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Journal of Orthopaedic Translation May 2024Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1 mice displaying accelerated skeletal aging...
BACKGROUND
Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1 mice displaying accelerated skeletal aging represent a useful model for testing interventions against premature jaw bone loss. As an anti-aging agent, metformin may ameliorate molecular dysfunction driving osteoporosis pathogenesis. We explored the mechanisms of mandibular osteopenia in Bmi1 mice and prevention by metformin treatment.
METHODS
Three mouse groups were utilized: wild-type controls, untreated Bmi1, and Bmi1 receiving 1 g/kg metformin diet. Mandibular bone phenotype was assessed by X-ray, micro-CT, histology, and immunohistochemistry. AMPK-mTOR pathway analysis, senescence markers, osteoblast and osteoclast gene expression were evaluated in jaw tissue. Osteoclast differentiation capacity and associated signaling molecules were examined in cultured Bmi1 bone marrow mononuclear cells ± metformin.
RESULTS
Bmi1 loss reduced mandible bone density concomitant with decreased AMPK activity, increased mTOR signaling and cellular senescence in jaw tissue versus wild-type controls. This was accompanied by impaired osteoblast function and upregulated osteoclastogenesis markers. Metformin administration normalized AMPK-mTOR balance, oxidative stress and senescence signaling to significantly improve mandibular bone architecture in Bmi1 mice. In culture, metformin attenuated excessive osteoclast differentiation from Bmi1 marrow precursors by correcting dysregulated AMPK-mTOR-p53 pathway activity and suppressing novel pro-osteoclastogenic factor Stfa1.
CONCLUSIONS
Our study newly demonstrates metformin prevents accelerated jaw bone loss in a premature aging murine model by rectifying molecular dysfunction in cellular energy sensors, redox state, senescence and osteoclastogenesis pathways. Targeting such age-associated mechanisms contributing to osteoporosis pathogenesis may help maintain oral health and aesthetics in the growing elderly population.
TRANSLATIONAL POTENTIAL
The pronounced mandibular osteopenia exhibited in Bmi1 mice represents an accelerated model of jaw bone deterioration observed during human aging. Our finding that metformin preserves mandibular bone integrity in this progeroid model has important clinical implications. As an inexpensive oral medication already widely used to manage diabetes, metformin holds translational promise for mitigating age-related osteoporosis. The mandible is essential for chewing, swallowing, speech and facial structure, but progressively loses bone mass and strength with advancing age, significantly impacting seniors' nutrition, physical function and self-image. Our results suggest metformin's ability to rectify cellular energy imbalance, oxidative stress and osteoclast overactivity may help maintain jaw bone health into old age. Further research is still needed given metformin's multifaceted biology and bone regulation by diverse pathways. However, this preclinical study provides a strong rationale for clinical trials specifically examining mandibular outcomes in elderly subjects receiving standard metformin treatment for diabetes or prediabetes. Determining if metformin supplementation can prevent or delay oral disability and disfigurement from senescent jaw bone loss in the growing aged population represents an important public health priority. In summary, our mechanistic findings in a genetic mouse model indicate metformin merits investigation in rigorous human studies for alleviating morbidity associated with age-related mandibular osteoporosis.
PubMed: 38867742
DOI: 10.1016/j.jot.2024.03.001 -
Cancer Management and Research 2024Desmoid tumors (DT) are rare, intermediate-grade sarcomas characterized by locally aggressive growths that commonly occur intra-abdominally, in the abdominal wall, or in... (Review)
Review
Desmoid tumors (DT) are rare, intermediate-grade sarcomas characterized by locally aggressive growths that commonly occur intra-abdominally, in the abdominal wall, or in the extremities. Desmoid tumors are 2-3-fold more common in females than males, with most patients aged <40 years at diagnosis. Clinical course of DT is highly variable but rarely fatal, with median overall survival >80% at 20 years. However, patient morbidity and DT symptom burden can be high. DT significantly reduce patient quality of life, imposing substantial physical, emotional, and social burdens. Pain, fatigue, and insomnia are common symptoms; disfigurement, mobility restrictions, and, rarely, the need for amputation may also result. Despite its limited impact on survival, patients with DT may have anxiety and depression levels commensurate with those associated with malignant sarcomas. Thus, DT impose an array of significant, long-term morbidities on a young patient population. In order to evaluate the impact of these morbidities, patient-reported outcome (PRO) tools are used, which assess outcomes of importance to patients that extend beyond traditional oncology endpoints. General or oncology-related PROs can be used; although currently, the only DT-specific, validated PRO measure is the GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS), consisting of an 11-item DT Symptom Scale (DTSS) and a 17-item DT Impact Scale (DTIS). DTSS and DTIS were secondary endpoints in DeFi, a randomized phase 3 trial of nirogacestat; blinded, pooled data from DeFi were used to validate GODDESS reliability and responsiveness as a PRO measure in DT. Another DT-specific PRO measure, the Desmoid-Type Fibromatosis Quality of Life (DTF-QoL) questionnaire, has been developed but not validated. As novel DT therapies continue to be developed, incorporating DT-specific PRO measures into clinical trials will be key to capturing patient voice, improving outcomes of importance to this unique patient population, and assisting patients and providers in selecting optimal treatment.
