AT2R Activation Improves Wound Healing in a Preclinical Mouse Model.

Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor (AT2R) signaling pathway was modulated to determine its impact on cutaneous wound healing. Balb/c mice received two splinted full-thickness wounds. Topical treatments with the selective AT2R agonist compound 21 (C21) and/or selective antagonist PD123319 or saline vehicle were administered until sacrifice on post-wounding days 7 or 10. The rate of wound re-epithelialization was accelerated by PD123319 and combination treatments. In vitro, C21 significantly reduced human fibroblast migration. C21 increased both collagen and vascular densities at days 7 and 10 post-wounding and collagen I:III ratio at day 10, while PD123319 and combination treatments decreased them. Genes associated with regeneration and repair were upregulated by C21, while PD123319 treatment increased the expression of genes associated with inflammation and immune cell chemotaxis. C21 treatment reduced wound total leukocyte and neutrophil staining densities, while PD123319 increased these and macrophage densities. Overall, AT2R activation with C21 yields wounds that mature more quickly with structural, cellular, and gene expression profiles more closely approximating unwounded skin. These findings support AT2R signal modulation as a potential therapeutic target to improve skin quality during wound healing.

Ketotifen directly modifies the fibrotic response of human skin fibroblasts.

Fibrosis is a destructive, end-stage disease process. In the skin, it is associated with systemic sclerosis and scarring with considerable health burden. Ketotifen is a clinical antihistamine and mast cell stabilizer. Studies have demonstrated mast cell-dependent anti-fibrotic effects of ketotifen but direct effects on fibroblasts have not been determined. Human dermal fibroblasts were treated with pro-fibrotic transforming growth factor-ß1 (TGFß) followed by ketotifen or control treatments to determine direct effects on fibrotic fibroblasts. Ketotifen impaired TGFß-induced α-smooth muscle actin gene and protein responses and decreased cytoskeletal- and contractility-associated gene responses associated with fibrosis. Ketotifen reduced Yes-associated protein phosphorylation, transcriptional coactivator with PDZ binding motif transcript and protein levels, and phosphorylation of protein kinase B. In a fibroblast-populated collagen gel contraction assay, ketotifen reduced the contractile activity of TGFß-activated fibroblasts. In a murine model of bleomycin-induced skin fibrosis, collagen density and dermal thickness were significantly decreased in ketotifen-treated mice supporting in vitro findings. These results support a novel, direct anti-fibrotic activity of ketotifen, reducing pro-fibrotic phenotypic changes in fibroblasts and reducing collagen fibres in fibrotic mouse skin. Together, these findings suggest novel therapeutic potential and a novel mechanism of action for ketotifen in the context of fibrosis.

Clomiphene Citrate and Enclomiphene Hydrochloride Exposure Is Associated With Interfrontal Suture Fusion in Zebrafish.

Background: The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may be responsible. This study examined effects of the fertility drug clomiphene citrate (CC) on calvarial development in an established model for craniofacial development, the zebrafish Danio rerio. Results: Zebrafish larvae were exposed to clomiphene citrate or its isomer enclomiphene for five days at key points during calvarial development. Larvae were then raised to adulthood in normal rearing water. Zebrafish were analyzed using whole-mount skeletal staining. We observed differential effects on survivability, growth and suture formation depending on the treatment. Treatments with CC or enclomiphene at 5.5 mm SL led to increased fusion of the interfrontal suture (p < .01) compared to controls. Conclusions: Exposure to fertility drugs appears to affect development of the cranial vault, specifically the interfrontal suture, in zebrafish. Further research is required to identify the signaling mechanisms at play. This work suggests that fertility drug treatment may contribute to the increased incidence of metopic craniosynostosis observed globally.

