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11 pages, 1094 KiB  
Systematic Review
Correlations between Obstructive Sleep Apnea Syndrome and Periodontitis: A Systematic Review and Meta-Analysis
by Marco Portelli, Ignazio Russo, Angela Mirea Bellocchio, Angela Militi and Riccardo Nucera
Dent. J. 2024, 12(8), 236; https://doi.org/10.3390/dj12080236 - 26 Jul 2024
Viewed by 487
Abstract
The focus of this article was to evaluate the link between obstructive sleep apnea syndrome (OSAS) and periodontitis, considering various hypotheses supporting the relationship between respiratory disorders and periodontitis. The literature review for this study was performed using the PubMed, Google Scholar, Cochrane [...] Read more.
The focus of this article was to evaluate the link between obstructive sleep apnea syndrome (OSAS) and periodontitis, considering various hypotheses supporting the relationship between respiratory disorders and periodontitis. The literature review for this study was performed using the PubMed, Google Scholar, Cochrane library, and Proquest databases. The review process was guided by the PRISMA guidelines. The PECOS protocol (Population, Exposure, Control, Outcome, Study) was followed in developing the search strategy to ensure consistent and accurate selection of articles. To evaluate quality, cross-sectional studies were reviewed using the Joanna Briggs Institute (JBI) critical appraisal tool. Case-control studies were assessed with the Newcastle–Ottawa Scale (NOS). The research included a total of 10 studies, encompassing 88,040 participants. The meta-analysis observed a statistically significant association between OSAS and periodontitis, with an odds ratio OR = 2.4620 (95%-CI: 1.7345–3.4946 p ≤ 0.0001). The results suggest a potential association between OSA and periodontitis. Further investigations are warranted to confirm this association and elucidate its underlying mechanism. Full article
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<p>Flow chart of study selection performed according tot PRISMA guidelines.</p>
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<p>Forest plot of the association between OSAS and periodontitis [<a href="#B18-dentistry-12-00236" class="html-bibr">18</a>,<a href="#B19-dentistry-12-00236" class="html-bibr">19</a>,<a href="#B25-dentistry-12-00236" class="html-bibr">25</a>,<a href="#B26-dentistry-12-00236" class="html-bibr">26</a>,<a href="#B27-dentistry-12-00236" class="html-bibr">27</a>,<a href="#B28-dentistry-12-00236" class="html-bibr">28</a>,<a href="#B29-dentistry-12-00236" class="html-bibr">29</a>,<a href="#B30-dentistry-12-00236" class="html-bibr">30</a>,<a href="#B31-dentistry-12-00236" class="html-bibr">31</a>,<a href="#B32-dentistry-12-00236" class="html-bibr">32</a>].</p>
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12 pages, 660 KiB  
Review
Dietary Habits and Caries Prevalence in Older Adults: A Scoping Review
by Grigoria Gkavela, Eftychia Pappa, Christos Rahiotis and Panagiota Mitrou
Dietetics 2024, 3(3), 249-260; https://doi.org/10.3390/dietetics3030020 - 19 Jul 2024
Viewed by 446
Abstract
Caries is very common in the elderly as there are several aggravating factors, such as a decrease of the ability to self-care and, by extension, insufficient oral hygiene, a carious diet, limited exposure to fluoride, xerostomia, gingival recession, and limited access to dental [...] Read more.
Caries is very common in the elderly as there are several aggravating factors, such as a decrease of the ability to self-care and, by extension, insufficient oral hygiene, a carious diet, limited exposure to fluoride, xerostomia, gingival recession, and limited access to dental care. This study aimed to review the dietary risk factors for root caries prevalence in older adults, from socially active people to frail patients. A comprehensive search strategy was used to select studies from PubMed and Scopus databases. Two evaluators performed data extraction, screening, and quality assessment independently. Only studies written in English were included. Root caries is prevalent in the elderly due to gingival recession and root exposure to the oral environment. Dietary risk factors significantly affect root caries prevalence in older adults, including a high intake of sugars and an alteration of their composition preference in this age group. Caries risk appears more significant in frail, institutionalized patients fed softer food or supplements. Full article
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<p>The flow chart shows the number of studies during identification and screening.</p>
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13 pages, 1189 KiB  
Review
Hepatitis C Virus (HCV) Infection: Pathogenesis, Oral Manifestations, and the Role of Direct-Acting Antiviral Therapy: A Narrative Review
by Dario Di Stasio, Agostino Guida, Antonio Romano, Massimo Petruzzi, Aldo Marrone, Fausto Fiori and Alberta Lucchese
J. Clin. Med. 2024, 13(14), 4012; https://doi.org/10.3390/jcm13144012 - 9 Jul 2024
Viewed by 537
Abstract
Hepatitis C virus (HCV) infection is a global health concern with significant systemic implications, including a range of oral manifestations. This review aims to provide a comprehensive overview of the oral and dental pathologies related to HCV, the etiopathogenetic mechanisms linking such conditions [...] Read more.
Hepatitis C virus (HCV) infection is a global health concern with significant systemic implications, including a range of oral manifestations. This review aims to provide a comprehensive overview of the oral and dental pathologies related to HCV, the etiopathogenetic mechanisms linking such conditions to HCV and the impact of direct-acting antiviral (DAA) therapy. Common oral manifestations of HCV include oral lichen planus (OLP), periodontal disease, and xerostomia. The pathogenesis of these conditions involves both direct viral effects on oral tissues and indirect effects related to the immune response to HCV. Our literature analysis, using PubMed, Scopus, Web of Science, and Google Scholar, suggests that both the HCV infection and the immune response to HCV contribute to the increased prevalence of these oral diseases. The introduction of DAA therapy represents a significant advancement in HCV treatment, but its effects on oral manifestations, particularly OLP, are still under evaluation. Although a possible mechanism linking HCV to OSCC is yet to be determined, existing evidence encourages further investigation in this sense. Our findings highlight the need for established protocols for managing the oral health of patients with HCV, aiming to improve outcomes and quality of life. Full article
(This article belongs to the Special Issue Stomatognathic Diseases: State of the Art and Future Perspectives)
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<p>Aetiopathogenic hypotheses of the relationship between HCV infection and OLP.</p>
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<p>Aetiopathogenic hypotheses of the relationship between HCV infection and Xerostomia and Sjögren’s syndrome-like manifestations.</p>
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<p>Aetiopathogenic hypotheses of the relationship between HCV infection and periodontitis.</p>
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<p>Aetiopathogenic hypotheses of the relationship between HCV infection and HNSCC.</p>
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10 pages, 3218 KiB  
Article
Long-Term Follow-Up of Computer-Assisted Microvascular Mandibular Reconstruction: A Retrospective Study
by Erika Crosetti, Pierluigi Tos, Mattia Berrone, Bruno Battiston, Giulia Arrigoni and Giovanni Succo
J. Clin. Med. 2024, 13(13), 3899; https://doi.org/10.3390/jcm13133899 - 3 Jul 2024
Viewed by 553
Abstract
Background: Virtual surgical planning has become a well-established practice in head and neck surgery. In oncological surgery, it permits the achievement of safe margins resections and ensures functional reconstructions and optimal esthetic outcomes. This study aimed to evaluate the long-term outcomes after virtually [...] Read more.
