Midterm Outcomes of Multimodal Approach to Treating Severe Scoliosis in Patients With Osteogenesis Imperfecta.

INTRODUCTION: The surgical management of severe scoliosis in patients with osteogenesis imperfecta (OI) is challenging because of curve rigidity, small stature, and inherent bone fragility. This study evaluated the midterm outcomes of our multimodal approach to address these issues, integrating perioperative bisphosphonate therapy, preoperative/intraoperative traction, various osteotomies, segmental pedicle screw instrumentation with cement augmentation, and bone morphogenetic protein-2 application. METHODS: A single-center retrospective review of 30 patients (average age 14.1 ± 2.2 years; 18 were female) diagnosed with OI and scoliosis was conducted. These patients underwent posterior spinal fusion between 2008 and 2020 and completed a minimum follow-up of 2 years. We measured radiographic parameters at each visit and reviewed the incidence of complications. A mixed-effects model was used to evaluate changes in radiographic parameters from preoperative measurements to the first and latest follow-ups. RESULTS: The patient cohort consisted of 2 individuals with type I OI, 20 with type III, 6 with type IV, and 2 with other types (types V and VIII). Surgical intervention led to a notable improvement in the major curve magnitude from 76° to 36°, with no notable correction loss. In addition, the minor curve, apical vertical translation, lowest instrumented vertebra tilt, and pelvic obliquity were also improved. In the sagittal plane, thoracic kyphosis and lumbar lordosis remained unchanged while thoracolumbar kyphosis markedly improved. Two patients experienced proximal junctional kyphosis with screw pullout, one of whom required revision surgery. One patient developed a superficial infection that was successfully treated with oral antibiotics. No instances of neurologic deficits or cement extravasation were observed. DISCUSSION: This study demonstrated the effectiveness and safety of our multimodal approach to treating scoliosis in patients with OI, achieving a 53% major curve correction with minimal complications over 2-year follow-up. These findings provide notable insights into managing scoliosis in this population. LEVEL OF EVIDENCE: Level IV (case series).

Synthesis of Borylated (Aminomethyl)cyclopropanes Using C1-Bisnucleophiles.

Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.

The Sanders Classification and Obesity: Do Obese Kids With AIS Present With More Advanced Skeletal Maturity?

INTRODUCTION: Obese and overweight (OOW) patients with adolescent idiopathic scoliosis (AIS) have been shown to initially present with a more advanced Risser score compared to normal weight (NW) patients. The Sanders Maturity Scale (SMS) is now more commonly used by surgeons to assist with treatment decisions because it more reliably predicts skeletal maturity. However, the relationship between SMS and obesity has not been described. We hypothesize that in patients with AIS, OOW patients will have a higher SMS score on initial presentation when compared to NW patients. METHODS: Billing data from 2 different institutions were used to identify patients with AIS presenting to a pediatric orthopaedic spine surgeon for an initial visit between July 2012 and March 2020. We excluded those without height/weight data, spine radiographs, or left-hand radiographs for measuring SMS stage. Body mass index-for-age percentiles were calculated and used to group patients into NW (<85th percentile) or OOW (85th percentile and above) per Centers for Disease Control guidelines. After collecting preliminary data, a power analysis was performed using average SMS scores between NW and OOW patients with an alpha of 0.5, determining a needed sample size of approximately 300 male and 300 female subjects. RESULTS: Five hundred ninety patients (296 female, 294 male) were identified. The SMS stage at presentation was significantly greater in OOW compared to NW patients for both females (5.9±1.8 vs. 5.2±1.7; P =0.003) and males (4.9±1.9 vs. 4.1±1.8; P =0.002). The major curve magnitude for OOW females was significantly different from NW females (36±16 degrees vs. 30±16 degrees; P =0.004). The major curve magnitude was not different for OOW and NW males ( P =0.3). CONCLUSION: At initial presentation, OOW patients present at a greater skeletal maturity as measured by the SMS compared with NW patients. OOW female patients present with a greater major curve magnitudes than NW female patients. These results highlight negative implications of the pediatric obesity epidemic as it relates to the AIS population. These findings can be used to counsel families and provide anticipatory guidance for the AIS treatment plan. LEVEL OF EVIDENCE: Level III-cross-sectional study.

A Fracture From a Physical Exam: A Case Report of Osteogenesis Imperfecta and the Use of Fassier-Duval Rods.