PubMed: 38863992
DOI: 10.2147/CMAR.S362694 -
Puerto Rico Health Sciences Journal Jun 2024Vitiligo is a dermatological autoimmune condition characterized by areas of progressive skin depigmentation. Vitiligo lesions are cosmetically disfiguring and associated...
OBJECTIVE
Vitiligo is a dermatological autoimmune condition characterized by areas of progressive skin depigmentation. Vitiligo lesions are cosmetically disfiguring and associated with significant psychological conditions such as depression and anxiety and comorbidities such as thyroid disease and diabetes. All races, ethnicities, ages, and regions of the world are impacted by vitiligo, with a global prevalence of about 0.5-2%. Currently, there is no published information available on the prevalence of vitiligo in Puerto Rico. Our study's aim was to estimate the prevalence of vitiligo among patients attending the specialized clinic of dermatology at UPR School of Medicine in Puerto Rico and describe the distribution of cases by age and sex.
METHODS
We performed a descriptive study to evaluate the patients attending the University of Puerto Rico School of Medicine Clinics from January 2017 to May 2022. Using ICD-10 code L80 and medical records, we identified 581 patients with vitiligo and their respective demographic data distributed by sex and age.
RESULTS
Of the 581 vitiligo patients, 350 (60.2%) were women, and 231 (39.8%) were men. The median age in the vitiligo population was 33.5 years. Out of the studied sample, 30.2% were under the age of 18. Overall, there was an estimated prevalence of 5.2%.
CONCLUSION
We report a vitiligo prevalence of 5.2% in a specialized clinic in Puerto Rico, suggesting further studies are necessary to discover possible underlying factors contributing to this increased prevalence.
Topics: Humans; Vitiligo; Puerto Rico; Male; Female; Adult; Young Adult; Adolescent; Middle Aged; Prevalence; Child; Aged; Child, Preschool; Sex Distribution; Age Distribution; Infant
PubMed: 38860963
DOI: No ID Found -
Journal of the American Academy of... Jun 2024In this part 2 of a 2-part continuing medical education series, the management, outcomes, and morbidities for fungal skin neglected tropical diseases (NTDs), including... (Review)
Review
In this part 2 of a 2-part continuing medical education series, the management, outcomes, and morbidities for fungal skin neglected tropical diseases (NTDs), including eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis are reviewed. While fungal skin NTDs are associated with poverty in resource-limited settings, they are more often associated with immunosuppression and global migration in the United States. These infections have a high morbidity burden, including disfigurement, physical disability, coinfection, malignant transformation, mental health issues, and financial impact. For most fungal skin NTDs, management is difficult and associated with low cure rates. Dermatologists play a central role in initiating appropriate treatment early in disease course in order to improve patient outcomes.
PubMed: 38851491
DOI: 10.1016/j.jaad.2024.03.057 -
Military Medicine Jun 2024Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional...
INTRODUCTION
Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional impairment, and significant psychological distress. This condition is understood to be caused by autoimmunity to the hair follicle and subsequent arrest of hair growth. New medications, baricitinib and ritlecitinib, belong to the Janus kinase (JAK) inhibitor family and are among the first FDA-approved treatments for severe AA. In this manuscript, we aim to answer the question: What treatment options exist for AA in the military health care system (MHS)? In doing so, we review the pathogenesis, physical and psychosocial impact of AA, conventional treatment of AA, and the efficacy and safety of baricitinib and ritlecitinib.