Background: Virtual surgical planning has become a well-established practice in head and neck surgery. In oncological surgery, it permits the achievement of safe margins resections and ensures functional reconstructions and optimal esthetic outcomes. This study aimed to evaluate the long-term outcomes after virtually planned mandibular microvascular reconstruction, focusing on functional and esthetic results, as well as health-related quality of life. Methods: A long-term retrospective evaluation of 17 patients with oral cavity malignancy who underwent computer-assisted mandibular resection and reconstruction was performed. Functional and esthetic outcomes were analyzed using the EORTC, QLQ-C30, H&N35, and FACE-Q questionnaires. Results: Time since reconstruction ranged from 7 to 14 years. Patients reported high functional levels on the QLQ-C30 functional scales but lower scores on H&N35. On FACE-Q, patients demonstrated higher appraisal and satisfaction with their smiles compared to their overall facial appearance. Conclusions: In this retrospective case series, patients undergoing computer-assisted mandibular reconstruction for oral malignancies achieved good long-term functional and esthetic outcomes. Although limited by the small sample size, these results support the enduring benefits of virtual planning for mandibular reconstruction. To minimize declines in function and appearance, considerations should include immediate dental implants, enhanced reconstruction of the temporomandibular joint, newer methods of radiotherapy to minimize xerostomia, and oral exercises to prevent trismus. Full article
(This article belongs to the Special Issue New Advances in Oral and Facial Surgery)
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<p>Functional and esthetic results 11th years after surgery.</p>
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<p>Functional and esthetic results 10th years after surgery.</p>
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15 pages, 284 KiB  
Review
Role of Lutetium Radioligand Therapy in Prostate Cancer
by Ignacy Książek, Artur Ligęza, Franciszek Drzymała, Adam Borek, Marcin Miszczyk, Marcin Radosław Francuz, Akihiro Matsukawa, Takafumi Yanagisawa, Tamás Fazekas, Łukasz Zapała and Paweł Rajwa
Cancers 2024, 16(13), 2433; https://doi.org/10.3390/cancers16132433 - 1 Jul 2024
Viewed by 772
Abstract
Theranostics utilize ligands that chelate radionuclides and selectively bind with cancer-specific membrane antigens. In the case of prostate cancer (PCa), the state-of-the-art lutetium-177-PSMA combines the radioactive β-emitter 177Lu with Vipivotide Tetraxetan, a prostate-specific membrane antigen (PSMA)-binding ligand. Several studies have been conducted, [...] Read more.
Theranostics utilize ligands that chelate radionuclides and selectively bind with cancer-specific membrane antigens. In the case of prostate cancer (PCa), the state-of-the-art lutetium-177-PSMA combines the radioactive β-emitter 177Lu with Vipivotide Tetraxetan, a prostate-specific membrane antigen (PSMA)-binding ligand. Several studies have been conducted, and the therapy is not without adverse effects (e.g., xerostomia, nausea, and fatigue); however, few events are reported as severe. The available evidence supports the use of 177Lu-PSMA in selected metastatic castration-resistant prostate cancer patients, and the treatment is considered a standard of care in several clinical scenarios. Emerging research shows promising results in the setting of hormone-sensitive prostate cancer; however, evidence from high-quality controlled trials is still missing. In this review, we discuss the available evidence for the application of 177Lu-PSMA in the management of PCa patients. Full article
(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Genitourinary Cancers)
30 pages, 5103 KiB  
Article
Exploring Salivary Metabolic Alterations in Type 2 Diabetes: Implications for Dental Caries and Potential Influences of HbA1c and Vitamin D Levels
by Ashwaq Alkahtani, Martin Grootveld, Mohammed Bhogadia and Aylin Baysan
Metabolites 2024, 14(7), 372; https://doi.org/10.3390/metabo14070372 - 30 Jun 2024
Viewed by 814
Abstract
Diabetes mellitus is considered to be the most common health issue affecting almost 1 in 11 adults globally. Oral health complications including xerostomia, periodontal disease, dental caries, and soft tissue lesions are prevalent among individuals with diabetes, and therefore an understanding of the [...] Read more.
Diabetes mellitus is considered to be the most common health issue affecting almost 1 in 11 adults globally. Oral health complications including xerostomia, periodontal disease, dental caries, and soft tissue lesions are prevalent among individuals with diabetes, and therefore an understanding of the potential association between salivary metabolites and dental caries progression would enable the early detection and prevention of this non-communicable disease. Therefore, the aim of this study was to compare salivary biomarkers between individuals with type 2 diabetes (T2DM) with those without this disorder (ND) using 1H NMR-based metabolomics strategies. The objectives were to identify T2DM-associated biomarker signatures and their potential impact on dental caries. In addition, HbA1c and vitamin D levels were also analysed for this purpose. Methods: Stimulated whole-mouth saliva (SWS) samples were collected from T2DM and ND (n = 30 in each case) participants randomly selected from a group of 128 participants recruited for this case–control study. All participants were advised to refrain from eating, drinking, and smoking for at least 1–2 h prior to sample collection. Following preparation, SWS supernatants underwent 1H NMR analysis at an operating frequency of 800 MHz, and the dataset acquired was analysed using a range of multivariate metabolomics techniques. Results: Metabolomics analysis of data acquired demonstrated that, together with up- and downregulated blood HbA1c and vitamin D levels, key salivary discriminators between these two classifications included lactate, taurine, creatinine, α-glucose, and formate to a lesser extent. The bacterial catabolites lactate and formate were both significantly upregulated in the T2DM group, and these have previously been implicated in the pathogenesis of dental caries. Significance analysis of metabolites (SAM)-facilitated AUROC analysis yielded an 83% accuracy for this distinction. Conclusion: In conclusion, this study highlights the significant differences in salivary metabolites between individuals with T2DM and healthy controls. Such differences appear to be related to the development and progression of dental caries in T2DM patients. Full article
(This article belongs to the Section Metabolomic Profiling Technology)
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<p>Partial <sup>1</sup>H NMR profiles of a saliva sample collected from an ND group participant. Diagrams show the 0.80–2.50 (<b>top</b>), 2.35–4.50 (<b>middle</b>), and 5.50−8.50 ppm regions (<b>bottom</b>) of spectra acquired. A typical spectrum is shown. Resonances specified as uncoded in <a href="#metabolites-14-00372-t002" class="html-table">Table 2</a> were visible in general, but not in the spectral profiles shown in the figure. Abbreviations: assignment codes correspond to those listed in <a href="#metabolites-14-00372-t002" class="html-table">Table 2</a>.</p>
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<p>Partial <sup>1</sup>H NMR profiles of a saliva sample collected from an ND group participant. Diagrams show the 0.80–2.50 (<b>top</b>), 2.35–4.50 (<b>middle</b>), and 5.50−8.50 ppm regions (<b>bottom</b>) of spectra acquired. A typical spectrum is shown. Resonances specified as uncoded in <a href="#metabolites-14-00372-t002" class="html-table">Table 2</a> were visible in general, but not in the spectral profiles shown in the figure. Abbreviations: assignment codes correspond to those listed in <a href="#metabolites-14-00372-t002" class="html-table">Table 2</a>.</p>
