Osteoarthritis Disease Severity in the Temporomandibular Joint and the Knee Joint: A Comparative Cadaveric Study.

OBJECTIVE: The objective of this study was to determine the level of disease severity in a pilot cohort of temporomandibular joints (TMJs) and compare them to the pathology findings previously characterized in cadaveric knee joints. DESIGN: Thirty-one intact TMJs from 17 cadaveric donors were harvested and arthritic lesioning seen in the knee joint was investigated on the condyle and the fossa of the TMJ. Prevalence of gross alterations was equated and disease severity was determined for sex- and age-based donor pools using a validated, osteoarthritis (OA) disease severity scale (DSS). Knee joint DSS scores were also compared to the TMJ condyle and fossa DSS scores and a case study was carried out on a male donor that demonstrated severe OA in the both joints. RESULTS: The mandibular fossa demonstrated an increase in disease severity compared to the mandibular condyle in a mixed sex donor pool (P = 0.035). It was discovered that the younger females demonstrated statistically more pathological condyles compared to the older half of the female subgroup (P = 0.02). TMJ fossa and knee joints demonstrated comparable OA severity and similar signs of cartilage disease in a single donor highlighting the systemic nature of OA. CONCLUSIONS: This study demonstrates that gross signs of OA in the TMJs of cadavers are comparable to pathology found in the knee. The mandibular fossa appears to be the site of more profound disease, implying translational movements may be more likely to induce biomechanically abnormal movement, loading, and OA.

Remediation practices for health profession students and clinicians: An integrative review.

BACKGROUND: The current state of practices in health care remediation is not well known. The purpose of this review is to characterize, assess, and present synthesized results of current student and professional remediation practices described in the literature. METHODS: This study used an integrative review process including article extraction and review, descriptive characterization and statistics, classification of levels of evidence, assessment of risk of bias, and examination of relationships between factors and types of remediation. Articles were located in a search of PubMed (MEDLINE) and EBSCO (CINAHL Complete) last accessed in May 2022. INCLUSION CRITERIA: Full text journal articles and Briefs published between January 2001 and May 2022, English language, focus on remediation in health science education programs and professionals, identified key words in title, abstract, or article. EXCLUSION CRITERIA: Published outside the date range; focus of study or article outside health sciences; main focus not on remediation process or program (defined above), books, presentations and abstracts. RESULTS: 97 articles were included. Design rigor clustered around Level 6 (case-controlled studies, case series, case reports). All programs and activities were reported as successful. There was a statistically significant relationship (p < 0.01) between healthcare discipline and type of remediation. CONCLUSIONS: A variety of remediation methods for health care students and professionals are reported to be successful. Higher level studies are needed to help define best practices for remediation activities in health care professional knowledge and skill.

Selective blockade of the OGF-OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing.

Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10(-6) M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF-OGFr regulatory axis.

Topical Naltrexone as Treatment for Type 2 Diabetic Cutaneous Wounds.

Objective: Type 2 diabetes (T2D) is associated with impaired cutaneous wound healing and can result in ulceration, infection, and/or amputation. More than 25 million people in the United States have T2D and are vulnerable to epithelial-related complications. Current therapies are limited in their efficacy. New treatments for full-thickness cutaneous wounds that focus on underlying diabetic pathways are needed. Approach: Topical application of the opioid receptor antagonist naltrexone (NTX) dissolved in cream reverses delayed wound closure in type 1 diabetic rat by the acceleration of reepithelialization and enhancement of angiogenesis and remodeling. NTX blocks the opioid growth factor (OGF)-OGF receptor (OGFr) axis and upregulates DNA synthesis and cell proliferation. To investigate whether NTX is an effective therapy for T2D wound closure, genetically obese mice (db/db) and normal C57Bl/6J mice received full-thickness cutaneous wounds. Wounds (5 mm in diameter) were treated topically three times daily with 10-5 M NTX or sterile saline dissolved in cream and photographed every 2 days. Results: Wounds in db/db mice treated with saline were 11-92% larger than those in normal mice throughout the 2-week observation. Topical NTX therapy in T2D mice reduced the residual wound size by 13-30% between days 8 and 14 relative to diabetic mice receiving saline. Reepithelialization and DNA synthesis, as analyzed by epithelial thickness and BrdU labeling indexes, respectively, were accelerated in NTX-treated wounds. Innovation and Conclusion: These data suggest that the OGF-OGFr axis plays a role in epithelial-related complications of T2D and that blockade of this pathway by NTX may be an effective treatment for wound repair.

Ocular surface abnormalities related to type 2 diabetes are reversed by the opioid antagonist naltrexone.

BACKGROUND: Ocular surface complications of type 2 diabetes are associated with reductions in tear production, increased corneal surface sensitivity, and delayed corneal re-epithelialization. This study examined the efficacy of topical application of the opioid antagonist naltrexone (NTX) in reversing these diabetic-related ocular surface complications in mice. METHODS: The genetic db/db mouse model of type 2 diabetes, along with C57Bl/6 wild-type mice were investigated. Tear production was assessed by phenol red impregnated threads, and ocular surface sensitivity was measured using Von Frey filaments. Centrally located, circular corneal abrasions were created in mice and residual epithelial defects measured by fluorescein photography. Animals in each group received topical applications of drops of 10(-5) M NTX in sterile Vigamox (Vigamox, Alcon Laboratories, Fort Worth, Texas, USA) or sterile Vigamox alone, and tear production, corneal sensitivity, and reepithelialization were monitored. RESULTS: In comparison to diabetic mice receiving vehicle only, db/db mice treated with one drop of NTX demonstrated a marked reversal in dry eye and ocular surface hypersensitivity within 1 h of one drop of NTX. Reversal of the complications in db/db mice usually lasted for 48-90 h. Corneal epithelial repair in db/db mice was enhanced following a regimen of three drops of NTX daily such that by 72 h, residual wounds were one third the size in db/db mice receiving NTX relative to diabetic mice receiving vehicle. Application of Vigamox alone had no effect. No adverse effects of NTX administration were noted in the cornea. CONCLUSIONS: This is the first report of the efficacy of topical NTX in reversing corneal surface complications in type 2 diabetic mice.

Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats.

Wound repair involves a series of overlapping phases that include inflammation, proliferation, and tissue remodeling, with the latter phase requiring months for proper healing. Delays in any of these processes can result in infection, chronic ulceration, and possible amputation. Diabetes is a major risk factor for improper wound repair, and impaired wound healing is a major complication for more than 26 million people in the US diagnosed with diabetes. Previous studies have demonstrated that the opioid antagonist naltrexone (NTX) dissolved in moisturizing cream reverses delays in wound closure in streptozotocin-induced type 1 diabetic (T1D) rats. NTX accelerated DNA synthesis and increased the number of epithelial and mast cells, as well as new blood vessel formation. In this study, remodeling was evaluated in T1D rats up to eight weeks after initial wounding. Twenty days following wounding, diabetic rats treated with vehicle had elevated numbers of MMP-2+ fibroblasts, suggesting delayed healing processes; birefringence of granulation tissue stained with Sirius red revealed diminished collagen formation and maturation. Wound tissue from NTX-treated T1D rats had comparable numbers of MMP-2+ fibroblasts to control specimens, as well as accelerated maturation of granulation tissue. The integrity of wounded skin was evaluated by tensile strength measurements. T1D resulted in delayed wound healing, and wounded skin that displayed reduced tensile strength relative to normal rats. Topical NTX applied to wounds in T1D rats resulted in enhanced collagen formation and maturation over a 60-day period of time. Moreover, the force required to tear skin of NTX-treated T1D rats was elevated relative to the force necessary to tear the skin of vehicle-treated T1D rats, and comparable to that for normal rats. These data reveal that complications in wound healing associated with T1D involve the novel OGF-OGFr pathway, and that topical NTX is an effective treatment to enhance wound healing.

Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis.

Delays in wound healing often result in infection, chronic ulceration, and possible amputation of extremities. Impaired wound healing is a major complication of the 23 million people in the USA with diabetes, and financial and medical burdens are demanding new treatments for wound healing. Previous studies have demonstrated that topical application of the opioid antagonist naltrexone (NTX) dissolved in moisturizing cream reverses delays in wound closure in rats with streptozotocin-induced type 1 diabetes. A target of NTX's action is DNA synthesis and cell proliferation. In this study, granulation tissue was evaluated to ascertain the specific cellular targets that were impaired in diabetic wounds, as well as those that were enhanced following NTX application. Mast cell number as well as the number of new blood vessels immunoreactive to fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and alpha smooth muscle actin (α-SMA) antibodies were recorded at 3, 5, 8, 10, 15, and 20 days following creation of full-thickness dorsal cutaneous wounds in normal and type 1 diabetic rats. Diabetic rats displayed delays in wound closure as well as a reduction in the number of mast cells responding to the injury, and delays in the spatial and temporal expression of FGF-2, VEGF, and α-SMA in capillaries. Topical NTX accelerated the rate of wound closure and stimulated expression of angiogenic factors within granulation tissue of diabetic rats relative to control animals receiving saline in moisturizing cream. These data support observations that a novel biological pathway is impaired under diabetic conditions and can be modulated by topical NTX to enhance proliferative events in wound healing.

Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats.

A major problem associated with diabetes is the complication of chronic non-healing wounds that can lead to the formation of debilitating ulcers, and can progress to more serious problems including amputation. There is no fully effective prevention of these complications, constituting an unmet medical need to understand the pathophysiology and treatment of wound healing in diabetes. This study determined whether blockade of opioid receptors from opioid peptides, known to inhibit cell proliferation and be overexpressed in diabetes, by topical application of the opioid antagonist naltrexone (NTX) reverses delays in wound closure. Rats with streptozotocin-induced type 1 diabetes (T1D) received topical applications of NTX (10(-4)-10(-6) mol/L) or vehicle in a variety of carriers; DNA synthesis was evaluated 12 h later. DNA synthesis in the epithelium of T1D rats was significantly reduced from normal animals. Both systemic and topical application of NTX increased DNA synthesis (up to 2-fold higher) within 12 h of administration. In a second study, diabetic and normal rats received full-thickness cutaneous wounds and were treated three times daily with either 10(-5) mol/L NTX or vehicle in topical carriers. Wound sizes were analyzed, and BrdU (5-bromo-2'-deoxyuridine) labeling in the skin was evaluated to determine DNA synthesis. Application of NTX in a variety of carriers to rats with full-thickness wounds resulted in significantly smaller wound areas relative to T1D animals receiving vehicle, and comparable to that of normal rats. Wound contraction in T1D animals was 50% of that in normal rats, with NTX-treated wounds restoring wound contraction to that of normal cohorts. DNA synthesis was also enhanced in NTX-treated T1D animals compared with T1D vehicle controls. These data suggest that topical application of NTX is a non-toxic and efficacious facilitator for healing full thickness wounds in T1D, with wound contraction serving as a particular target of NTX action.