The origins and roles of osteoclasts in bone development, homeostasis and repair.

The mechanisms underlying bone development, repair and regeneration are reliant on the interplay and communication between osteoclasts and other surrounding cells. Osteoclasts are multinucleated monocyte lineage cells with resorptive abilities, forming the bone marrow cavity during development. This marrow cavity, essential to hematopoiesis and osteoclast-osteoblast interactions, provides a setting to investigate the origin of osteoclasts and their multi-faceted roles. This Review examines recent developments in the embryonic understanding of osteoclast origin, as well as interactions within the immune environment to regulate normal and pathological bone development, homeostasis and repair.

Management patterns of multiple magnet ingestion reported to New Jersey Poison Information and Education System.

BACKGROUND: Ingestion of multiple high-powered neodymium rare-earth magnets poses a significant risk for gastrointestinal (GI) injury such as bowel perforation or ischemia. Given the rising incidence of rare earth magnetic ingestions and the corresponding increase in serious injuries in children, published guidelines recommend urgent endoscopic removal of all magnets within endoscopic reach in cases involving ingestions of two or more magnets. RESEARCH QUESTION: Do management patterns for multiple magnet ingestion align with current practice guidelines, and does hospital length of stay (LOS) differ based on the initial emergency department (ED) approach? METHODS: This is a retrospective chart review of consecutive patient encounters reported to the New Jersey Poison Information and Education System (NJPIES) between January 2021 and April 2022 involving multiple magnet ingestion. Potential cases were retrieved from the NJPIES TOXICALL® database, using substance codes relating to magnet or foreign body ingestion. Two-sample T tests were used to determine the statistical difference in the hospital LOS between the group of patients receiving early emergent esophagogastroduodenoscopy (EGD) versus those receiving expectant management on initial presentation. RESULTS: There was a difference in the average LOS of 2.7 days (p = 0.023) longer in the expectant management group with no medical complications in either group. Twenty-five percent or 2 out of 8 cases deviated from guidelines. CONCLUSION: The initial ED decision to pursue expectant management instead of attempting emergent EGD removal of magnets may result in prolonged hospitalization, increased risk for readmission, and delayed definitive removal of magnets due to nonprogression along the GI tract.

Clinical Versus Histologic Margins for Cutaneous Squamous Cell Carcinoma: Comparing Outcomes for High-Risk Tumors Treated With Mohs Micrographic Surgery.

BACKGROUND: High-risk cutaneous squamous cell carcinoma (cSCC) is associated with poor clinical outcomes. Traditionally, preoperative clinical tumor size ≥2 cm, based on Brigham and Women's Hospital (BWH) staging criteria, is high risk. OBJECTIVE: To compare outcomes of cSCC treated with Mohs micrographic surgery (MMS) with a preoperative size ≥2 cm (clinically ≥2 cm) versus cSCC with preoperative size <2 cm and postoperative defect size ≥2 cm (histologically ≥2 cm). METHODS: Prospective data were collected from January 1, 2014, to December 31, 2020, on MMS cases for cSCC with a preoperative and/or postoperative size ≥2 cm. Clinical outcomes were followed until March 15, 2023. Data were analyzed using multivariate regression. RESULTS: Three hundred thirty cases of MMS for cSCC were included. Cutaneous squamous cell carcinoma clinically ≥2 cm occurred more frequently in elderly patients; cSCC histologically ≥2 cm were more commonly located in the H region, required wider surgical margins, and more MMS stages to achieve clearance. There were no significant differences in rates of recurrence and metastasis between the groups. CONCLUSION: These data suggest that postoperative (histologic) MMS defect size may allow for better risk stratification of high-risk cSCC and improved staging of cSCC.

Spatial distribution, pollution level and human health risk assessment of heavy metals in urban street dust at neighbourhood scale.