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<p>(<b>a</b>) A three-dimensional (3D) PLS-DA scores plot displaying some level of metabolite pattern distinction between the ND and T2DM groups. The red triangles indicate saliva samples obtained from ND participants (A), and the green crosses indicate those collected from the T2DM participant group (B). (<b>b</b>) Validation of the PLS-DA model applied by the application of 2000 permutation tests, which were based on separation distance (<span class="html-italic">p</span> = 0.008).</p>
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<p>(<b>a</b>) A three-dimensional (3D) PLS-DA scores plot displaying some level of metabolite pattern distinction between the ND and T2DM groups. The red triangles indicate saliva samples obtained from ND participants (A), and the green crosses indicate those collected from the T2DM participant group (B). (<b>b</b>) Validation of the PLS-DA model applied by the application of 2000 permutation tests, which were based on separation distance (<span class="html-italic">p</span> = 0.008).</p>
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<p>(<b>a</b>) Orthogonal partial least squares discriminant analysis (OPLS-DA) scores plot of high-resolution <sup>1</sup>H NMR data derived from saliva samples donated by the T2DM and ND groups. The red sample data points indicate saliva samples obtained from the ND group, whereas green points indicate those obtained from the T2DM group. (<b>b</b>) A permutation analysis of the OPLS-DA model was established, which also shows the observed and cross-validated R<sup>2</sup>Y and Q<sup>2</sup> coefficient values (<span class="html-italic">p</span> = 5.00 × 10<sup>−4</sup> for Q<sup>2</sup>). An MV AUROC analysis.</p>
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<p>(<b>a</b>) Orthogonal partial least squares discriminant analysis (OPLS-DA) scores plot of high-resolution <sup>1</sup>H NMR data derived from saliva samples donated by the T2DM and ND groups. The red sample data points indicate saliva samples obtained from the ND group, whereas green points indicate those obtained from the T2DM group. (<b>b</b>) A permutation analysis of the OPLS-DA model was established, which also shows the observed and cross-validated R<sup>2</sup>Y and Q<sup>2</sup> coefficient values (<span class="html-italic">p</span> = 5.00 × 10<sup>−4</sup> for Q<sup>2</sup>). An MV AUROC analysis.</p>
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<p>A multivariate AUROC analysis. (<b>a</b>) The model receiver operating characteristic (ROC) area under curves (AUROCs) for 6 PLS-DA classification models. The key shows the number of features for each model, with their respective AUROC values and associated 95% confidence interval (CI) values. Models 1, 2, 3, 4, 5, and 6 had 3, 5, 10, 20, 30, and 60 predictor variables incorporated, respectively. From their AUROC values, the best model was obtained with 20 predictor variables/metabolites (model 4). (<b>b</b>) The receiver operating characteristic (ROC) area under the curve (AUC) plot for PLS-DA classification model number 3, with 10 feature variables. The 95% confidence interval ellipse (CIE) for this AUROC model is also shown.</p>
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<p>Predicted class probabilities (average of the cross-validation) for each sample using the best classifier model (based on the AUROC values obtained). The classification boundary was set to PLS-DA classification model number 4, with 20 metabolite variables. The dotted vertical line represents the distinction boundary. The hollow dots depict class A (ND), while the solid dots depict class B (T2DM). This analysis demonstrates that 21/27 ND and 22/29 T2DM participants were correctly classified.</p>
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<p>Significant predictor variable features identified by the application of the (<b>a</b>) SAM and (<b>b</b>) EBAM techniques to the dataset. Delta values for these analyses were set to their default values of 0.50 and 0.90, respectively. The green circles show the variable features that exceeded the specified thresholds. (<b>c</b>) ROC curve analysis of the seven significant biomarker variable datasets extracted from the FDR-corrected SAM analysis shown in (<b>a</b>).</p>
Full article ">Figure 6 Cont.
<p>Significant predictor variable features identified by the application of the (<b>a</b>) SAM and (<b>b</b>) EBAM techniques to the dataset. Delta values for these analyses were set to their default values of 0.50 and 0.90, respectively. The green circles show the variable features that exceeded the specified thresholds. (<b>c</b>) ROC curve analysis of the seven significant biomarker variable datasets extracted from the FDR-corrected SAM analysis shown in (<b>a</b>).</p>
Full article ">Figure 6 Cont.
<p>Significant predictor variable features identified by the application of the (<b>a</b>) SAM and (<b>b</b>) EBAM techniques to the dataset. Delta values for these analyses were set to their default values of 0.50 and 0.90, respectively. The green circles show the variable features that exceeded the specified thresholds. (<b>c</b>) ROC curve analysis of the seven significant biomarker variable datasets extracted from the FDR-corrected SAM analysis shown in (<b>a</b>).</p>
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<p>A schematic representation of the investigation conducted, showing the discovery of <sup>1</sup>H NMR-detectable salivary biomarkers for T2DM and T2DM-linked dental caries.</p>
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12 pages, 250 KiB  
Article
Co-Existence of Dry Mouth, Xerostomia, and Focal Lymphocytic Sialadenitis in Patients with Sjögren’s Syndrome
by Katarzyna Błochowiak
Appl. Sci. 2024, 14(13), 5451; https://doi.org/10.3390/app14135451 - 23 Jun 2024
Viewed by 685
Abstract
Background: Some patients with Sjögren’s syndrome (SS) do not develop xerostomia despite advanced involvement of the salivary glands and the presence of focal lymphocytic sialadenitis (FLS). The aim of the study is to determine possible correlations between xerostomia, symptoms of sicca syndrome, FLS, [...] Read more.
Background: Some patients with Sjögren’s syndrome (SS) do not develop xerostomia despite advanced involvement of the salivary glands and the presence of focal lymphocytic sialadenitis (FLS). The aim of the study is to determine possible correlations between xerostomia, symptoms of sicca syndrome, FLS, and other features in SS patients. Methods: The study group comprised 50 patients with SS. The comprehensive assessment of patients included clinical, laboratory, and serological examinations. All patients underwent labial salivary gland biopsies. Dry mouth and dry eyes were assessed by unstimulated whole salivary flow rate (USWSF) and Schirmer’s test, respectively. Results: Xerostomia and xerophthalmia are closely related components of sicca syndrome. Xerostomia did not correlate with any serological or laboratory values, including ANA titers, SSA, SSB, Ro52 antibodies, rheumatoid factor, C-reactive protein, and Erythrocyte Sedimentation Rate. There were no correlations between xerostomia and FLS or Focus score. USWSF results correlated with xerostomia reported by patients, contrary to Schirmer’s test, which did not correlate with xerophthalmia. Conclusions: Dry mouth in SS is independent of any serological or inflammatory parameters. The occurrence of FLS does not determine xerostomia and its severity. Dry mouth in SS is influenced by other undetermined factors and mechanisms independent of salivary gland involvement. Full article
20 pages, 2894 KiB  
Review
Oral Health Implications of Obstructive Sleep Apnea: A Literature Review
by Antonino Maniaci, Salvatore Lavalle, Riccardo Anzalone, Antonino Lo Giudice, Salvatore Cocuzza, Federica Maria Parisi, Filippo Torrisi, Giannicola Iannella, Federico Sireci, Gianluca Fadda, Mario Lentini, Edoardo Masiello and Luigi La Via
Biomedicines 2024, 12(7), 1382; https://doi.org/10.3390/biomedicines12071382 - 21 Jun 2024
Viewed by 716
Abstract
Background: Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by repeated episodes of partial or complete obstruction of the upper airway during sleep. While the systemic implications of OSA are well documented, the dental consequences are less frequently discussed yet equally [...] Read more.