Historique : L'incidence de craniosynostoses métopiques a augmenté ces dernières décennies. D'après les études en population, l'exposition aux médicaments in utero pourrait en être responsable. La présente étude traite des effets d'un agent ovulatoire, le citrate de clomifène (CC), sur le développement de la voûte crânienne d'un modèle établi de développement crâniofacial, le poisson-zèbre Danio rerio. Résultats : Les chercheurs ont exposé des larves de poisson-zèbre au citrate de clomifène ou à son isomère, l'enclomiphène, sur une période de cinq jours à des moments clés du développement de la voûte crânienne. Ils les ont ensuite élevés jusqu'à l'âge adulte dans de l'eau normale. Ils ont analysé les poissons-zèbres par coloration du squelette entier et observé des effets différentiels sur la capacité de survie, la croissance et la formation des sutures en fonction du traitement. Les traitements au CC ou à l'enclomiphène d'une longueur standard de 5,5 mm ont entraîné une fusion accrue de la suture métopique (p < 0,01) par rapport aux sujets témoins. Conclusions : L'exposition aux agents ovulatoires semble influer sur le développement de la voûte crânienne, notamment la suture métopique, chez le poisson-zèbre. D'autres recherches devront être réalisées pour déterminer les mécanismes de signalisation en jeu. Selon la présente étude, les agents ovulatoires peuvent contribuer à l'incidence accrue de craniosynostose métopique sur la scène mondiale.

Measuring the Unilateral Cleft Lip Nasal Deformity: Lateral Deviation of Subnasale Is a Clinical and Morphologic Index of Unrepaired Severity.

OBJECTIVE: Objective measurement of pre-operative severity is important to optimize evidence-based practices given that the wide spectrum of presentation likely influences outcomes. The purpose of this study was to determine the correlation of objective measures of form with a subjective standard of cleft severity. DESIGN: 3D images were ranked according to severity of nasal deformity by 7 cleft surgeons so that the mean rank could be used as the severity standard. PATIENTS: 45 patients with unilateral cleft lip and 5 normal control subjects. INTERVENTIONS: Each image was assessed using traditional anthropometric analysis, 3D landmark displacements, and shape-based analysis to produce 81 indices for each subject. MAIN OUTCOME: The correlation of objective measurements with the clinical severity standard. RESULTS: Lateral deviation of subnasale from midline was the best predictor of severity (0.86). Other strongly-correlated anthropometric measurements included columellar angle, nostril width ratio, and lateral lip height ratio (0.72, 0.80, 0.79). Almost all shape-based measurements had tight correlation with the severity standard, however, dorsum deviation and point difference nasolabial symmetry were the most predictive (0.84, 0.82). CONCLUSIONS: Quantitative measures of severity transcend cleft type and can be used to grade clinical severity. Lateral deviation of subnasale was the best measure of severity and may be used as a surrogate of uncoupled premaxillary growth; it should be recorded as an index of pre-operative severity with every cleft lip repair. The correlation of other measures evaluated clarify treatment priorities and could potentially be used to grade outcomes.

Sternal cleft reconstruction with acellular dermal matrix and full-thickness calvarial graft.

We describe reconstruction of a sternal cleft in a neonate using acellular dermal matrix, full-thickness calvarial bone graft and myocutaneous pectoralis flaps.

Patient Safety and Quality Improvement Initiatives in Cleft Lip and Palate Surgery: A Systematic Review.

BACKGROUND: Cleft lip and/or palate repair techniques require continued reevaluation of best practice through high-quality evidence. The objective of this systematic review was to highlight the existing evidence for patient safety and quality improvement (QI) initiatives in cleft lip and palate surgery. METHODS: A systematic review of published literature evaluating patient safety and QI in patients with cleft lip and/or palate was conducted from database inception to June 9, 2022, using Preferred Reporting Items for Systematic Reviews guidelines. Quality appraisal of included studies was conducted using Methodological Index for Non-Randomized Studies, Cochrane, or a Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 instruments, according to study type. RESULTS: Sixty-one studies met inclusion criteria, with most published between 2010 and 2020 (63.9%). Randomized controlled trials represented the most common study design (37.7%). Half of all included studies were related to the topic of pain and analgesia, with many supporting the use of infraorbital nerve block using 0.25% bupivacaine. The second most common intervention examined was use of perioperative antibiotics in reducing fistula and infection (11.5%). Other studies examined optimal age and closure material for cleft lip repair, early recovery after surgery protocols, interventions to reduce blood loss, and safety of outpatient surgery. CONCLUSIONS: Patient safety and QI studies in cleft surgery were of moderate quality overall and covered a wide range of interventions. To further enhance PS in cleft repair, more high-quality research in the areas of perioperative pharmaceutical usage, appropriate wound closure materials, and optimal surgical timing are needed.