Urban street dust (UStD) is a vital issue for human health and is crucial for urban sustainability. This study aims to enhance the creation of safe, affordable, and resilient cities by examining environmental contamination and health risks in urban residential areas. Specifically, it investigates the concentrations and spatial distribution of chromium (Cr), cadmium (Cd), nickel (Ni), copper (Cu), lead (Pb), and zinc (Zn) in UStD in Yenimahalle, Ankara. The mean concentrations of Zn, Cr, Pb, Cd, Ni, and Cu in UStD were 97.98, 66.88, 55.22, 52.45, 38.37, and 3.81 mg/kg, respectively. The geoaccumulation pollution index (Igeo) values for these elements were: Cd (5.12), Ni (1.61), Cr (1.21), Pb (1.13), Cu (0.78), and Zn (0.24). These indices indicate that the area is moderately polluted with Cr, Pb, and Ni, uncontaminated to moderately contaminated with Cu and Zn, and extremely polluted with Cd. The hazard index (HI) values for Cr, Cd, Ni, Cu, Pb, and Zn were below the non-carcinogenic risk threshold for adults, indicating no significant risk. However, for children, the HI values for Pb, Ni, Cd, and Zn were 3.37, 1.80, 1.25, and 1.25, respectively, suggesting a higher risk. Carcinogenic risk (RI) of Cd, Ni, and Pb was significant for both children and adults, indicating that exposure through ingestion, inhalation, and dermal contact is hazardous. The findings highlight the need for strategic mitigation measures for both natural and anthropogenic activities, providing essential insights for residents, policymakers, stakeholders, and urban planners.

Permanent section margin concordance after Mohs micrographic surgery with immunohistochemistry for invasive melanoma and melanoma in situ: A retrospective dual-center analysis.

BACKGROUND: Mohs micrographic surgery (MMS) for melanoma practices vary among dermatologic surgeons. The implementation of immunohistochemical staining in MMS for melanoma mitigates challenges associated with slide interpretation; however, the reliability of melanoma antigen recognized by T cells 1 (MART-1), the preferred immunostain for melanoma, has yet to be compared with permanent section pathology. OBJECTIVE: To assess concordance rates of MART-1 frozen sections and permanent section pathologic interpretation of melanoma treated with MMS. METHODS: A dual-center retrospective analysis was conducted to collect concordance and demographic data. Chi-square tests were performed for group comparisons of categorical variables. RESULTS: Of the 379 permanent sections sent, 367 were concordant with frozen section pathology for an overall concordance rate of 96.8%. Cases were stratified into indeterminately concordant and indisputably concordant. Twenty-two (6%) of cases were indeterminately concordant, whereas 345 (94.0%) of cases were indisputably concordant. LIMITATIONS: The concordance rate is derived from a comparison of adjacent tissue margins, an inevitable consequence of utilizing 2 techniques. CONCLUSION: To the author's knowledge, this study represents the largest investigation examining concordance rates of MART-1 frozen sections in Mohs for melanoma. High concordance disputes the ongoing need for additional permanent margins when using MART-1 in routine cases.

Review of radiofrequency microneedling: history, devices and uses.

Radiofrequency microneedling (RFM) has recently become a popular choice for the treatment of various dermatologic conditions and rejuvenation. Many studies have sought to evaluate the efficacy of RFM. However, its role in the management of these conditions remains unclear. A comprehensive literature search including randomized controlled trials, cohort studies, and case series evaluating the efficacy of RFM in various skin conditions was performed. In this review, we discuss the history and mechanism of RFM, describe various device features, and discuss the use of RFM in various skin conditions and rejuvenation.

Health action process approach: promoting physical activity, and fruit and vegetable intake among Australian adults.

Based on the health action process approach (HAPA) this study examined whether changes in social cognition constructs could predict change in physical activity and fruit and vegetable intake for adult participants in My health for life, an Australian health promotion behaviour change program. Variance-based structural equation modelling was used to analyse data obtained from Australian adult program participants (n = 167) at baseline (T1), week 14 (T2), week 26 (T2), and 6-month post-program (T4). Change scores were calculated for the social cognition constructs and behaviour. Changes in action self-efficacy and outcome expectancies positively predicted changes in intentions. Action self-efficacy changes also predicted changes in maintenance self-efficacy which, in turn, mediated the effect of action self-efficacy on recovery self-efficacy and planning. Planning was predicted by changes in intentions and maintenance self-efficacy. Findings support the use of the HAPA model in designing complex health behaviour change interventions to achieve sustained behaviour change.