Background: Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by repeated episodes of partial or complete obstruction of the upper airway during sleep. While the systemic implications of OSA are well documented, the dental consequences are less frequently discussed yet equally significant. This review aims to elucidate the oral health impacts of OSA, emphasizing the importance of interdisciplinary care. Methods: A comprehensive literature search was conducted across several databases to identify studies examining the relationship between OSA and various oral health parameters. The review included observational studies, clinical trials, and systematic reviews published in English up to January 2024. Results: OSA was significantly associated with heightened risks of bruxism, dry mouth, periodontal disease, temporomandibular joint disorders, palatal and dental changes, and alterations in taste sensation. Mouth breathing associated with OSA was a critical factor in exacerbating xerostomia and dental caries. Furthermore, the systemic inflammation induced by OSA appeared to correlate with the severity of periodontal disease. Patients using oral appliance therapy for OSA also showed notable changes in dental occlusion and required ongoing dental monitoring. Conclusions: The findings underscore the bidirectional relationship between OSA and oral health, highlighting the need for dental professionals to be integral participants in the management of OSA. Early dental evaluation and intervention can contribute to the overall health and quality of life of individuals with OSA. The review advocates for the development of clinical guidelines to facilitate the early identification and management of OSA-related oral health issues within dental practice and encourages a collaborative approach to patient care. Full article
(This article belongs to the Special Issue Relationship between Periodontal Disease and Systemic Disease)
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<p>Main alteration in OSA patients and oral diseases. This figure was created with BioRender.com.</p>
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<p>Molecular pathways of inflammation in OSA patients and oral diseases.</p>
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<p>Taste disorders molecular mechanisms in OSA patients.</p>
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28 pages, 4244 KiB  
Article
Submandibular Gland Pathogenesis Following SARS-CoV-2 Infection and Implications for Xerostomia
by Estela Sasso-Cerri, Vitor Dallacqua Martinelli, Salmo Azambuja de Oliveira, André Acácio Souza da Silva, Juliana Cerini Grassi de Moraes and Paulo Sérgio Cerri
Int. J. Mol. Sci. 2024, 25(13), 6820; https://doi.org/10.3390/ijms25136820 - 21 Jun 2024
Viewed by 613
Abstract
Although SARS-CoV-2 induces mucin hypersecretion in the respiratory tract, hyposalivation/xerostomia has been reported by COVID-19 patients. We evaluate the submandibular gland (SMGs) pathogenesis in SARS-CoV-2-infected K18-hACE2 mice, focusing on the impact of infection on the mucin production and structural integrity of acini, ductal [...] Read more.
Although SARS-CoV-2 induces mucin hypersecretion in the respiratory tract, hyposalivation/xerostomia has been reported by COVID-19 patients. We evaluate the submandibular gland (SMGs) pathogenesis in SARS-CoV-2-infected K18-hACE2 mice, focusing on the impact of infection on the mucin production and structural integrity of acini, ductal system, myoepithelial cells (MECs) and telocytes. The spike protein, the nucleocapsid protein, hACE2, actin, EGF, TNF-α and IL-1β were detected by immunofluorescence, and the Egfr and Muc5b expression was evaluated. In the infected animals, significant acinar hypertrophy was observed in contrast to ductal atrophy. Nucleocapsid proteins and/or viral particles were detected in the SMG cells, mainly in the nuclear membrane-derived vesicles, confirming the nuclear role in the viral formation. The acinar cells showed intense TNF-α and IL-1β immunoexpression, and the EGF-EGFR signaling increased, together with Muc5b upregulation. This finding explains mucin hypersecretion and acinar hypertrophy, which compress the ducts. Dying MECs and actin reduction were also observed, indicating failure of contraction and acinar support, favoring acinar hypertrophy. Viral assembly was found in the dying telocytes, pointing to these intercommunicating cells as viral transmitters in SMGs. Therefore, EGF-EGFR-induced mucin hypersecretion was triggered by SARS-CoV-2 in acinar cells, likely mediated by cytokines. The damage to telocytes and MECs may have favored the acinar hypertrophy, leading to ductal obstruction, explaining xerostomia in COVID-19 patients. Thus, acinar cells, telocytes and MECs may be viral targets, which favor replication and cell-to-cell viral transmission in the SMG, corroborating the high viral load in saliva of infected individuals. Full article
(This article belongs to the Section Molecular Biology)
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<p>(<b>A</b>–<b>J</b>) Photomicrographs of submandibular gland sections subjected to immunofluorescence for detection of hACE2 (<b>A</b>,<b>B</b>), actin + spike double immunofluorescence (<b>C</b>–<b>F</b>) and nucleocapsid protein (<b>G</b>–<b>J</b>). In (<b>A</b>,<b>B</b>), hACE2 is observed mainly in the acini (Ac) and some punctual immunoexpression in the GCTs (arrowheads). In (<b>C</b>), the GCTs are surrounded by discontinuous actin immunoexpression (green), and an evident spike immunolabeling is observed in the acinar cells (Ac). In (<b>D</b>–<b>F</b>), co-localization of actin and spike (yellow) is noted in the myoepithelial cells (arrowheads) surrounding GCTs. In (<b>G</b>), nucleocapsid protein is observed in the acinar cells (Ac). In (<b>H</b>–<b>J</b>), nucleocapsid immunolabeling is observed filling the cytoplasm of acinar cells; note immunofluorescent reaction in close contact or within the nucleus (arrows).</p>
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<p>(<b>A</b>–<b>F</b>) Photomicrographs of SMGs showing immunofluorescence reactions for detection of TNF-α (<b>A</b>–<b>C</b>) and IL-1 β (<b>D</b>–<b>F</b>). In (<b>A</b>), a subtle TNF-α immunolabeling is observed in the acini (arrowheads) whereas in (<b>B</b>,<b>C</b>), a strong immunoreaction is observed in the acini (arrowheads) and basal portion of GCTs (arrows). In (<b>D</b>), the acinar IL-1β immunoreaction is weak (arrowheads) when compared to the strong acinar immunoreaction observed in E and F (arrowheads). Unspecific labelled erythrocytes are normally observed in the blood vessels (Bv).</p>
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<p>(<b>A</b>–<b>F</b>) Photomicrographs of submandibular gland sections stained by HE (<b>A</b>,<b>B</b>) and PAS method (<b>C</b>–<b>F</b>). In (<b>A</b>,<b>B</b>), acini (Ac) and GCTs are observed. Note that in (<b>B</b>) (IG), the acinar area is increased and the GCTs diameter reduced (double headed arrows) when compared to CG. In (<b>C</b>,<b>D</b>), PAS-positive secretory granules (magenta) are observed in the GCTs; however, in IG, an intense PAS staining is filling almost all the cytoplasm in comparison to the normal apical staining pattern observed in CG. Note that most GCTs show a PAS-positive secretory content in the lumen (asterisks) in comparison to CG. Ac (acini). In (<b>E</b>,<b>F</b>), GCTs show PAS-positive granules in the apical portion ((<b>E</b>); asterisk) and filling almost all the cytoplasm ((<b>F</b>); asterisk). In (<b>F</b>) (IG), either the acinar (white arrows) or GCTs (black arrows) cells show irregular nuclei with strongly basophilic condensed chromatin in comparison to CG.</p>
