Traumatic life events may shape how individuals utilize health care, yet their impact on medical and dental service utilization is underexplored. This study investigates how such events influence subsequent health care use. We analyzed data from the Mexican Health and Aging Study, the first longitudinal cohort in Mexico of middle-aged and older adults. The analytic sample comprised 17,424 unique individuals across 39,875 total observations. Three traumatic events were examined in relation to their effects on medical and dental service use: (1) experience of a natural disaster, (2) experience of the death of a child, and (3) experience of a crime or accident. We combined propensity score weighting with multivariable mixed-effects logistic regression to account for both confounding and correlation arising from repeated measures. We estimated the effect of exposure to each traumatic event by parametric g-computation, calculating risk differences with 95% confidence intervals (CIs). Exposure to a natural disaster increased medical service use by 4.2% (95% CI, 2.2 to 6.2) while reducing utilization of dental care by 4.8% (95% CI, -7.0 to -2.5). The death of a child increased medical service use by 4.9% (95% CI, 2.7 to 7.2) while reducing utilization of dental care by 6.0% (95% CI, -8.6 to -3.4). Crime or accidents increased utilization of medical services by 12.7% (95% CI, 11.1 to 14.2) while having no clear effect on utilization of dental care. Traumatic events have substantial and differential impacts on health care utilization. In particular, among middle-aged and older adults in Mexico, natural disasters and the death of a child have divergent effects on the utilization of medical versus dental care, while crime and accidents only affect medical care. Future research into this underdeveloped area may help to develop a more precise understanding of the underlying mechanisms.
The entire vertebrate facial skeleton is derived from Hox-negative cranial neural crest cells (CNCCs) that populate the embryonic frontonasal prominence and the first pharyngeal arches. Previous studies have shown that the Edn1/Ednra-Dlx5/Dlx6-Hand2 regulatory network specifies the maxillomandibular identity of CNCCs in the first pharyngeal arches in mice and that the combined application of retinoic acid and noggin to the presumptive maxillary domain in avian embryos transformed maxillary tissues to frontonasal structures, but the molecular mechanisms regulating frontonasal CNCC identity remain unresolved. Biallelic loss of function of any of the aristaless-like homeobox genes, including ALX1, ALX3, and ALX4, which exhibit partly overlapping patterns of expression in the frontonasal CNCCs, causes frontonasal dysplasia. In this study, we show that mice with combined inactivation of Alx1 and Alx3 throughout CNCCs exhibit disruption of frontonasal CNCC identity with ectopic activation of maxillary CNCC developmental profiles. We show that transgenic Alx1 expression throughout the CNCCs, starting from when they were migrating toward the facial primordia, caused ectopic activation of frontonasal CNCC marker genes and suppression of the maxillomandibular marker genes in the developing maxillary and mandibular processes and resulted in the formation of duplicated premaxilla at the expense of maxillary structures. These data identify the ALX transcription factors as key regulators specifying frontonasal CNCC identity and fill a long-standing gap in the molecular mechanism patterning the regional identities of the CNCC-derived craniofacial mesenchyme.
Abnormal enamel mineralization has been reported in genetic conditions associated with hypocalcemia but never with hypercalcemia. In the present study, we report 10 patients from 2 unrelated families in whom hypomineralized enamel co-segregated with hypercalcemia due to a complete deletion or frameshifting premature truncation (p.(Ser18Argfs*2)) of the guanine nucleotide-binding protein (G-protein) subunit α11 (GNA11) gene. Both GNA11 variants were heterozygous and predicted to cause a loss of function of Gα11. Multiproxy imaging analyses of naturally exfoliated primary teeth and clinically extracted permanent teeth from 2 affected patients revealed abnormal enamel mineralization, with constitutive patches of hypomineralization following no set pattern. In parallel, the study of wild-type mouse tooth germs using combined molecular and protein analyses showed Gna11 and Gα11 protein expression in ameloblasts at the secretion and maturation stages, as well as in odontoblasts, suggesting a role for Gα11 in tooth formation. Furthermore, the analysis of a mouse model of Familial Hypocalciuric Hypercalcemia 2 (FHH2) revealed delayed onset of enamel mineralization in the continuously growing incisors and hypomineralized enamel in both incisor and molars of heterozygous (Gna11Tm1b+/-) mice, with defects that are very similar to those affecting human FHH2 teeth. In conclusion, our study reveals that abnormal enamel mineralization may occur in association with hypercalcemia due to loss-of-function GNA11 mutations, opening a new field of investigation and highlighting the need to include a dentist in the multidisciplinary team in charge of patients with monogenic calcium disorders.