Osteogenesis Imperfecta (OI) is a rare hereditary disorder that leads to fragile bone mineralization and is most often due to a genetic defect in type I collagen, the primary collagen subtype that comprises bone. Patients with OI suffer from a significant burden of fractures and bony deformities. It has been recognized in countries throughout the world and has a variable age and severity of presentation depending on the subtype of OI. Recognition of this disorder requires a high index of suspicion on the part of the clinician, as it can easily be mistaken for non-accidental trauma in children. The current approach to care for patients with this disorder comprises surgical care with intramedullary rod fixation, cyclic bisphosphonate therapy, and rehabilitation to maximize the patient's quality of life and function. This case report demonstrates the importance of considering OI in the differential diagnosis of a child presenting with recurrent fractures so that appropriate testing and treatment interventions can be implemented. The case presented here is that of a male patient with osteogenesis imperfecta who suffered from recurrent long bone fractures, including his femurs bilaterally. His index fracture occurred after a visit to the pediatric ER for an unrelated issue, where his mother claimed that the boy demonstrated pain in his affected leg shortly after the visit. There was a delay in his diagnosis, and the patient suffered multiple fractures before undergoing the insertion of Fassier-Duval rods bilaterally into his femurs to prevent further injury.

Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives.

There is an increasing interest in cyclobutanes within the medicinal chemistry community. Therefore, methods to prepare cyclobutanes that contain synthetic handles for further elaboration are of interest. Herein, we report a new approach for the synthesis of 3-borylated cyclobutanols via a formal [3 + 1]-cycloaddition using readily accessible 1,1-diborylalkanes and epihalohydrins or epoxy alcohol derivatives. 1-Substituted epibromohydrin starting materials provide access to borylated cyclobutanols containing substituents at three of the four positions on the cyclobutane core, and enantioenriched epibromohydrins lead to enantioenriched cyclobutanols with high levels of enantiospecificity (>98%). Finally, derivatization studies demonstrate the synthetic utility of both the OH and Bpin handles.

Effect of pelvic fixation on ambulation in children with neuromuscular scoliosis.

BACKGROUND: The effect of posterior spinal fusion (PSF) incorporating the pelvis on an ambulatory patient's ability to mobilize after the fusion is not well understood. AIM: To see whether a posterior spinal fusion with pelvic fixation using iliac or sacral alar iliac screws in ambulatory neuromuscular scoliosis (NMS) patients influences postoperative ambulatory ability. METHODS: A retrospective review of all patients with NMS that underwent PSF with fixation incorporating the pelvis between January 1, 2012 and February 29, 2019. A total of 118 patients were eligible, including 11 ambulatory patients. The primary outcome was the maintenance of ambulatory status postoperatively. Secondary outcomes included postoperative curve magnitude, pelvic obliquity, and complications, comprising infections, instrumentation failure, and any unplanned returns to the operative room. RESULTS: The ambulatory function was maintained in all 11 ambulatory NMS patients. One patient had an improvement in functional status with equipment-free ambulation postoperatively. An average postoperative follow-up was 19 mo. The overall complication rate was 19.4% (n = 23) with no significant differences between the groups in infection (P = 0.365), hardware failure (P = 0.505), and reoperation rate (P = 1.0). Ambulatory status did not affect complication rate (P = 0.967). CONCLUSION: Spinal fusion to the pelvis in ambulatory patients with NMS provides effective deformity correction without the reduction in ambulatory capabilities.

Outcomes of medial patellofemoral ligament reconstruction and tibial tubercle osteotomy in syndromic adolescents with patellar dislocation.

