Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride's actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization.

/pdf/fluoride-s-effects-on-the-formation-of-teeth-and-bones-and-27arg0kmf0.pdf

Fluoride's Effects on the Formation of Teeth and Bones, and the Influence of Genetics

BackgroundExposure to excessive amounts of fluoride (F−) causes dental fluorosis in susceptible individuals; however, the mechanism of F−-induced toxicity is unclear. Previously, we have shown that...

Fluoride Induces Endoplasmic Reticulum Stress and Inhibits Protein Synthesis and Secretion

Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal. We addressed a question: are salubrinal’s actions more potent to the cells isolated from the osteoporotic mice than those isolated from the control mice? Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and β-glycerophosphate. The results revealed that salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate-resistant acid phosphatase. The results support the notion that salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples.

/pdf/effects-of-salubrinal-on-development-of-osteoclasts-and-50e0foq1r3.pdf

Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells

The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7−/− strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7−/− became significantly altered in the BALB/cJ P2X7−/− when compared to their wild type littermates. The BALB/cJ P2X7−/− showed reduced levels of serum C-telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7−/− mice strongly influences the bone phenotype of the P2X7−/− mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies.

/pdf/genetic-background-strongly-influences-the-bone-phenotype-of-3u96z9je1i.pdf

Genetic Background Strongly Influences the Bone Phenotype of P2X7 Receptor Knockout Mice

Systemic exposure to greater than optimal fluoride (F) can lead to dental fluorosis (DF). Parental A/J (DF-susceptible) and 129P3/J (DF-resistant) inbred mice were used for histological studies and to generate F2 progeny. Mice were treated with 0 or 50 ppm F in their drinking water for 60 days. A clinical criterion (modified Thylstrup and Fejerskov categorical scale) was used to assess the severity of DF for each individual F2 animal. Parental strains were subjected to histological examination of maturing enamel. F treatment resulted in accumulation of amelogenins in the maturing enamel of A/J mice. Quantitative trait loci (QTL) detection was performed using phenotypic extreme F2 animals genotyped for 354 single nucleotide polymorphism-based markers distributed throughout the mouse genome followed by χ2 analysis. Significant evidence of association was observed on chromosomes 2 and 11 for a series of consecutive markers (p < 0.0001). Further analyses were performed to examine whether the phenotypic effects were found in both male and female F2 mice or whether there was evidence for gender-specific effects. Analyses performed using the markers on chromosomes 2 and 11 which were significant in the mixed-gender mice were also significant when analyses were limited to only the male or female mice. The QTL detected on chromosomes 2 and 11 which influence the variation in response to fluorosis have their effect in mice of both genders. Finally, the QTL in both chromosomes appear to have an additive effect.

/pdf/detection-of-dental-fluorosis-associated-quantitative-trait-1sqjxhi860.pdf

Detection of Dental Fluorosis-Associated Quantitative Trait Loci on Mouse Chromosomes 2 and 11

Genetic background influences fluoride's effects on osteoclastogenesis

BACKGROUND
Digital peer support enhances engagement in mental and physical health services despite barriers such as location, transportation, and other accessibility constraints. Digital peer support involves live or automated peer support services delivered through technology media such as peer-to-peer networks, smartphone apps, and asynchronous and synchronous technologies. Supervision standards for digital peer support can determine important administrative, educative, and supportive guidelines for supervisors to maintain the practice of competent digital peer support, develop knowledgeable and skilled digital peer support specialists, clarify the role and responsibility of digital peer support specialists, and support specialists in both an emotional and developmental capacity.


OBJECTIVE
Although digital peer support has expanded recently, there are no formal digital supervision standards. The aim of this study is to inform the development of supervision standards for digital peer support and introduce guidelines that supervisors can use to support, guide, and develop competencies in digital peer support specialists.


METHODS
Peer support specialists that currently offer digital peer support services were recruited via an international email listserv of 1500 peer support specialists. Four 1-hour focus groups, with a total of 59 participants, took place in October 2020. Researchers used Rapid and Rigorous Qualitative Data Analysis methods. Researchers presented data transcripts to focus group participants for feedback and to determine if the researcher's interpretation of the data match their intended meanings.