The Role of ACE-Inhibitors and ARBs in reducing hypertrophic scarring following bilateral breast reduction.

BACKGROUND: The angiotensin-renin system (ARS) has been shown to play a role in the promotion of tissue fibrosis through angiotensin II activation of the angiotensin-receptor 1 and subsequently transforming growth factor beta-1 (TGF- ß1). Breast reduction surgery is known to have a potential complication of hypertrophic scarring. The primary objective of this study is to assess whether the use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARBs) by patients undergoing bilateral reduction mammoplasty is correlated with a reduction in hypertrophic scarring complications post-operatively. METHODS: A retrospective chart review of all patients who received bilateral breast reduction surgery in our province over a 10-year period was performed. Patient charts were reviewed for post-operative hypertrophic scarring as well as medications being used around the time of surgery. The rate of hypertrophic scarring within patients treated with an ACEi or ARB for existing hypertension were compared with the rest of the population. RESULTS: A total of 981 patients met the inclusion criteria of the study. The overall incidence of hypertrophic scarring was 6%. Within the population, 132 (14%) of patients had a clinical diagnosis of hypertension. Of the patients who were managed with an ACEi or ARB, one (2%) patient developed hypertrophic scarring post-operatively. This was significantly less than the total population and the remainder of the population with hypertension treated with a medication other than an ACEi or ARB. CONCLUSIONS: This study investigated the impact of routine ACEi or ARB use by patients undergoing bilateral reduction mammoplasty and demonstrated a statistically significant reduction in the incidence of hypertrophic scarring. This study is one of the first to investigate ACEi or ARB use in humans to reduce rates of unsightly scarring. LEVEL OF EVIDENCE: Level III.

Oral Losartan After Limited Mandibulectomy for Treatment of Desmoid-Type Fibromatosis.

Desmoid-type fibromatosis (DF) is a rare soft tissue lesion with an annual incidence of 2 to 4 per million population and peak incidence occurring at approximately 4.5 years of age. While benign, the tumor has a locally aggressive infiltrative growth pattern and a high rate of recurrence. Given the functional and aesthetic implications of excision and reconstruction in the facial skeleton, novel medical treatment options are highly desirable. We describe the case of a 3-year-old boy who presented with an enlarging, asymptomatic mass involving the left mandible. Biopsy revealed an immunohistochemical profile consistent with DF. Despite the high likelihood of recurrence, conservative, mandible-sparing en bloc resection and limited mandibulectomy were performed. Pathological and immunohistochemical analysis of the resection specimen revealed DF with grossly positive margins and elevated expression of angiotensin II type 1 receptor. Postoperative medical treatment with the angiotensin receptor blocker losartan was initiated. The patient remains medically stable and disease progression-free on repeat imaging at 20 months post-resection. We describe for the first time the successful use of the angiotensin blocker losartan following conservative surgery for management of DF.

Comparison of two Specialized Cleft Palate Feeders.

OBJECTIVE: To evaluate feeding efficiency and weight gain in infants with cleft palate fed using 1 of the 2 specialty feeders. DESIGN: Retrospective cohort study. SETTING: Cleft palate clinic in a tertiary pediatric hospital. PARTICIPANTS: Infants with cleft palate (with or without cleft lip) fed using the Medela SpecialNeeds® Feeder (n = 39) or the Dr. Brown's® Specialty Feeding System (n = 16) and who had documented feeding and growth data available from the time of initial assessment in the first month of life and at subsequent follow-up between 2 and 4 months. PRIMARY OUTCOME MEASURE: Feeding velocity (mL/min). SECONDARY OUTCOMES MEASURES: Calorie velocity (kcal/min), weight gain, and complications associated with poor feeding. RESULTS: No statistically significant differences in feeding or calorie velocities were identified between infants with cleft palate fed with the Medela SpecialNeeds® feeder and those fed with the Dr. Brown's® feeder. Mean weight z-scores by month did not differ significantly between the 2 bottle groups at the time of initial assessment (P = .84) and follow-up (P = .20). Mean weight z-scores by month for the infants included in this study fell below the 50th percentile. The proportion of infants who developed otitis media, reflux requiring treatment, or who required hospital admission for nasogastric (NG) feeds did not differ significantly between the 2 groups. CONCLUSIONS: Despite being adequately powered for the primary outcome, no significant differences were identified between infants fed with the Medela or the Dr. Brown's feeders in terms of feeding velocity, calorie velocity, weight gain, or complications.

