Radiographic signs associated with absence of MC cortical bone are: radiolucent band, loss of MC border, change in MC direction, and superimposition. The number of risk factors was significantly increased with an increasing depth of inclusion. CBCT revealed a significant association between the absence of MC cortical bone and a lingual or interradicular position of the MC. CONCLUSIONS: In cases in which panoramic radiographs do not exclude contiguity between the MC and tooth, careful assessment the signs and risks on CBCT radiographs is indicated for proper identification of the relationships between anatomic structures. Key words:Panoramic radiography, Cone-Beam computed tomography, third molar, mandibular nerve.

In Vitro and In Vivo Differentiation of Progenitor Stem Cells Obtained After Mechanical Digestion of Human Dental Pulp.

Human population is facing a revolutionary change in the demographic structure with an increasing number of elderly people requiring an unmet need to ensure a smooth aging process and dental care is certainly an important aspect that has to be considered. To date, dentistry has been conservative and the need of transferring the scientific models of regenerative dentistry into clinical practice is becoming a necessity. The aim of this study was to characterize the differentiation commitment (in vitro) and the clinical grafting ability (in vivo) of a population of progenitor stem cells obtained after mechanical digestion of dental pulp with an innovative system recently developed. This approach was successfully used in previous studies to obtain a clinical-grade ready to use dental pulp fragments that could be grafted in autologous tissues to obtain bone. We are thus showing that micro grafts resulting from mechanical digestion contain stem cells with a mesenchymal phenotype, able to differentiate toward different cell types and to generate new bone in patients. We are providing data for the establishment of standardized and routinely oral surgery approaches, having outlined the cellular properties of human stem cells obtained from the dental pulp. This method can represent a valid tool for both regenerative medicine and tissue engineering purposes not only applicable to the cranio-maxillofacial region but, likely, to different bone pathologies for a fastening and healing recovering of patients. J. Cell. Physiol. 232: 548-555, 2017. © 2016 Wiley Periodicals, Inc.

Rehabilitation with implant-retained removable dentures and its effects on perioral aesthetics: a prospective cohort study.

BACKGROUND: The onset of perioral wrinkles often prompts patients to request treatment. This aesthetic deterioration linked to aging may be associated with tooth and alveolar bone loss in fully edentulous patients. PURPOSE: To evaluate perioral wrinkles before and after maxillary and mandibular rehabilitation with implant-retained dentures in fully edentulous patients. METHODS: In this prospective cohort, single-center, blinded study, patients requiring maxillary and mandibular rehabilitation with implant-retained dentures were enrolled. The patients were photographed in the same position before and after oral rehabilitation. Wrinkles were evaluated in the photographs by blinded observers using validated rating scales. The following parameters were analyzed: upper and lower radial lip lines, marionette lines, upper and lower lip fullness, nasolabial folds, corner of the mouth lines, and the labiomental crease. Statistical analysis was performed using the Wilcoxon signed ranks test for paired data, with P<0.05 considered significant. RESULTS: Upper and lower implant-retained dentures were applied in 31 patients (15 males; mean ± standard deviation age 62.13±8.69 years, range 47-77 years). The oral rehabilitation procedures significantly improved (P<0.05) the upper and lower radial lip lines, marionette lines, upper and lower lip fullness, the nasolabial folds, and the corner of the mouth lines. CONCLUSION: Maxillary and mandibular rehabilitation with implant-retained dentures in fully edentulous patients improves perioral aesthetics. Patients requiring oral rehabilitation and desiring perioral aesthetic improvement could benefit from treatment with this type of prosthesis.

Radiographic evaluation of regenerated bone following poly(lactic-co-glycolic) acid/hydroxyapatite and deproteinized bovine bone graft in sinus lifting.