RESULTS
We identified 51 codes and 11 themes related to the development of supervision standards for digital peer support. Themes included (1) education on technology competency (43/197, 21.8%), (2) education on privacy, security, and confidentiality in digital devices and platforms (33/197, 16.8%), (3) education on peer support competencies and how they relate to digital peer support (25/197, 12.7%), (4) administrative guidelines (21/197, 10.7%), (5) education on the digital delivery of peer support (18/197, 9.1%), (6) education on technology access (17/197, 8.6%), (7) supervisor support of work-life balance (17/197, 8.6%), (8) emotional support (9/197, 4.6%), (9) administrative documentation (6/197, 3%), (10) education on suicide and crisis intervention (5/197, 2.5%), and (11) feedback (3/197, 1.5%).


CONCLUSIONS
Currently, supervision standards from the Substance Abuse and Mental Health Services Administration (SAMHSA) for in-person peer support include administrative, educative, and supportive functions. However, digital peer support has necessitated supervision standard subthemes such as education on technology and privacy, support of work-life balance, and emotional support. Lack of digital supervision standards may lead to a breach in ethics and confidentiality, workforce stress, loss of productivity, loss of boundaries, and ineffectively serving users who participate in digital peer support services. Digital peer support specialists require specific knowledge and skills to communicate with service users and deliver peer support effectively, while supervisors require new knowledge and skills to effectively develop, support, and manage the digital peer support role.

Introduction to the Coproduction of Supervision Standards for Digital Peer Support: Qualitative Study.

Importance
People with serious mental illness (SMI), defined as a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or disabling major depressive disorder) die approximately 10 to 25 years earlier than the general population.


Objective
To develop the first-ever lived experience-led research agenda to address early mortality in people with SMI.


Evidence Review
A virtual 2-day roundtable comprising 40 individuals convened on May 24 and May 26, 2022, and used a virtual Delphi method to arrive at expert group consensus. Participants responded to 6 rounds of virtual Delphi discussion via email that prioritized research topics and agreement on recommendations. The roundtable was composed of individuals with lived experience of mental health and/or substance misuse, peer support specialists, recovery coaches, parents and caregivers of people with SMI, researchers and clinician-scientists with and without lived experience, policy makers, and patient-led organizations. Twenty-two of 28 (78.6%) of the authors who provided data represented people with lived experiences. Roundtable members were selected by reviewing the peer-reviewed and gray literature on early mortality and SMI, direct email, and snowball sampling.


Findings
The following recommendations are presented in order of priority as identified by the roundtable participants: (1) improve the empirical understanding of the direct and indirect social and biological contributions of trauma on morbidity and early mortality; (2) advance the role of family, extended families, and informal supporters; (3) recognize the importance of co-occurring disorders and early mortality; (4) redefine clinical education to reduce stigma and support clinicians through technological advancements to improve diagnostic accuracy; (5) examine outcomes meaningful to people with an SMI diagnosis, such as loneliness and sense of belonging, and stigma and their complex relationship with early mortality; (6) advance the science of pharmaceuticals, drug discovery, and choice in medication use; (7) use precision medicine to inform treatment; and (8) redefine the terms system literacy and health literacy.


Conclusions and Relevance
The recommendations of this roundtable are a starting point for changing practice and highlighting lived experience-led research priorities as an option to move the field forward.

/pdf/lived-experience-led-research-agenda-to-address-early-death-3g4etq4v.pdf

Lived Experience-Led Research Agenda to Address Early Death in People With a Diagnosis of a Serious Mental Illness: A Consensus Statement.

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Papers

Genetic background influences fluoride's effects on osteoclastogenesis

Introduction to the Coproduction of Supervision Standards for Digital Peer Support: Qualitative Study.

Lived Experience-Led Research Agenda to Address Early Death in People With a Diagnosis of a Serious Mental Illness: A Consensus Statement.