Patient Safety Initiatives in Cosmetic Breast Surgery: A Systematic Review.

BACKGROUND: Improved patient safety (PS) in cosmetic breast surgery relies upon high-quality evidence. The objective of this study was to systematically review the existing evidence for PS and quality improvement (QI) in cosmetic breast surgery. METHODS: A systematic review of published plastic surgery literature from 1965 to 2021 was undertaken through a computerized search following PRISMA guidelines. Publication descriptors, methodological details, and overall results were extracted. Articles were assessed for methodological quality using either the MINORS, Cochrane ROB2, or AMSTAR 2 instrument depending on the type of study. RESULTS: Sixty studies were included. Most studies were retrospective, and 43.3 percent were from the 3rd level of evidence. Overall, the scientific quality was moderate, with randomized controlled trials and non-comparative non-randomized studies generally being rated of higher quality. Studies investigating approaches to antisepsis (38.3 percent) in cosmetic breast surgery indicated conflicting opinions on prophylactic antibiotics. Studies focusing on risk factor assessment tools (8.3 percent) held possible utility in identifying high-risk patients for cosmetic surgery. Studies assessing anesthesia in cosmetic breast surgery (5 percent) demonstrated a significant benefit to tumescent local anesthesia. Drains for decreasing hematoma and seroma (8.3 percent) largely showed no benefit. CONCLUSIONS: Overall, PS and QI studies were of moderate quality and investigated numerous interventions. Our review identified a need for additional studies to decrease infection and other breast implant morbidities, specifically breast implant-associated anaplastic large cell lymphoma and capsular contracture.

Systematic Review of Patient Safety and Quality Improvement Initiatives in Breast Reconstruction.

BACKGROUND: Improving patient care and safety requires high-quality evidence. The objective of this study was to systematically review the existing evidence for patient safety (PS) and quality improvement initiatives in breast reconstruction. METHODS: A systematic review of the published plastic surgery literature was undertaken using a computerized search and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Publication descriptors, methodological details, and results were extracted. Articles were assessed for methodological quality and clinical heterogeneity. Descriptive statistics were completed, and a meta-analysis was considered. RESULTS: Forty-six studies were included. Most studies were retrospective (52.2%) and from the third level of evidence (60.9%). Overall, the scientific quality was moderate, with randomized controlled trials generally being higher quality. Studies investigating approaches to reduce seroma (28.3% of included articles) suggested a potential benefit of quilting sutures. Studies focusing on infection (26.1%) demonstrated potential benefits to prophylactic antibiotics and drain use under 21 days. Enhanced recovery after surgery protocols (10.9%) overall did not compromise PS and was beneficial in reducing opioid use and length of stay. Interventions to increase flap survival (10.9%) demonstrated a potential benefit of nitroglycerin on mastectomy skin flaps. CONCLUSIONS: Overall, studies were of moderate quality and investigated several worthwhile interventions. More validated, standardized outcome measures are required, and studies focusing on interventions to reduce thromboembolic events and bleeding risk could further improve PS.

Psychosocial Distress in Parents with Children Awaiting Surgery during the COVID-19 Pandemic.