Antibiotic Use and Surgical Site Infections in Immunocompromised Patients After Mohs Micrographic Surgery: A Single-Center Retrospective Study.

BACKGROUND: As Mohs micrographic surgery becomes more widely used in immunosuppressed patients, it is important to understand the risks in this unique population. OBJECTIVE: To determine whether immunosuppressed patients are at an increased risk for surgical site infection and evaluate the utility of postoperative antibiotics for the prevention of surgical site infection. MATERIALS AND METHODS: A single-center retrospective review of patients who underwent Mohs micrographic surgery between October 9, 2014, and August 20, 2021, was performed. RESULTS: Five thousand eight hundred eighty-six independent cases were identified. Factors associated with an increased incidence of antibiotic use included preoperative lesion size >40 mm (86.7%, n = 13; p < .01) and high-risk lesion location (46.4%, n = 1,268; p < .01). Patients were not more likely to be prescribed antibiotics if immunosuppressed (37.0%, n = 269 vs 34.2%, n = 1765; p = .14), and immunosuppression was not independently associated with antibiotic use on multivariate analysis (odds ratio 1.2, 95% confidence interval 1.0-1.5). Infection rates were similar between immunocompromised patients and immunocompetent patients (2.1%, n = 15 vs 1.6%, n = 80, respectively; p = .30). In immunosuppressed patients, antibiotic use did not decrease the likelihood of infection (3.0%, n = 8 vs 1.5%, n = 7; p = .19). CONCLUSION: There was no association between immunosuppression and surgical infection rate. Furthermore, postoperative antibiotics should not be indicated in these patients unless other high-risk criteria exist.

Knowledge hiding in organizational crisis: The moderating role of leadership.

The COVID-19 pandemic has caused organizational crises leading to shutdowns, mergers, downsizing or restructuring to minimize survival costs. In such organizational crises, employees tend to experience a loss or lack of resources, and they are more likely to engage in knowledge hiding to maintain their resources and competitive advantage. Knowledge hiding has often caused significant adverse consequences, and the research on knowledge hiding is limited. Drawing upon the Conservation of Resources and Transformational Leadership theories, a conceptual framework was developed to examine knowledge hiding behavior and its antecedents and consequences. We collected data from 281 Vietnamese employees working during the COVID-19 pandemic. Our results show that role conflict, job insecurity, and cynicism positively impact knowledge hiding behavior. Knowledge hiding behavior negatively affects job performance and mediates the antecedents of knowledge hiding on job performance. Transformational leadership moderated the impact of role conflict on knowledge hiding.

Oxidative stress by Ca2+ overload is critical for phosphate-induced vascular calcification.

Hyperphosphatemia is the primary risk factor for vascular calcification, which is closely associated with cardiovascular morbidity and mortality. Recent evidence showed that oxidative stress by high inorganic phosphate (Pi) mediates calcific changes in vascular smooth muscle cells (VSMCs). However, intracellular signaling responsible for Pi-induced oxidative stress remains unclear. Here, we investigated molecular mechanisms of Pi-induced oxidative stress related with intracellular Ca2+ ([Ca2+]i) disturbance, which is critical for calcification of VSMCs. VSMCs isolated from rat thoracic aorta or A7r5 cells were incubated with high Pi-containing medium. Extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin were activated by high Pi that was required for vascular calcification. High Pi upregulated expressions of type III sodium-phosphate cotransporters PiT-1 and -2 and stimulated their trafficking to the plasma membrane. Interestingly, high Pi increased [Ca2+]i exclusively dependent on extracellular Na+ and Ca2+ as well as PiT-1/2 abundance. Furthermore, high-Pi induced plasma membrane depolarization mediated by PiT-1/2. Pretreatment with verapamil, as a voltage-gated Ca2+ channel (VGCC) blocker, inhibited Pi-induced [Ca2+]i elevation, oxidative stress, ERK activation, and osteogenic differentiation. These protective effects were reiterated by extracellular Ca2+-free condition, intracellular Ca2+ chelation, or suppression of oxidative stress. Mitochondrial superoxide scavenger also effectively abrogated ERK activation and osteogenic differentiation of VSMCs by high Pi. Taking all these together, we suggest that high Pi activates depolarization-triggered Ca2+ influx via VGCC, and subsequent [Ca2+]i increase elicits oxidative stress and osteogenic differentiation. PiT-1/2 mediates Pi-induced [Ca2+]i overload and oxidative stress but in turn, PiT-1/2 is upregulated by consequences of these alterations.NEW & NOTEWORTHY The novel findings of this study are type III sodium-phosphate cotransporters PiT-1 and -2-dependent depolarization by high Pi, leading to Ca2+ entry via voltage-gated Ca2+ channels in vascular smooth muscle cells. Cytosolic Ca2+ increase and subsequent oxidative stress are indispensable for osteogenic differentiation and calcification. In addition, plasmalemmal abundance of PiT-1/2 relies on Ca2+ overload and oxidative stress, establishing a positive feedback loop. Identification of mechanistic components of a vicious cycle could provide novel therapeutic strategies against vascular calcification in hyperphosphatemic patients.