Although numerous biomaterials are used for maxillary sinus-lift surgery, the ideal material for such procedures has not yet been identified. Both heterologous and alloplastic bone substitutes have a solely osteoconductive effect and lack the osteoinductive properties of the bone morphogenetic proteins typical of autologous bone. Our group assessed a new alloplastic graft material, poly(lactic-co-glycolic) acid/hydroxyapatite (PLGA/HA), implanted in a human model of maxillary sinus-lift surgery. For this prospective, random, double-blind trial, we used deproteinized bovine bone (DBB) as the comparison material. Radiographic bone vertical height and density were assessed at approximately 28 weeks after grafting using cone-beam computed tomography. The vertical dimension of the regenerated bone was equivalent between the 2 groups. The density of the bone regenerated using PLGA/HA was significantly lower than that obtained with DBB. Despite clinical assessments demonstrating that PLGA/HA has sufficient characteristics for use in sinus-lift surgery, DBB provided greater bone density and an equivalent vertical dimension of grafted bone. Further studies are needed to supplement the radiologic findings with histologic and micromorphometric examinations.

Evaluation of bacterial adhesion on machined titanium, Osseotite® and Nanotite® discs.

PURPOSE: Bacterial adhesion and colonization play a crucial function in the pathogenesis of peri-implant tissue infection, which is considered the main cause of fixture loss. The aim of this study is to evaluate the differences in bacterial adhesion between a machined titanium surface, a double acid etched surface (Osseotite®) and an Osseotite surface with Nanometer-scale Discrete Crystalline Deposition (DCD™) of calcium phosphate (CaP)(Nanotite®). METHODS: Surface roughness properties of each sample were determined by a laser profilometer and scanning electron microscopy (SEM) observation. Bacterial adhesion on machined, Osseotite®, and Nanotite® discs were performed using the following bacterial strains: Streptococcus mutans CCUG 35176, Streptococcus sanguis CCUG 17826, Streptococcus salivarius CCUG 11878, Actinobacillus actinomycetecomitans CCUG 37002, Porphyromonas gingivalis CCUG 2521. The assessment of bacterial adhesion was performed by comparing two methods: Total Viable Count (TVC) estimation and Confocal Laser Scanning Microscopic (CSLM) studies. RESULTS: The surface roughness parameter increased as follows: machined

Mandibular traumatic peripheral osteoma: a case report.

An osteoma is a slow-growing, benign lesion comprising mature bone tissue. Osteomas rarely occur in maxillary bones, with the exception of the maxillary sinuses. Various possible etiologies have been proposed, including congenital anomalies, chronic inflammation, muscular activity, embryogenetic changes, and trauma. Here we present a case of an osteoma of the buccal plate of the mandible at the site where a sports-related traumatic injury occurred 15 years earlier. Both conventional and 3-dimensional x-ray examinations were used for diagnosis and preoperative evaluation of the possible involvement of the adjacent anatomic structures. The lesion was treated surgically without complications and the patient made a complete recovery. Histologic tests confirmed the preoperative diagnosis. A review of the international literature is also presented.

Latent membrane protein 1 of Epstein-Barr virus activates the hTERT promoter and enhances telomerase activity in B lymphocytes.

Transformation of primary B lymphocytes by Epstein-Barr virus requires the establishment of a strictly latent infection, the expression of several latent viral proteins, and sustained telomerase activity. Our previous findings indicated that induction of hTERT, the rate-limiting catalytic unit of the telomerase complex, was associated with the expression of the viral latent membrane protein 1 (LMP1). In the present study, we demonstrate that ectopic expression of LMP1 in BJAB and Ramos B cells resulted in an increase of hTERT transcripts, thus suggesting that LMP1 acts at the transcriptional level. This was confirmed by transient expression of a luciferase reporter plasmid containing the hTERT promoter cotransfected with an LMP1-expressing vector or transfected into B cells in which LMP1 expression was inducible. Consistently, silencing of LMP1 by small interfering RNA resulted in a reduction of hTERT transcripts. We also provide evidence indicating that LMP1-induced hTERT activation is independently mediated by NF-kappaB and by mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways, whereas CD40, Akt, and mTOR signaling has no involvement. Moreover, our results do not support a role for c-Myc in mediating these effects on hTERT, since ectopic expression of LMP1 did not upregulate c-Myc and silencing of this oncogene or E box mutagenesis failed to inhibit LMP1-induced hTERT activation. These findings indicate that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity, thus confirming the pleiotropic nature of this viral oncoprotein.

Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma.

Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.

Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins.