BACKGROUND: Treatment of congenital and habitual dislocation of the patella in syndromic adolescents can be difficult due to accompanying soft-tissue and/or osseous abnormalities often present in the knee. The aim of this study was to report the results of surgical treatment of congenital and habitual patellar dislocation with medial patellofemoral ligament (MPFL) reconstruction and tibial tubercle osteotomy (TTO) in adolescents with an underlying syndrome. METHODS: Syndromic adolescent patients with congenital or habitual patellar dislocation treated with MPFL reconstruction and TTO between 2005 and 2019 with a minimum of one year of follow-up were identified. Demographic, clinical, radiographic, and surgical data were recorded, and any complications were noted. Kujala and Lysholm scores were used to quantitate knee function. RESULTS: Seventeen knees in 11 patients met the criteria for inclusion. The mean age at operation was 14.8 years (range, 13.3-18.3 years). Patients were identified as having Ehlers-Danlos (four), Down (two), trichorhinophalangeal (one), McCune-Albright (one), Klippel-Feil (one), and generalized joint hypermobility (two) syndromes. The mean follow-up was 2.2 years for each individual knee (range, 1-5.9 years). The mean Kujala score increased from 56 ± 10 preoperatively to 86 ± 6 at the most recent postoperative visit (p < 0.001). The mean Lysholm score increased from 53 ± 10 preoperatively to 85 ± 7 at the most recent postoperative visit (p < 0.001). Knee flexion increased significantly from 117° ± 15° preoperatively to 154° ± 13° postoperatively (p < 0.001). However, knee extension was no different pre- and postoperatively (4° ± 8° vs. 1° ± 4°, respectively, p = 0.2). CONCLUSIONS: Congenital and habitual patellar dislocation in adolescent-aged patients with an underlying syndromic diagnosis can be successfully treated with MPFL reconstruction combined with TTO.

When successful, anterior vertebral body tethering (VBT) induces differential segmental growth of vertebrae: an in vivo study of 51 patients and 764 vertebrae.

PURPOSE: This study aimed to determine (1) does vertebral body tethering (VBT) produce differential growth modulation in individual vertebrae in patients with idiopathic scoliosis, (2) does VBT change disc shape, and (3) does VBT affect total spine length? METHODS: Patients with idiopathic scoliosis treated with VBT of the main thoracic curve and minimum 2-year follow-up were included. Vertebrae and discs were categorized as uninstrumented proximal thoracic, instrumented main thoracic, or uninstrumented thoracolumbar-lumbar. The left- and right-sided heights of each vertebra and disc were measured on subsequent radiographs to assess for differential growth. T1-T12 thoracic and T1-S1 thoracolumbar growth velocities were compared with standardized reference data. RESULTS: Fifty-one patients (764 vertebrae and 807 discs) were analyzed. The average major curve magnitude improved from 46° ± 11° to 17° ± 11° at 2-year follow-up. Differential growth was observed in MT vertebrae, in which the left/concave side grew 2.0 ± 2.2 mm compared with 1.5 ± 2.3 mm on the right/convex (tethered) side (p < 0.001). Differential height changes were observed for all discs, but were most pronounced in instrumented MT discs, in which the right/convex sides decreased by an average of 1.2 mm each, compared with no significant height change on the left/concave side. Total spinal growth velocities were not significantly different from standard reference data. CONCLUSION: Vertebral body tethering limits convex spinal growth as designed while permitting concave growth. Curve correction results from differential vertebral growth and decreased convex disc height. Overall spinal growth continues at the expected rate. LEVEL OF EVIDENCE: Level IV case series.

Does Obesity Affect Preoperative Shoulder Balance in Adolescent Idiopathic Scoliosis?

BACKGROUND: Obese patients with adolescent idiopathic scoliosis (AIS) have been shown to present with larger curve magnitudes preoperatively. However, the effect of obesity on shoulder balance in AIS remains unknown. The purpose of our study was to determine if overweight and obese patients with AIS have worse radiographic shoulder balance on initial presentation when compared with normal weight patients. METHODS: AIS patients <18 years old, with Lenke 1 or 2 curves, who underwent a posterior spinal fusion between March 2013 and December 2018 were retrospectively evaluated. BMI-for-age percentiles as defined by the Center for Disease Control and Prevention were used: obese (≥95th percentile), overweight (85th to <95th percentile), and normal weight (5th to <85th percentile). Shoulder height was measured via the radiographic shoulder height (RSH) method, with an RSH ≤ 1 cm considered balanced. The primary outcome was preoperative shoulder balance. Secondary outcomes included postoperative shoulder balance, major curve correction, and UIV selection. RESULTS: One hundred eighty-four patients (116 [63%] normal weight and 68 [37%] overweight/obese) were included. The mean age at surgery was 13.1 ± 2 years, and mean follow-up was 17.4 ± 13 months. Preoperative shoulder imbalance was significantly greater in the overweight/obese group compared to the normal weight group (1.9 ± 1 cm vs. 1.5 ± 1 cm, p = 0.04). The odds ratio of presenting with unbalanced shoulders was 2.0 (95% CI: 1.02-3.83, p = 0.04) for the overweight/obese group. No significant differences were found for postoperative shoulder balance, UIV selection, or major curve correction. CONCLUSIONS: Overweight and obese patients with AIS are twice as likely to present with unbalanced shoulders preoperatively; however, this difference is not clinically relevant with a mean difference of 0.4 cm between cohorts. Finally, the preoperative BMI percentile did not show a significant effect on the chosen UIV or curve magnitude correction. LEVEL OF EVIDENCE: Level III: this is a retrospective case-control study.