Due to resource restrictions related to the COVID-19 pandemic, many pediatric patients are facing substantial delays for surgery, potentially resulting in additional distress for caregivers. We aimed to assess the experiences and psychosocial distress of parents during COVID-19 as they relate to the pandemic, waiting for surgery, and the combined effects of both events. The was a cross-sectional qualitative study. Parents with children who faced treatment delays during the initial wave of the COVID-19 pandemic for elective, non-emergent procedures across a variety of surgical specialties were recruited. Semi-structured telephone interviews and thematic analysis were utilized. Thematic saturation was reached with eighteen participants. Four themes were identified: coping with COVID-19, distress levels, quality and nature of communication with the surgical team, and the experience of COVID-19 related hospital restrictions. Participants reported varying levels of distress due to the delay in surgery, such as the fear of developmental delay or disease progression for their child. They also indicated their own physical and mental health had been impacted by emotional distress related to both COVID-19 and delays in treatment. Most participants experienced the COVID-19-related hospital restrictions as distressing. This related predominantly to limiting in-hospital caregivers to only one caregiver. Participants were found to have substantial levels of psychosocial distress. Targeted social and emotional support may be helpful in reducing parental distress as the pandemic timeframe continues. Within the limits of individual health systems, reducing restrictions to the number of allowed care givers may help allay distress felt by parents.

A Systematic Review of Feeding Interventions for Infants with Cleft Palate.

OBJECTIVE: Various devices and techniques have been proposed to reduce feeding difficulties experienced by infants with cleft palate. The aim of this review is to identify and assess the scope and quality of evidence for these interventions. METHODS: A systematic review of published literature evaluating feeding interventions for infants with cleft palate (with or without cleft lip) from database inception to 2021 was conducted using Preferred Reporting Items for Systematic Reviews guidelines. Quality appraisal of included studies was conducted using a methodological index for nonrandomized studies, Cochrane, or a measurement tool to assess systematic reviews 2 instruments, according to study type. RESULTS: Fourteen studies met inclusion criteria, with the majority (71%) of studies consisting of second-level evidence. Included interventions were specialty bottles (21%), alternative feeding delivery systems (14%), obturators (14%), and educational programs (14%). Specialty bottles and palatal obturators did not appear to offer any substantial growth advantages compared to traditional bottles or no intervention, respectively. Designated education programs for the mothers of infants with clefts had a positive impact on infant growth. CONCLUSIONS: Overall evidence evaluating feeding interventions for infants with cleft palate was moderate to low. While it does not appear that specialized feeding delivery systems or palatal obturators significantly improve growth in infants with clefts compared to children without cleft conditions, education programs do appear to be beneficial.

Piezosurgery versus Conventional Cutting Techniques in Craniofacial Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Despite its increasing use in craniofacial surgery, the evidence for piezosurgery over conventional bone-cutting techniques has not been critically appraised. The purpose of this systematic review and meta-analysis was to identify and assess the evidence that exists for the use of piezosurgery in craniofacial surgery. METHODS: A systematic review was undertaken using a computerized search. Publication descriptors, methodologic details, and outcomes were extracted. Articles were assessed using the methodologic index for nonrandomized studies and Cochrane instruments. Random effects meta-analysis was completed. RESULTS: Thirty-nine studies were included. Most studies were published within the past 5 years (51.3 percent) and were randomized controlled trials (56.4 percent). The mean age of patients was 27 years (range, 0.2 to 57 years), and the mean sample size was 44 (range, 12 to 180). Meta-analysis revealed that compared to conventional instruments, piezosurgery had a lower postoperative incidence of sensory disturbance, principally in mandibular procedures (OR, 0.29; 95 percent CI, 0.11 to 0.77; p = 0.01) and pain at postoperative day 3 (mean difference, -0.86; 95 percent CI, -1.20 to -0.53; p < 0.01). There was no statistically significant difference in operating room time (mean difference, 8.60; 95 percent CI, -1.27 to 18.47; p = 0.80) or osteotomy time (mean difference, 0.35; 95 percent CI, -2.99 to 3.68; p = 0.84). Most studies were clinically homogenous (92 percent) and of high quality based on the methodologic index for nonrandomized studies instrument (84 percent). Few studies had domains at high risk of bias based on the Cochrane instrument (28.6 percent). CONCLUSIONS: Piezosurgery has considerable benefits when compared to conventional instruments. Future studies should investigate its cost-effectiveness and benefits in terms of blood loss, edema/ecchymosis, and patient satisfaction.

The Effect of Tongue-Tie Release on Speech Articulation and Intelligibility.