METHODS
A literature search was performed using PubMed, Embase, and Ovid for the history and pathogenesis of AA, psychosocial impact of disease, functional impairments, and current treatments. Keywords "alopecia areata," "current therapy for alopecia areata," "pathogenesis alopecia areata," "baricitinib," "ritlecitinib," "JAK inhibitor alopecia," "JAK inhibitor safety," "baricitinib efficacy," "alopecia eyelash," "alopecia nails," and "psychosocial impact of alopecia" were used for the search. The TRICARE manual was searched for guidelines applicable to the treatment of AA, DoD Instruction 6130.03 Volume 2 for medical standards for military service, and the U.S. Central Command Modification 15 for fitness of deployment to Central Command area of operations.
RESULTS
Traditional treatments such as intralesional steroids may be effective for some patients, but difficulty lies in controlling extensive or refractory disease. Janus kinase inhibitors, baricitinib and ritlecitinib, are found effective at improving severe refractory disease; baricitinib induced hair regrowth in 32.6% more patients than placebo, and ritlecitinib was found to be superior to placebo by at least 24%. Currently, there is no coverage for therapeutic treatment of hair growth in the MHS. Additionally, military members are disqualified for continued service if they require immunomodulator medications such as baricitinib and ritlecitinib. Those on immunomodulators are unable to deploy worldwide.
CONCLUSIONS
Baricitinib and ritlecitinib are effective treatments for widespread, progressive, and refractory AA. Although JAK inhibitors demonstrate improved effectiveness compared to non-immunomodulator treatments, their use in the MHS for this purpose is limited.
PubMed: 38850223
DOI: 10.1093/milmed/usae292 -
The British Journal of Dermatology Jun 2024Infantile haemangioma (IH), the most common vascular tumour of infancy, is comprised of diverse cell types including endothelial cells, pericytes, fibroblasts and immune...
Infantile haemangioma (IH), the most common vascular tumour of infancy, is comprised of diverse cell types including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1 - 10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into these underlying biological processes, with some of the key IH-related pathways identified, including VEGF, RAAS, HIF-1α, Notch, PDGF, PI3K/Akt/mTOR, JAK/STAT, FGF, PPARγ, IGF. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH. This involves identifying differentially expressed genes, targeted proteins, and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis.
PubMed: 38845569
DOI: 10.1093/bjd/ljae241 -
Indian Journal of Dermatology,... May 2024
PubMed: 38841937
DOI: 10.25259/IJDVL_1061_2023 -
Frontiers in Immunology 2024Vascularized composite allotransplantation (VCA) offers the potential for a biological, functional reconstruction in individuals with limb loss or facial disfigurement....
BACKGROUND
Vascularized composite allotransplantation (VCA) offers the potential for a biological, functional reconstruction in individuals with limb loss or facial disfigurement. Yet, it faces substantial challenges due to heightened immune rejection rates compared to solid organ transplants. A deep understanding of the genetic and immunological drivers of VCA rejection is essential to improve VCA outcomes.
METHODS
Heterotopic porcine hindlimb VCA models were established and followed until reaching the endpoint. Skin and muscle samples were obtained from VCA transplant recipient pigs for histological assessments and RNA sequencing analysis. The rejection groups included recipients with moderate pathological rejection, treated locally with tacrolimus encapsulated in triglycerol-monostearate gel (TGMS-TAC), as well as recipients with severe end-stage rejection presenting evident necrosis. Healthy donor tissue served as controls. Bioinformatics analysis, immunofluorescence, and electron microscopy were utilized to examine gene expression patterns and the expression of immune response markers.
RESULTS
Our comprehensive analyses encompassed differentially expressed genes, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways, spanning various composite tissues including skin and muscle, in comparison to the healthy control group. The analysis revealed a consistency and reproducibility in alignment with the pathological rejection grading. Genes and pathways associated with innate immunity, notably pattern recognition receptors (PRRs), damage-associated molecular patterns (DAMPs), and antigen processing and presentation pathways, exhibited upregulation in the VCA rejection groups compared to the healthy controls. Our investigation identified significant shifts in gene expression related to cytokines, chemokines, complement pathways, and diverse immune cell types, with CD8 T cells and macrophages notably enriched in the VCA rejection tissues. Mechanisms of cell death, such as apoptosis, necroptosis and ferroptosis were observed and coexisted in rejected tissues.