Surgical Outcomes of Obese Patients With Adolescent Idiopathic Scoliosis From Endemic Areas of Obesity in the United States.

BACKGROUND: Obesity rates continue to rise among children and adolescents across the globe. A multicenter research consortium composed of institutions in the Southern US, located in states endemic for childhood obesity, was formed to evaluate the effect of obesity on pediatric musculoskeletal disorders. This study evaluates the effect of body mass index (BMI) percentile and socioeconomic status (SES) on surgical site infections (SSIs) and perioperative complications in patients with adolescent idiopathic scoliosis (AIS) treated with posterior spinal fusion (PSF). METHODS: Eleven centers in the Southern US retrospectively reviewed postoperative AIS patients after PSF between 2011 and 2017. Each center contributed data to a centralized database from patients in the following BMI-for-age groups: normal weight (NW, 5th to <85th percentile), overweight (OW, 85th to <95th percentile), and obese (OB, ≥95th percentile). The primary outcome variable was the occurrence of an SSI. SES was measured by the Area Deprivation Index (ADI), with higher scores indicating a lower SES. RESULTS: Seven hundred fifty-one patients were included in this study (256 NW, 235 OW, and 260 OB). OB and OW patients presented with significantly higher ADIs indicating a lower SES (P<0.001). In addition, SSI rates were significantly different between BMI groups (0.8% NW, 4.3% OW, and 5.4% OB, P=0.012). Further analysis showed that superficial and not deep SSIs were significantly different between BMI groups. These differences in SSI rates persisted even while controlling for ADI. Wound dehiscence and readmission rates were significantly different between groups (P=0.004 and 0.03, respectively), with OB patients demonstrating the highest rates. EBL and cell saver return were significantly higher in overweight patients (P=0.007 and 0.002, respectively). CONCLUSION: OB and OW AIS patients have significantly greater superficial SSI rates than NW patients, even after controlling for SES. LEVEL OF EVIDENCE: Level III.

The value-added benefit of utilizing two attending surgeons for patients with scoliosis secondary to cerebral palsy.

PURPOSE: The use of two attending surgeons during posterior spinal fusion (PSF) for cerebral palsy (CP) patients has been shown to improve perioperative outcomes. This study aims to determine if the use of two surgeons is associated with an increase in the number of subsequent surgeries that can be performed in the same operating room (OR) during business hours. METHODS: Patients with scoliosis and CP treated with PSF with minimum 90-day follow-up were included. Patients were grouped based on whether one or two attending surgeons performed the case. The primary outcome was the number of surgeries that followed in the same OR before 5 PM. Secondary outcomes included operative time, estimated blood loss (EBL), length of stay, rate of surgical site infection, and rate of unplanned return to the operating room. RESULTS: Thirty-six patients were included (10 with 1 surgeon and 26 with 2 surgeons). The two surgeon group had a significant increase in the average number of surgeries subsequently performed in the same OR during business hours (1.1 vs. 0.3, p = 0.01), as well as shorter mean operative time (159 vs. 307 min, p = 0.007) and EBL (554 vs. 840 cc, p = 0.01; 26 vs. 39%EBV, p = 0.03). CONCLUSION: The use of two attending surgeons was associated with a significant increase in the number of cases subsequently performed in the same OR during business hours, and significant decreases in operative time and EBL. Hospitals should consider the patient care and potential system-level improvements when considering implementation of two surgeon teams for PSF in CP patients. LEVEL OF EVIDENCE: Therapeutic Level III.

Selective Carbon-Carbon Bond Cleavage of Cyclopropanols.

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, ß-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

Barriers to Increasing Diversity in Orthopaedics: The Residency Program Perspective.