OBJECTIVE: The relationship between ankyloglossia and speech is controversial. The objective of this study was to determine the effect of tongue-tie release on speech articulation and intelligibility. METHODS: A prospective cohort study was conducted. Pediatric patients (>2 years of age) being referred for speech concerns due to ankyloglossia were assessed by a pediatric otolaryngologist, and speech articulation was formally assessed by a speech language pathologist using the Goldman-Fristoe Test of Articulation 2 (GFTA-2). Patients then underwent a tongue-tie release procedure in clinic. After 1 month, speech articulation was reassessed with GFTA-2. Audio-recordings of sessions were evaluated by independent reviewers to assess speech intelligibility before and after tongue-tie release. RESULTS: Twenty-five participants were included (mean age 3.7 years; 20 boys). The most common speech errors identified were phonological substitutions (80%) and gliding errors (56%). Seven children (28%) had abnormal lingual-alveolar and interdental sounds. Most speech sound errors (87.9%) were age/developmentally appropriate. GFTA-2 standard scores before and after tongue-tie release were 85.61 (SD 9.75) and 87.54 (SD 10.21), respectively, (P=.5). Mean intelligibility scores before and after tongue-tie release were 3.15 (SD .22) and 3.21 (SD .31), respectively, (P=.43). CONCLUSION: The majority of children being referred for speech concerns thought to be due to ankyloglossia had age-appropriate speech errors at presentation. Ankyloglossia was not associated with isolated tongue mobility related speech articulation errors in a consistent manner, and there was no benefit of tongue-tie release in improving speech articulation or intelligibility.

Physician Scientists Of Yesterday, Today And Tomorrow - Published 44(3) September 2021.

In this issue, Ryan Kirkpatrick and Gordon Boyd speculated on the reasons for the dwindling number of physician scientists in Canada. To help stimulate discussion on this important issue, Clinical and Investigative Medicine invited two distinguished scientists to present their views on this issue.

Distinct Metalloproteinase Expression and Functions in Systemic Sclerosis and Fibrosis: What We Know and the Potential for Intervention.

Systemic sclerosis (SSc) is a chronic debilitating idiopathic disorder, characterized by deposition of excessive extracellular matrix (ECM) proteins such as collagen which leads to fibrosis of the skin and other internal organs. During normal tissue repair and remodeling, the accumulation and turnover of ECM proteins are tightly regulated by the interaction of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinases (TIMPs). SSc is associated with dysregulation of the activity of these proteolytic and inhibitory proteins within the tissue microenvironment, tipping the balance toward fibrosis. The resultant ECM accumulation further perpetuates tissue stiffness and decreased function, contributing to poor clinical outcomes. Understanding the expression and function of these endogenous enzymes and inhibitors within specific tissues is therefore critical to the development of therapies for SSc. This brief review describes recent advances in our understanding of the functions and mechanisms of ECM remodeling by metalloproteinases and their inhibitors in the skin and lungs affected in SSc. It highlights recent progress on potential candidates for intervention and therapeutic approaches for treating SSc fibrosis.

A case of migraine treatment in a patient with a clinical diagnosis of CHARGE syndrome using onabotulinum toxin A.

CHARGE syndrome is a genetic disorder that affects multiple organ and sensory systems. Cranial nerve involvement is one of the key clinical diagnostic criteria. We present the case of an 8-year-old girl with CHARGE syndrome, associated right-sided facial palsy, and chronic severe migraines, that were intractable to medical treatment. At age 6, onabotulinum toxin A was used to weaken the contralateral non-paralyzed side of her face to address her stigmatizing asymmetry. Onabotulinum toxin A chemodenervation was performed on the left lower lip depressors to relax the muscles and improve left lower lip position. Coincidentally, it was noted that with these treatments, migraine symptoms resolved. As the chemodenervation subsided over the next 3-4 months, the severe migraines returned. Continued treatment with onabotulinum toxin A injections every 3 months has resulted in ongoing improvements in facial symmetry and migraine control. Onabotulinum toxin A is a well-known treatment of chronic migraine. Injections are usually directed to the occipitalis, frontalis, and corrugator muscles. The literature has no reports of injections to the lower lip depressors as a useful therapy for migraine, making the results from this case unique.