CONCLUSION
Our study provides insights into the genetic profile of tissue rejection in the porcine VCA model. We comprehensively analyze the molecular landscape of immune rejection mechanisms, from innate immunity activation to critical stages such as antigen recognition, cytotoxic rejection, and cell death. This research advances our understanding of graft rejection mechanisms and offers potential for improving diagnostic and therapeutic strategies to enhance the long-term success of VCA.
Topics: Animals; Graft Rejection; Swine; Gene Expression Profiling; Vascularized Composite Allotransplantation; Transcriptome; Disease Models, Animal; Hindlimb
PubMed: 38840906
DOI: 10.3389/fimmu.2024.1390163 -
The Journal of Craniofacial Surgery Jun 2024Thyroid eye disease (TED) is characterized by a variety of disfiguring periocular changes. Vertical globe changes affecting the relative position of the eyelids are not...
PURPOSE
Thyroid eye disease (TED) is characterized by a variety of disfiguring periocular changes. Vertical globe changes affecting the relative position of the eyelids are not well understood in patients with TED. This study seeks to determine the effect of orbital decompression on vertical globe displacement in patients with TED, without TED, and with intraconal tumor (ICT).
METHODS
For this cross-sectional study, a clinical database was used to identify patients with TED. Comparison groups were drawn from separate anonymized databases. Vertical position and interpupillary distance (IPD) were measured from photographs and exophthalmos was measured via Hertel's exophthalmometer. Primary outcomes were vertical globe position at baseline and postoperatively in patients with TED and ICT. Secondary outcomes included the relationship between vertical globe position, exophthalmos, and IPD.
RESULTS
Among 269 participants meeting the inclusion criteria, mean vertical globe position was significantly lower in patients with TED following lateral decompression surgery compared to controls, after accounting for race, age, and sex. While patients with ICT had a significant difference in preoperative and postoperative IPD, patients with TED did not. Medial or inferior decompression did not significantly change globe position and lateral decompression did not cause lateral canthal dystopia in patients with TED. No association between postoperative changes in exophthalmometry, IPD, and globe position was found in patients with TED.
CONCLUSIONS
Patients with TED experience hypoglobus that does not improve following decompression surgery. There was no correlation between change in vertical globe position and exophthalmos or IPD among patients with TED. Surgeons should discuss the possibility of hypoglobus as a persistent finding for patients with TED undergoing decompression surgery.
PubMed: 38838355
DOI: 10.1097/SCS.0000000000010345 -
Journal of the European Academy of... Jun 2024Autoimmune blistering diseases (AIBDs) are severe dermatologic disorders known for their debilitating physical impact. Recent research has reported that AIBDs lead to...
BACKGROUND
Autoimmune blistering diseases (AIBDs) are severe dermatologic disorders known for their debilitating physical impact. Recent research has reported that AIBDs lead to psychosocial impairment, including depression and anxiety. Missing from the extant literature is an examination of the impact of AIBDs on body image and related psychological constructs.
OBJECTIVES
The current study seeks to characterize the psychological and social consequences of AIBD diagnosis, with particular attention to body image dissatisfaction.
METHODS
We conducted a survey study of adults with AIBDs. The survey was open from February 2023 to March 2023. Validated self-report questionnaires assessed depressive symptomatology, body image disturbance and quality of life. Demographic information and self-reported psychiatric history before and after AIBD diagnosis were collected via self-report. Participants were 451 adults with AIBDs, recruited through the International Pemphigus and Pemphigoid Foundation newsletters, email distribution lists and social media.
RESULTS
Participants reported increased incidence of psychiatric disorders following AIBD diagnosis. Participants reported high levels of depressive symptomatology and impairments to quality of life compared to other patient groups. The sample reported extremely high levels of body image disturbance, more so than other patients with disfiguring diseases or injury. Correlation analyses revealed significant relationships between body image variables and quality of life, even after controlling for depression.
CONCLUSIONS
Current treatment guidelines for AIBDs focus primarily on the management of disease flares and the consequences of immunosuppression, without consideration of the psychosocial consequences of the disease. The current study underscores the need for mental health support for patients with AIBDs.
PubMed: 38837452
DOI: 10.1111/jdv.20156