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<p>(<b>A</b>,<b>B</b>) Diameter and PAS-positive granular area in GCTs of animals from the CG and IG. (<b>C</b>) Volume density (Vv) of GCTs and acini in the animals from the CG and IG.</p>
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<p>(<b>A</b>,<b>B</b>) Photomicrographs of SMGs showing immunofluorescence reactions for detection of EGF. In (<b>A</b>), an evident EGF immunoreaction is observed in the apical portion of GCTs whereas, in (<b>B</b>), a granular immunofluorescence is filling almost all the cytoplasm of tubular cells. (<b>C</b>) Immunofluorescent area of EGF in the SMGs of animals from the CG and IG. (<b>D</b>) <span class="html-italic">Egfr</span> mRNA levels in the SMG of animals from the CG and IG.</p>
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<p>(<b>A</b>–<b>I</b>) Photomicrographs of sections of SMGs stained by silver impregnation (<b>A</b>–<b>E</b>) and AB (<b>F</b>–<b>I</b>). In (<b>A</b>), acini (Ac) and GCTs are surrounded by evident basement membrane in black (arrows). In IG (<b>B</b>–<b>E</b>), the basement membrane is discontinuous in some points where acinus (Ac) and GCT are interconnected (arrows), indicating fusion between these structures. In (<b>F</b>), AB-positive mucin is evident in the acini (Ac). The acinar–GCT interface is well delimited (arrowheads). In (<b>G</b>,<b>H</b>), the GCTs are compressed by the large AB-positive acini (Ac), and the AB-positive mucin seems to be invading the juxtaposed tubular cells (arrowheads). In (<b>G</b>,<b>I</b>), clusters of GCT cells (GCTc) are enclosed by the acinar cells (Ac). (<b>J</b>) A significant increase in <span class="html-italic">Muc5b</span> mRNA expression is observed in the IG in comparison to the CG.</p>
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<p>(<b>A</b>–<b>D</b>) Photomicrographs of semithin sections of SMGs stained by toluidine blue. In (<b>A</b>), the normal acini show mucin granules (Ac) and GCT contains apical granules (white box). An intercalated duct is also observed with typical lumen (ID). In (<b>B</b>,<b>C</b>) (IG), the acinar cells are larger and filled with numerous mucin granules (Ac) in comparison to the CG. In GCTs, the granules are filling almost all the cytoplasm (white boxes). Narrow and compressed portions of GCT (stars) are continuous with intercalated ducts (ID), whose cells are compacted, showing flattened and irregular nuclei (arrows). Lumen (Lu). In (<b>D</b>), a GCT portion in close contact with acini (Ac) shows mucin granules, apparently inside GCT cells’ cytoplasm (white arrowheads); some of these cells are intermingled with the acinar cells (black arrowhead). (<b>E</b>–<b>J</b>) Electron micrographs of portions of GCTs and intercalated ducts (ID). In (<b>E</b>) (CG), the GCT cell shows rough endoplasmic reticulum (RER) and numerous homogeneous spherical secretory granules (asterisks) in the apical portion. In (<b>F</b>) (IG), a high granular density is noted in the cytoplasm; some granules show irregular shape (asterisks). The RER cisternae are larger and more electron-lucent than in the CG. Nu (nucleus). In (<b>G</b>) (similar to <a href="#ijms-25-06820-f005" class="html-fig">Figure 5</a>C), a damaged and compressed GCT portion with typical granules is in contact with an intercalated duct (ID), whose cells show flattened nuclei (Nu) with electron-dense masses of chromatin (asterisks), indicating cell death. In the stroma, note two dying cells (C1 and C2) with the nuclei showing a peripheral condensed chromatin (asterisks) and irregular outline (black arrowheads). In (<b>H</b>) (high magnification of the intercalated duct in (<b>G</b>); white box), the apical portions of epithelial cells are attached by desmosomes (asterisks) and delimiting the lumen (Lu), in which viral particles (white arrows) are observed. The viral particles are surrounded by a membrane and contain nucleocapsid proteins (inset; white arrowheads). Nu (nucleus). In (<b>I</b>), intercalated duct cells (Nu) are delimiting the lumen (Lu). In (<b>J</b>) (high magnification of (<b>I</b>); black box), viral particles are seen in the lumen (black arrows). Some microvilli of the ductal cells containing actin filaments (arrowheads) are protruding towards the lumen. Desmosomes (asterisks) are also observed.</p>
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<p>(<b>A</b>–<b>D</b>) Electron micrographs of acini of submandibular gland sections of animals from the CG and IG. In (<b>A</b>), note the organized rough endoplasmic reticulum cisternae (RER) filling almost all the cytoplasm, and mucus granules (Mg) intermingled with the RER. The intact nuclear membrane is surrounded by typical circular RER cisternae (white arrows and inset). In (<b>B</b>), numerous mucus secretory granules (Mg) are filling almost all the cytoplasm; some of them are fusing with each other (asterisks), forming large mucus granules (pink circles). The remaining cytoplasm is filled with rough endoplasmic reticulum (RER) and mitochondria (Mi). Note that the nucleus (Nu), differently from the CG (<b>A</b>), shows an irregular nuclear membrane forming protrusions towards the cytoplasm (inset; black arrows). In (<b>C</b>), a binuclear acinar cell (Nu) shows dilated rough endoplasmic reticulum (RER) cisternae intermingling with large mucus secretory granules (Mg). Irregular masses of mucus secretion (asterisks), derived from the granules’ fusion, are spread through the cytoplasm. Portions of myoepithelial cells (MEC). In (<b>D</b>) (high magnification of delimited portion of (<b>C</b>)), RER cisternae-like structures (in pink) seem to be interconnected with a dilation of the nuclear intermembrane space (white asterisks). Nu (nucleus); Mi (mitochondria).</p>
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<p>(<b>A</b>,<b>B</b>) Electron micrographs of portions of acinar cells of submandibular glands of animals from the IG. In (<b>A</b>), large vesicles (delimited by the pink line) are observed in the cytoplasm (pink asterisks). These vesicles are derived from dilations of the nuclear intermembrane space (black asterisks), forming irregular outlined vesicles (black arrows) continuous with the nuclear membrane. Some folded portions of these vesicles (named DMVs) are seen in cross sections within the dilation itself (black box and inset). Under high magnification (inset), a vesicle with double membrane (arrowhead) containing viral particles/nucleocapsid proteins (white arrows) is observed. Convoluted membranes (CMs) are also seen between the nuclear vesicles and the large cytoplasmic vesicles. In (<b>B</b>), a dilation of the nuclear intermembrane space (asterisks) forms a long vesicle (pink line) containing several DMVs (yellow lines) derived from the nuclear membrane folding itself, incorporating the cytoplasmic content with nucleocapsid proteins (white arrow), which are also observed inside DMVs (black arrows). Under high magnification (black box and inset), a DMV delimited by a double membrane (arrowheads) contains nucleocapsid proteins (black arrows). Mitochondria (Mi). Nu (nucleus). (<b>C</b>–<b>E</b>), Photomicrographs of semithin sections of SMGs stained by toluidine blue. In (<b>C</b>–<b>E</b>), telocytes with telopodes (arrowheads) are observed. In (<b>D</b>,<b>E</b>), the telocytes (arrows) show an atypical nucleus in comparison to (<b>C</b>). In (<b>E</b>), a vacuolar structure is observed in a telocyte cytoplasm (asterisk). (<b>F</b>,<b>G</b>) Electron micrographs of