Periodontitis is a chronic inflammatory disease characterized by dysregulated neutrophil responses that contribute to progressive periodontal tissue destruction. Here, we observed aberrant fibrin accumulation in inflamed periodontal tissues and hypothesized that fibrin acts as a pathogenic mediator that promotes neutrophil recruitment and activation, thereby triggering neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production. To therapeutically target fibrin deposition, we developed a ROS-responsive hydrogel (PVHA@tPA) that enables localized delivery of tissue plasminogen activator (tPA), activating plasminogen to mediate fibrin degradation. In vitro, tPA released from the hydrogel degraded fibrin matrices in the presence of plasminogen, which restrained fibrin-mediated neutrophil adhesion and migration while suppressing subsequent NETs formation and ROS overproduction. By attenuating this neutrophil overactivation, the treatment improved the osteogenic capacity of periodontal ligament stem cells (PDLSCs) and the angiogenic potential of human umbilical vein endothelial cells (HUVECs). In vivo, PVHA@tPA treatment in a mouse periodontitis model reduced gingival fibrin deposition, attenuated neutrophil-associated inflammation, downregulated proinflammatory factors, and alleviated alveolar bone loss. Together, these findings identify fibrin deposition as a key driver of neutrophil dysregulation in periodontitis and establish fibrin-targeted therapy as a promising strategy to rebalance neutrophil responses and ameliorate periodontitis.
The dental pulp resides within a rigid dentin chamber with a limited blood supply, creating a hypoxic environment that impedes tissue regeneration. While growth factor signaling in pulpal revascularization is well documented, the direct cellular mechanisms that protect endothelial cells (ECs) from hypoxia-induced apoptosis remain unclear. This study identifies intercellular mitochondrial transfer (MT) from dental pulp stem cells (DPSCs) to ECs as a critical survival and angiogenic mechanism under hypoxic stress. Using MitoTracker labeling and flow cytometry, we demonstrated that mitochondria are preferentially transferred from DPSCs to ECs, a process significantly upregulated by hypoxia. We found that contact-dependent mechanisms involving tunneling nanotube-like structures contribute to MT, as cytochalasin B treatment or Miro1 knockdown in DPSCs significantly reduced MT and impaired EC function. To assess the impact of this organelle exchange, we isolated mitochondria-recipient (Mito+) and nonrecipient (Mito-) ECs for analysis. Mito+ ECs exhibited enhanced mitochondrial membrane potential, improved energy metabolism, and yielded superior tube-forming capacity as compared with Mito- ECs. Furthermore, MT significantly reduced EC apoptosis under cobalt chloride-induced hypoxic stress. The in vivo Matrigel plug assay showed that inhibiting MT from DPSCs, genetically or by inhibiting mitochondrial respiration, markedly suppressed DPSC-supported angiogenesis and increased EC apoptosis. Mechanistically, RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that MT revives the EC transcriptome and activates the PI3K-AKT signaling pathway. Immunofluorescence confirmed upregulation of AKT signaling in recipient ECs and colocalization of P-AKT with transferred mitochondria. Furthermore, inhibition of AKT signaling with MK-2206 abolished the proangiogenic and prosurvival role associated with MT, suggesting a direct regulatory role. Collectively, these findings establish MT as a vital metabolic lifeline that prevents EC collapse and drives DPSC-supported angiogenesis in the hypoxic pulp during the vulnerable window of pulpal restoration, thereby emphasizing MT as a transformative regenerative endodontic target.