Specific complications associated with non-surgical rhinoplasty.

Non-surgical rhinoplasty is becoming an increasingly common procedure to alter the appearance and cosmesis of the nose. Although rare, complications with this procedure do exist, some of which can be devastating. Major complications include infection, vascular compromise, skin necrosis, and blindness. Here we discuss the nasal anatomy, complications associated with non-surgical rhinoplasty, and techniques to prevent these complications.

Complications associated with infraorbital filler injection.

Soft tissue augmentation with injectable fillers is increasingly being performed, and providers must be prepared to understand and treat complications. Periorbital skin presents unique challenges due to its thin nature, easily evident pigmentary and textural irregularities, and anatomical considerations including vasculature and subcutaneous layers. The most common complications of infraorbital filler include ecchymosis, malar edema, blue-gray hue, and contour irregularities. Uncommon complications include infection and biofilm formation, skin necrosis, and blindness. This purpose of this review is to highlight the infraorbital anatomy, complications of filler injection in this region, and techniques to avoid these complications.

SON controls cell-cycle progression by coordinated regulation of RNA splicing.

It has been suspected that cell-cycle progression might be functionally coupled with RNA processing. However, little is known about the role of the precise splicing control in cell-cycle progression. Here, we report that SON, a large Ser/Arg (SR)-related protein, is a splicing cofactor contributing to efficient splicing of cell-cycle regulators. Downregulation of SON leads to severe impairment of spindle pole separation, microtubule dynamics, and genome integrity. These molecular defects result from inadequate RNA splicing of a specific set of cell-cycle-related genes that possess weak splice sites. Furthermore, we show that SON facilitates the interaction of SR proteins with RNA polymerase II and other key spliceosome components, suggesting its function in efficient cotranscriptional RNA processing. These results reveal a mechanism for controlling cell-cycle progression through SON-dependent constitutive splicing at suboptimal splice sites, with strong implications for its role in cancer and other human diseases.

Cytotoxic Flavones from the Stem Bark of Bougainvillea spectabilis Willd.

Five new flavones possessing a fully substituted A-ring with C-6 and C-8 methyl groups, bougainvinones I - M (1: -5: ), along with three known congeners, 2'-hydroxydemethoxymatteucinol (6: ), 5,7,3',4'-tetrahydroxy-3-methoxy-6,8-dimethylflavone (7: ) and 5,7,4'-trihydroxy-3-methoxy-6,8-dimethylflavone (8: ), were isolated from the EtOAc extract of the stem bark of Bougainvillea spectabilis. Their structures were established by means of spectroscopic data (ultraviolet, infrared, high-resolution electrospray ionization mass spectrometry, and one-dimensional and two-dimensional nuclear magnetic resonance) and single-crystal X-ray crystallographic analysis. The in vitro cytotoxicity of all isolated compounds against five cancer cell lines (KB, HeLa S-3, MCF-7, HT-29, and HepG2) was evaluated. Compound 5: showed promising cytotoxic activity against the KB and HeLa S-3 cell lines, with IC50 values of 7.44 and 6.68 µM. The other compounds exhibited moderate cytotoxicity against the KB cell line.

Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion.

Elevated plasma levels of inorganic phosphate (Pi) are harmful, causing, among other complications, vascular calcification and defective insulin secretion. The underlying molecular mechanisms of these complications remain poorly understood. We demonstrated the role of Pi transport across the plasmalemma on Pi toxicity in INS-1E rat clonal ß cells and rat pancreatic islet cells. Type III sodium-phosphate cotransporters (NaPis) are the predominant Pi transporters expressed in insulin-secreting cells. Transcript and protein levels of sodium-dependent phosphate transporter 1 and 2 (PiT-1 and -2), isotypes of type III NaPi, were up-regulated by high-Pi incubation. In patch-clamp experiments, extracellular Pi elicited a Na+-dependent, inwardly rectifying current, which was markedly reduced under acidic extracellular conditions. Cellular uptake of Pi elicited cytosolic alkalinization; intriguingly, this pH change facilitated Pi transport into the mitochondrial matrix. Increased mitochondrial Pi uptake accelerated superoxide generation, mitochondrial permeability transition (mPT), and endoplasmic reticulum stress-mediated translational attenuation, leading to reduced insulin content and impaired glucose-stimulated insulin secretion. Silencing of PiT-1/2 prevented Pi-induced superoxide generation and mPT, and restored insulin secretion. We propose that Pi transport across the plasma membrane and consequent cytosolic alkalinization could be a therapeutic target for protection from Pi toxicity in insulin-secreting cells, as well as in other cell types.-Nguyen, T. T., Quan, X., Xu, S., Das, R., Cha, S.-K., Kong, I. D., Shong, M., Wollheim, C. B., Park, K.-S. Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion.

Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam.

BACKGROUND: Antimicrobial resistance has emerged as a major concern in developing countries. The present study sought to define the pattern of antimicrobial resistance in ICU patients with ventilator-associated pneumonia. METHODS: Between November 2014 and September 2015, we enrolled 220 patients (average age ~ 71 yr) who were admitted to ICU in a major tertiary hospital in Ho Chi Minh City, Vietnam. Data concerning demographic characteristics and clinical history were collected from each patient. The Bauer-Kirby disk diffusion method was used to detect the antimicrobial susceptibility. RESULTS: Antimicrobial resistance was commonly found in ceftriaxone (88%), ceftazidime (80%), ciprofloxacin (77%), cefepime (75%), levofloxacin (72%). Overall, the rate of antimicrobial resistance to any drug was 93% (n = 153/164), with the majority (87%) being resistant to at least 2 drugs. The three commonly isolated microorganisms were Acinetobacter (n = 75), Klebsiella (n = 39), and Pseudomonas aeruginosa (n = 29). Acinetobacter baumannii were virtually resistant to ceftazidime, ceftriaxone, piperacilin, imipenem, meropenem, ertapenem, ciprofloxacin and levofloxacin. High rates (>70%) of ceftriaxone and ceftazidime-resistant Klebsiella were also observed. CONCLUSION: These data indicated that critically ill patients on ventilator in Vietnam were at disturbingly high risk of antimicrobial resistance. The data also imply that these Acinetobacter, Klebsiella, and Pseudomonas aeruginosa and multidrug resistance pose serious therapeutic problems in ICU patients. A concerted and systematic effort is required to rapidly identify high risk patients and to reduce the burden of antimicrobial resistance in developing countries.

Transforming Growth Factor ß1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis.

TGF-ß is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-ß1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-ß1-induced apoptosis in immortalized podocytes. TGF-ß1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-ß receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTORΔ augmented TGF-ß1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-ß1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-ß1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-ß1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-ß1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-ß1-induced ERK1/2-mTORactivation. Our data suggest that TGF-ß1 increases translation of Nox4 through the Smad-ERK1/2-mTORC1 axis, which is independent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.