portions of SMGs of animals from the IG. In (<b>F</b>), a digitally colored electron micrograph shows portions of telocytes (pink) in the stroma. Note the moniliform aspect of the telopodes with an alternation between the podomers (white arrowheads) and the podoms (black arrows). Several vacuole-type vesicles are observed in the cytoplasm (asterisks). Bv (blood vessel); Ac (acini); GCT (granular convoluted tubule). In (<b>G</b>) (high magnification of (<b>F</b>)), a dilation of the nuclear intermembrane space (white asterisks) forming large vesicles (pink line and pink asterisks). In the nuclear vesicle, a DMV (black box) containing viral particles (left inset; black arrows) is observed. Note convoluted membranes (CMs) between the nucleus and the large vesicles. Nucleocapsid proteins (white arrows) are observed in viral assembly portions (yellow lines). A folded vesicle portion (delimited by the yellow line) inside the vesicle itself is observed. A vesicle containing viral particles (around 150 nm) is observed in the cell periphery (right inset; black arrows); in some of them, spike proteins (black arrowheads) can be seen. Note a centriole (white arrowhead) in the telocyte cytoplasm. Nu (nucleus).</p>
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<p>(<b>A</b>–<b>H</b>) Digitally colored electron micrographs of portions of stroma of SMGs of animals from the IG. In (<b>A</b>), a telocyte (pink) localized in the stroma between GCT and acinus (Ac). The telocyte shows a dichotomous pattern of branching (black arrowhead) and a moniliform aspect of the telopodes, with an alternation between the podomers (white arrowheads) and the podoms (black arrows). Note the large cytoplasmic portion containing convoluted vesicles (black asterisks). Mitochondria (Mi). In (<b>B</b>), a high magnification of (<b>A</b>), the convoluted large DMVs (asterisks) containing small, folded portions of the vesicles themselves (white arrows). Note the folded membrane during invagination (red arrow) and the formed vesicle after invagination (red arrowhead). In a large fold (black box and inset), note several viral particles, probably nucleocapsid proteins (white arrows). In (<b>C</b>) (high magnification of (<b>B</b>)—white box), several viral particles (nucleocapsid proteins) are seen outside the vesicle (arrowheads) and within the formed vesicles after invagination (white arrows). Note regions of the invagination process (pink circles). In (<b>D</b>), a dying telocyte with condensed clumps of chromatin in the nucleus (white asterisks) shows dilations of the nuclear intermembrane space (black asterisks). Mitochondria (Mi). In the cytoplasmic portion of the telocyte (black boxes), several viral particles are seen. In (<b>E</b>) (high magnifications of (<b>D</b>)—black boxes), note viral particles with spike proteins (arrowheads). In (<b>F</b>), a stroma portion between acinus (Ac) and GCT shows a collapsed blood vessel with a narrow lumen (Lu), surrounded by basal lamina (asterisks). Note DMVs (white arrows) with viral particles (black arrow) in the endotheliocyte. A DMV (white arrow) is also observed in a telopode (Tp) of a telocyte (in pink). Endotheliocyte nucleus (Nu). In (<b>G</b>,<b>H</b>) (high magnifications of DMV), viral particles (black arrows) and viral assembly sites containing nucleocapsid proteins (pink circles) are seen. In H, spike proteins are observed either on the viral surface (white arrowheads) or on the vesicle inner surface (black arrowheads).</p>
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<p>(<b>A</b>–<b>D</b>) Electron micrographs of the SMGs of animals from the IG showing portions of damaged MECs. In (<b>A</b>,<b>B</b>), dying MECs in close contact with acinus (Ac; (<b>A</b>)) and GCT (<b>B</b>) show electron dense masses of chromatin (asterisks) in the nucleus (Nu), and cytoplasm filled with actin filaments (Af). In (<b>B</b>), note the nuclear intermembrane space dilation (delimited by pink lines) and cytoplasmic vesicle (pink line and pink asterisk) derived from the nuclear dilation. Mucus granules (Mg); mitochondria (Mi). In (<b>C</b>), a portion of a damaged MEC shows cytoplasm filled with actin filaments (Af) and double membrane vesicles (white box and inset; white arrowheads). Several viral particles measuring around 130 nm are observed inside DMVs (inset; white arrows). In (<b>D</b>), a damaged MEC shows condensed chromatin (asterisks) in the nucleus (Nu). Note the DMVs (pink line and pink asterisks) derived from the nuclear intermembrane space dilation (pink line and white arrows). Double membrane of DMV is seen under high magnification (inset). Viral particles are observed either in groups, enclosed in large vesicles (black arrows), or isolated within small vesicles (black box and inset; white arrowheads) among actin filaments (Af), next to the plasma membrane. (<b>E</b>–<b>H</b>) Photomicrographs of SMGs showing actin immunofluorescence in MECs. In (<b>E</b>,<b>G</b>), strong and continuous actin immunolabelling (green; arrows) is observed in the MECs surrounding the acini and GCTs. In (<b>F</b>,<b>H</b>), a weak and discontinuous actin immunoreaction surrounding GCTs and acini (green; arrows) is observed in IG. In (<b>I</b>), a significant decrease in the actin immunofluorescent area is observed in IG in comparison with CG.</p>
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<p>Schematic representation of the SMG pathogenesis following SARS-CoV-2 infection. In normal SMGs, the acini and GCT, showing normal distribution of the secretory granules, release their secretory content in the intercalated (ID) and striated (SD)/excretory ducts (ED), respectively, and transport saliva to the oral cavity. Myoepithelial cells (MECs) surround acini, GCT and ducts. In the stroma, telocytes interconnect blood vessels (BV), acini, ducts and GCT. In the infected SMG, (<b>1</b>) SARS-CoV-2 from the blood stream reaches telocytes and MECs. In these branched and supportive cells, the virus is replicated and transmitted to other cell types, allowing a rapid viral transmission, mainly to acinar cells. (<b>2</b>) In these cells, the infection induces mucin hypersecretion and accumulation of granules in the cytoplasm, culminating in the acinar hypertrophy. (<b>3</b>) The acinar enlargement causes ID and GCT compression, impairing the transport of saliva to the oral cavity. The loss of acinar structural support, due to telocytes and MECs death, favors the acinar enlargement caused by mucin hypersecretion. (<b>4</b>) SARS-CoV-2 infection triggers pro-inflammatory cytokines production (IL-1β and TNF-α), which activate EGF-EGFR signaling, causing <span class="html-italic">Muc5b</span> upregulation, culminating in the mucin hypersecretion and accumulation.</p>
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11 pages, 272 KiB  
Article
Frequency of Oral Lesions, Olfactory, and Gustatory Disorders and Xerostomia in Patients with COVID-19
by Natália Lopes Castilho, Daniella R. Barbosa Martelli, Renato Assis Machado, Zêus Araujo Cunha, Claudiojanes dos Reis, Priscila Regina Queiroz, Dayane de Sá Silva, Eduardo Araujo Oliveira, Ricardo D. Coletta and Hercílio Martelli-Júnior
Dent. J. 2024, 12(6), 179; https://doi.org/10.3390/dj12060179 - 11 Jun 2024
Viewed by 899
Abstract
COVID-19, a respiratory illness with a global impact on millions, has recently been linked to manifestations affecting various bodily systems, including the oral cavity. Studies highlight oral issues, like ulcers, blisters, and white patches, alongside olfactory and gustatory dysfunction, influencing an individual’s quality [...] Read more.