Retinoic acid (RA) arrests the growth of EBV-immortalized lymphoblastoid B cell lines (LCLs) by upregulating the cyclin-dependent kinase inhibitor p27Kip1. Here, we show that in LCLs, RA inhibits ubiquitination and proteasome-dependent degradation of p27Kip1, a phenomenon that is associated with downregulation of Thr187 phosphorylation of the protein, whereas the phosphorylation on Ser10 is unaffected. Furthermore, we demonstrate that RA downregulates the expression of the p45Skp2 and Cks1 proteins, two essential components of the SCF(Skp2) ubiquitin ligase complex that target p27Kip1 for degradation. Downregulation of p45Skp2)and Cks1 occurs before the onset of growth arrest and is due to enhanced proteasome-mediated proteolysis of these proteins. Moreover, overexpression of p45Skp2 in DG75 cells prevents p27Kip1 protein accumulation and promotes resistance to the antiproliferative effects of RA. Treatment with Leptomycin B (LMB) blocked the translocation of p27Kip1 to the cytoplasm and prevented its degradation, indicating that CRM1-dependent nuclear export is required for p27Kip1 degradation. The shuttle protein p38Jab1, however, does not accumulate in the nucleus upon LMB treatment, nor does it interact with p27Kip1. Conversely, p45Skp2 is associated with p27Kip1 both in the nucleus and in the cytoplasm, accumulating within the nuclei after exposure to LMB and co-localizing with the exportin CRM1, suggesting a possible involvement of p45Skp2 in CRM1-dependent nuclear export of p27Kip1. These results indicate that downregulation of p45Skp2 is a key element underlying RA-induced p27Kip1 stabilization in B cells, resulting in an impaired targeting of the protein to the ubiquitin-proteasome pathway and probably contributing to the nuclear accumulation of p27Kip1.

Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.

Retinoic acid inhibits IL-6-dependent but not constitutive STAT3 activation in Epstein-Barr virus-immortalized B lymphocytes.

IL-6-mediated B-cell growth promotion is involved in the pathogenesis of EBV+ lymphoproliferative disorders of immunosuppressed patients. Since retinoic acid (RA) inhibits the proliferation of EBV-immortalized lymphoblastoid B-cell lines (LCLs), we have investigated the effects of RA on IL-6 signaling in these cells. RA down-regulated IL-6-receptor components with IL-6 agonist activity (membrane and soluble gp80) and increased the levels of soluble gp130, an IL-6 antagonist. These changes, however, were not related to the enhanced production of endogenous IL-6 induced by RA in LCLs. RA-induced modulation of IL-6 receptor components did not abolish IL-6-mediated phosphorylation of gp130, whereas JAK1 and STAT3 phosphorylation and activation induced by IL-6 were markedly inhibited. Overall, the effects of RA resulted in the induction of a complete resistance of LCLs to IL-6-mediated growth promotion. Conversely, RA did not inhibit the constitutive activation of JAK1, TYK2, STAT3 and ERK1/2, ruling out that the JAK/STAT and MAPK pathways may mediate the antiproliferative activity of RA. The finding that RA severely impairs IL-6-dependent signalings in LCLs and inhibits their growth despite the presence of constitutively active JAK/STAT and MAPK cascades provide additional support for a role of RA in the prevention and treatment of EBV-related lymphoproliferative disorders of immunosuppressed patients.

Mouthrinses with alcohol: cytotoxic effects on human gingival fibroblasts in vitro.

BACKGROUND: Mouthrinses are widely utilized in daily oral and dental hygiene to control plaque. However, most commercially available mouthrinses contain alcohol as an excipient. Most studies have focused on the clinical side effects related to the alcoholic fraction of mouthrinses, overlooking alcohol metabolism in the mouth. Due to this oral enzymatic process, the well-recognized toxic compound acetaldehyde is emitted in the mouth. Since gingival fibroblasts play a key role in oral connective tissue health maintenance, we investigated the effects of different doses of acetaldehyde on human gingival fibroblasts (HGFs) in order to better define the effects of alcohol-containing mouthrinses on oral tissue. METHODS: Cultured HGFs were exposed to different concentrations of acetaldehyde (10(-4) M to 10(-2) M). The cell adhesion rate was measured after a 3-hour incubation period, and cell viability over a 5-day period. In order to assess the reversibility of the damage produced by acetaldehyde, treatment was interrupted at critical doses (10(-3) M and 3 x 10(-3) M), and cell viability was evaluated on the third and fifth day of incubation. The HGF cytoskeleton was studied by immunocytochemical technique, and internal cell structures were observed with transmission electron microscopy to evaluate the morphological changes due to acetaldehyde. RESULTS: The results showed that acetaldehyde produced a dose- and time-dependent inhibition on cell adhesion and viability, together with disruption of cytoskeletal structures and cytoplasmic organelles. Nevertheless, these quantitative and qualitative damages were reversible when the treatment was interrupted. CONCLUSIONS: Although more knowledge is necessary, our results suggest that these deleterious effects may also occur in vivo. Pending further investigations, clinicians should be alerted to the potentially adverse effect of alcohol-containing mouthrinses and, to promote oral health, patients should be warned about improper use of these products.