COVID-19, a respiratory illness with a global impact on millions, has recently been linked to manifestations affecting various bodily systems, including the oral cavity. Studies highlight oral issues, like ulcers, blisters, and white patches, alongside olfactory and gustatory dysfunction, influencing an individual’s quality of life. In this context, our study aimed to assess the frequency of oral lesions, olfactory and gustatory disorders, and xerostomia resulting from COVID-19. An observational study was conducted with 414 patients to evaluate the frequency of oral symptoms resulting from COVID-19. Patients were diagnosed with mild symptoms and evaluated through clinical examination of the oral cavity and a questionnaire to assess functional alterations. The findings showed that 139 out of 414 patients presented clinical manifestations, with oral lesions being the most prevalent (19.1%), followed by gustatory disorders (18.1%), xerostomia (14.2%), and olfactory dysfunction (14%). The most prevalent oral lesions were ulcerations (n = 51), candidiasis (n = 8), and erythema or red plaques (n = 7). Unfortunately, 50 (12.1%) patients died during this study. Therefore, oral lesions, olfactory and gustatory dysfunctions, and xerostomia are common symptoms associated with COVID-19. Full article
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16 pages, 2286 KiB  
Systematic Review
Unlocking the Future: Bioprinting Salivary Glands—From Possibility to Reality
by Dobromira Shopova, Antoniya Yaneva, Anna Mihaylova, Atanaska Dinkova and Desislava Bakova
J. Funct. Biomater. 2024, 15(6), 151; https://doi.org/10.3390/jfb15060151 - 1 Jun 2024
Viewed by 724
Abstract
Salivary gland biofabrication represents a promising avenue in regenerative medicine, aiming to address the challenges of salivary gland dysfunction caused by various factors such as autoimmune diseases and radiotherapy. This review examines the current state of bioprinting technology, biomaterials, and tissue engineering strategies [...] Read more.
Salivary gland biofabrication represents a promising avenue in regenerative medicine, aiming to address the challenges of salivary gland dysfunction caused by various factors such as autoimmune diseases and radiotherapy. This review examines the current state of bioprinting technology, biomaterials, and tissue engineering strategies in the context of creating functional, implantable salivary gland constructs. Key considerations include achieving vascularization for proper nutrient supply, maintaining cell viability and functionality during printing, and promoting tissue maturation and integration with surrounding tissues. Despite the existing challenges, recent advancements offer significant potential for the development of personalized therapeutic options to treat salivary gland disorders. Continued research and innovation in this field hold the potential to revolutionize the management of salivary gland conditions, improving patient outcomes and quality of life. This systematic review covers publications from 2018 to April 2024 and was conducted on four databases: Google Scholar, PubMed, EBSCOhost, and Web of Science. The key features necessary for the successful creation, implantation and functioning of bioprinted salivary glands are addressed. Full article
(This article belongs to the Section Synthesis of Biomaterials via Advanced Technologies)
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<p>PRISMA flowchart illustrating the selection process of articles for the review.</p>
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<p>Major approaches to the biofabrication of salivary gland tissues. Reprinted from Ref. [<a href="#B22-jfb-15-00151" class="html-bibr">22</a>].</p>
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<p>The anatomical and structural features of salivatory glands. Reprinted from Ref. [<a href="#B18-jfb-15-00151" class="html-bibr">18</a>].</p>
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<p>Cell types and composition of vascular channels and their typical diameters according to Schöneberg. Reprinted from Ref. [<a href="#B49-jfb-15-00151" class="html-bibr">49</a>].</p>
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7 pages, 2334 KiB  
Case Report
HELIX Syndrome, a Claudinopathy with Relevant Dermatological Manifestations: Report of Two New Cases
by María Carmen Martínez-Romero, María Encarnación Hernández-Contreras, Juan Antonio Bafalliu-Vidal, María Barreda-Sánchez, Teresa Martínez-Menchón, Virginia Cabello-Chaves and Encarna Guillén-Navarro
Genes 2024, 15(6), 687; https://doi.org/10.3390/genes15060687 - 26 May 2024
Viewed by 683
Abstract
HELIX syndrome (Hypohidrosis–Electrolyte disturbances–hypoLacrimia–Ichthyosis–Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic CLDN10 variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, [...] Read more.
HELIX syndrome (Hypohidrosis–Electrolyte disturbances–hypoLacrimia–Ichthyosis–Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic CLDN10 variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, highlight the skin anomalies as an important clue, and expand the genotypic spectrum. Two adult brothers from consanguineous parents with suspected ectodermal dysplasia (ED) since early childhood were re-evaluated. A comprehensive phenotypic exam and an aCGH + SNP4 × 180 K microarray followed by Sanger sequencing of the CLDN10 gene were performed. They presented hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, palm hyperlinearity, alacrima, and xerostomia. In adulthood, they also developed a salt-losing nephropathy with hypokalemia and hypermagnesemia. The molecular study in both patients revealed a novel pathogenic homozygous deletion of 8 nucleotides in exon 2 of the CLDN10 gene [CLDN10 (NM_0006984.4): c.322_329delGGCTCCGA, p.Gly108fs*] leading to a premature truncation of the protein. Both parents were heterozygous carriers. Hypohidrosis, ichthyosis, and plantar keratosis associated with alacrima and xerostomia should raise suspicion for HELIX syndrome, which also includes nephropathy and electrolyte disturbances in adults. Given the potential for ED misdiagnosis in infancy, it is important to include the CLDN10 gene in a specific genodermatosis next-generation sequencing (NGS) panel to provide early diagnosis, accurate management, and genetic counseling. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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<p>Family tree where generations are indicated in Roman numerals (I-II) and members of each generation are indicated in Arabic numerals (1–3) (<b>a</b>). Exon 2 sequence of the <span class="html-italic">CLDN10</span> gene in Case 1 with c.322_329 delGGCTCCGA; p.Gly108fs* in homozygosis (<b>b</b>).</p>
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<p>Phenotypic manifestations in Case 1: hypoplastic and severely impaired enamel wear of the permanent teeth with sawed edges (<b>a</b>), normal eye with alacrimia confirmed by a pathological Schirmer test (<b>b</b>), redness and hyperlinearity in the palms (<b>c</b>), xerosis, mild ichthyosis, and plantar keratosis (<b>d</b>).</p>
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Article
Helium Ion Therapy for Advanced Juvenile Nasopharyngeal Angiofibroma
by Line Hoeltgen, Eva Meixner, Philipp Hoegen-Saßmannshausen, Ji-Young Kim, Maximilian Deng, Katharina Seidensaal, Thomas Held, Klaus Herfarth, Thomas Haberer, Jürgen Debus, Andrea Mairani, Semi Harrabi and Thomas Tessonnier
Cancers 2024, 16(11), 1993; https://doi.org/10.3390/cancers16111993 - 24 May 2024
Viewed by 770
Abstract
Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in [...] Read more.
Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications. Full article
(This article belongs to the Section Pediatric Oncology)
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<p>(<b>A</b>) Dose distribution on the axial, sagittal and coronal planning CT slices for an exemplary patient with protons and helium ions and the dose difference between the two modalities (Δ(p-He)). (<b>B</b>) Dose–volume histograms (DVH) for selected volumes for both modalities. The clinical target volume (CTV) is displayed together with bilateral hippocampus and brain (without the CTV) on the dose maps and DVH. DVH from protons and helium ions plans are represented with solid and dashed lines respectively.</p>
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<p>Differences in normal tissue complication probability (∆NTCP) and risk ratio (RR) for secondary CNS malignancies following helium ion therapy and proton therapy. All the presented results are statistically significant. ∆NTCP is expressed in %. IL: ipsilateral.</p>
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14 pages, 782 KiB  
Review
Impact of Relative Biologic Effectiveness for Proton Therapy for Head and Neck and Skull-Base Tumors: A Technical and Clinical Review
by Adam L. Holtzman, Homan Mohammadi, Keith M. Furutani, Daniel M. Koffler, Lisa A. McGee, Scott C. Lester, Mauricio E. Gamez, David M. Routman, Chris J. Beltran and Xiaoying Liang
Cancers 2024, 16(11), 1947; https://doi.org/10.3390/cancers16111947 - 21 May 2024
Viewed by 747
Abstract
Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary [...] Read more.
Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy’s potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice. Full article
(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)
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<p>Biological dose estimations from various phenomenological RBE models from Rørvik et al. [<a href="#B61-cancers-16-01947" class="html-bibr">61</a>], Phys Med Biol 63 (18), 185,013 (2018). © Institute A physics and engineering in medicine, reproduced with the permission of IOP Publishing Ltd. BEL, CAR, CHE, FRE, JON, MAI, MCN, PLR, RØRU, RØRW, TIL2, UNK, WED, and WIL represent various phenomenological models included in the study. Please refer to Table 1 in [<a href="#B61-cancers-16-01947" class="html-bibr">61</a>] for details on each model. LETd, the dose-averaged linear energy transfer, is represented on the right axis. RBE indicates relative biological effectiveness.</p>
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19 pages, 3305 KiB  
Article
Investigation of Hydrocolloid Plant Polysaccharides as Potential Candidates to Mimic the Functions of MUC5B in Saliva
by Christina Winter, Carolin Tetyczka, Duy Toan Pham, Dagmar Kolb, Gerd Leitinger, Sandra Schönfelder, Olaf Kunert, Tanja Gerlza, Andreas Kungl, Franz Bucar and Eva Roblegg
Pharmaceutics 2024, 16(5), 682; https://doi.org/10.3390/pharmaceutics16050682 - 18 May 2024
Viewed by 831
Abstract
The successful substitution of complex physiological fluids, such as human saliva, remains a major challenge in drug development. Although there are a large number of saliva substitutes on the market, their efficacy is often inadequate due to short residence time in the mouth, [...] Read more.
The successful substitution of complex physiological fluids, such as human saliva, remains a major challenge in drug development. Although there are a large number of saliva substitutes on the market, their efficacy is often inadequate due to short residence time in the mouth, unpleasant mouthfeel, or insufficient protection of the teeth. Therefore, systems need to be identified that mimic the functions of saliva, in particular the salivary mucin MUC5B and the unique physiological properties of saliva. To this end, plant extracts known to contain hydrocolloid polysaccharides and to have mucus-forming properties were studied to evaluate their suitability as saliva substitutes. The aqueous plant extracts of Calendula officinalis, Fucus sp. thalli, and lichenan from Lichen islandicus were examined for composition using a range of techniques, including GC-MS, NMR, SEC, assessment of pH, osmolality, buffering capacity, viscoelasticity, viscoelastic interactions with human saliva, hydrocolloid network formation, and in vitro cell adhesion. For this purpose, a physiologically adapted adhesive test was developed using human buccal epithelial cells. The results show that lichenan is the most promising candidate to mimic the properties of MUC5B. By adjusting the pH, osmolality, and buffering capacity with K2HPO4, it was shown that lichenan exhibited high cell adhesion, with a maximum detachment force that was comparable to that of unstimulated whole mouth saliva. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts, 2nd Edition)
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<p>Schematic illustration of the applied in vitro adhesion setup. In step 1, shear stresses of 0.1 to 100 rad/s are applied to simulate physiological shear rates in the oral cavity. In step 2, the system detaches the aqueous solution containing hydrocolloid polysaccharides from the TR146 cell layer.</p>
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<p>SEC of Calendula and Fucus extracts. A protein-based molecular weight marker was used as size reference. Detection was performed at 220 nm, and the intensity was normalized. TG: thyroglobulin 670 kDa, GG: gamma globulin 150 kDa, OV: ovalbumin 44.3 kDa, RA: ribonuclease A 13.7 kDa, pABA: p-Aminobenzoic acid 0.137 kDa.</p>
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<p>Viscoelastic behavior of 1% (<span class="html-italic">w</span>/<span class="html-italic">w</span> %) aqueous solution of Calendula (<b>A</b>), Fucus (<b>B</b>), and lichenan (<b>C</b>).</p>
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<p>Viscoelastic parameters of viscosity (<b>A</b>), elastic (<b>B</b>) and viscous moduli (<b>C</b>) of Calendula, Fucus, and lichenan, mixed with human saliva at low (0.1 rad/s) and high (100 rad/s) shear rates.</p>
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<p>Representative Cryo-SEM images of the polysaccharide structure of Calendula (<b>A</b>), Fucus (<b>B</b>), and lichenan (<b>C</b>).</p>
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<p>Representative force distance curves of Calendula (<b>A</b>), Fucus (<b>B</b>), lichenan (<b>C</b>), and UWS (<b>D</b>), obtained via tack tests from a coherent TR146 cell surface, compared to a blank Aclar sheet. The sheet was placed in cell medium for the same amount of time and washed with PBS.</p>
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