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells.

In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells. Ro 40-8757-induced apoptosis is associated with mitochondrial membrane depolarization, activation of caspase-3 and -9, and enhanced production of reactive oxygen species. These effects were related to a transient drop in intracellular ATP content, probably favored by a downregulation of NADH dehydrogenase subunit-1, a component of the mitochondrial respiratory chain (MRC) Complex I. Inhibition of MRC with thenoyltrifluoroacetone suppressed both the ATP recovery and apoptosis, confirming that the effects of Ro 40-8757 are mediated by changes in mitochondrial function. Compared to EBV-negative lines, EBV-carrying BLs were more resistant to Ro 40-8757-induced apoptosis. EBV infection and ectopic LMP-1 expression increased the resistance of BL cells to Ro 40-8757-induced apoptosis, probably through bcl-2 upregulation. Finally, we also show that 2-methoxyoestradiol, an inhibitor of the scavenger enzymes superoxide dismutases, enhanced Ro 40-8757-mediated apoptosis. These findings provide the rationale for evaluating the clinical efficacy of Ro 40-8757 in BL patients and suggest that the combination of Ro 40-8757 with inhibitors of scavenger enzymes may be a promising therapeutic approach for this aggressive lymphoma.

Behavior of the bone-titanium interface after push-in testing: a morphological study.

Fourteen titanium dental implants (Tioblast) were implanted singly in the proximal tibia of New Zealand rabbits for 120 days. A bone defect was surgically produced and filled with Bio-Oss around six of these implants. After the animals were sacrificed and their organs harvested, bone segments were fixed and methacrylate embedded after the push-in test had been performed. Microradiography was performed on longitudinal sections of the implants, whereas scanning electron microscope analysis was performed on the remaining embedded half-implants using secondary electrons only. The results showed that the implants were apically and coronally surrounded by bone, whether Bio-Oss was used or not. Fractures were evident through the newly formed bone and between the pre-existing and newly formed bone. Some fracture lines propagated through the bone and stopped at the implant surface without continuing along the bone-titanium interface. Detachment between the implant and the bone occurred at the coronal extremity of the implants and along its cervical region. These results highlight the fact that the bone-titanium interface has a high resistance to loading. It exhibited greater resistance than the newly formed bone and seems to behave in a manner similar to the cement lines of osteons.

Experimental procedure for the evaluation of the mechanical properties of the bone surrounding dental implants.

The mechanical stability of the fixture in bone is one of the most important factors for the long-term reliability of dental implants. This paper focuses on an experimental procedure to evaluate the mechanical properties of the bone surrounding dental implants. The procedure is based on a surgical animal model followed by mechanical tests. The experimental mechanical testing has been used for preliminary investigations on the role played by different parameters such as the healing time and the surgical technique (standard or with regenerative material). The procedure has been evaluated in some preliminary tests on a few specimens. Microradiographic analyses have been performed on the bone surrounding the implants in order to give an interpretation of the bone properties on the basis of the bone morphology and to distinguish the newly formed bone from the pre-existing bone. The preliminary results relevant to 10 threaded titanium implants are presented and discussed. Our findings show that the mechanical properties of the bone surrounding the implant improve with the increase in the healing time from 24 to 45 days. The ultimate loads recorded during mechanical tests arise from 395 N to 2665 N in case of coronal defects filled with bone regenerative and from 2200 N to 5700 N in case of standard technique.