BACKGROUND: There are little data to explain why the surgical subspecialty of orthopaedic surgery struggles with improving the racial/ethnic composition of its workforce. The current work sought to determine what orthopaedic residency program directors and coordinators believe are the barriers to improving diversity at their own programs. METHODS: Between November 17, 2018, and April 1, 2019, a 17-question survey was electronically distributed to the program directors and coordinators of 155 allopathic orthopaedic surgery residency programs. Seventy-five of 155 programs (48.4%) responded to the survey. A p-value of < 0.05 was used to determine statistical significance. RESULTS: The most commonly stated barriers to increasing diversity within the orthopaedic surgery programs were the following: "We do not have enough minority faculty, which may deter the applicants" (69.3%), "We consistently rank minority applicants high but can never seem to match them" (56%), and "Not enough minorities are applying to our program" (54.7%). Programs with higher percentages of underrepresented minority (URM) faculty had higher percentages of URM residents (p = 0.001). Programs participating in the Nth Dimensions and/or Perry Initiative programs had a higher percentage of URM faculty as compared to the residency programs that did not participate in these programs (p = 0.004). URM residents represented 17.5% of all residents who resigned and/or were dismissed in the 10 years preceding the survey while also only representing 6% of all orthopaedic residents during the same time period. CONCLUSIONS: From the orthopaedic residency program perspective, the greatest perceived barrier to increasing the racial/ethnic diversity of residents in their program is their lack of URM faculty. Surveyed programs with more URM faculty had more URM residents, and programs participating in Nth Dimensions and/or Perry Initiative programs had a higher percentage of URM faculty.

Synthesis of Chiral Spin-Labeled Amino Acids.

Spin-labeled amino acids (SLAAs) are often used to determine intermolecular distances and conformations in proteins via double electron-electron resonance. Currently available SLAAs can be difficult to incorporate selectively and have little resemblance to natural side chains in proteins. Enantioselective synthesis of three spin-labeled l-amino acids is described, starting from readily available 2,2,6,6-tetramethyl-4-piperidinone. These SLAAs better replicate canonical residues in proteins and aim for biological incorporation via genetic incorporation or solid-phase peptide synthesis.

Synthesis of trans-2-Substituted Cyclopropylamines from α-Chloroaldehydes.

Cyclopropylamines are prevalent in pharmaceuticals and agrochemicals. Herein, we report the synthesis of trans-2-substituted cyclopropylamines in high diastereoselectivity from readily available α-chloroaldehydes. The reaction proceeds via trapping of an electrophilic zinc homoenolate with an amine followed by ring closure to generate the cyclopropylamine. We have also observed that cyclopropylamine cis/trans-isomerization occurs in the presence of zinc halide salts and that this process can be turned off by the addition of a polar aprotic cosolvent.

Treatment of Distal Femur Fractures With the DePuy-Synthes Variable Angle Locking Compression Plate.

OBJECTIVES: To determine the failure rate of the DePuy-Synthes variable angle locking compression curved condylar plate (VA-LCP) and quantify failure modes. DESIGN: Retrospective review. SETTING: Level I Trauma Center. PATIENTS/PARTICIPANTS: One hundred thirteen patients with 118 OTA/AO classification 33A and 33C distal femoral fractures were included in the study. INTERVENTION: Internal fixation using only the DePuy-Synthes VA-LCP plate. MAIN OUTCOME MEASUREMENTS: Primary outcomes included mechanical failure rate of the DePuy-Synthes VA-LCP plate in open and closed fractures. Secondary outcomes included overall failure rate of treatment, risk factors for mechanical failure, and the specific location of failure: loss of fixation in the proximal segment, implant failure over the working length, or failure of locking screw fixation distally. RESULTS: There were 11 total failures (9.3%) in 118 fractures. Failure rates for the closed and open fracture groups were 5.4% and 15.9%, respectively. Twenty patients (16.9%) required reoperation to promote union. Open fractures (P = 0.00475), the presence of medial metaphyseal comminution (P = 0.037), the length of the zone of comminution (P = 0.037), and plate length (P = 0.0096) were significantly higher in those with implant failure. Most failures (63.6%) were in the working length of the implant. CONCLUSIONS: The use of the Synthes VA-LCP is a viable option in distal femoral fractures and has an acceptable failure rate and reoperation to promote union rate. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Stability of the Syndesmosis After Posterior Malleolar Fracture Fixation.

BACKGROUND: We sought to define the rate of syndesmotic instability after anatomic reduction of the posterior malleolus when posterior stabilization of a trimalleolar or trimalleolar equivalent ankle fracture was chosen vs when a supine position and initially conservative management of the posterior elements was chosen. METHODS: The types of syndesmotic and posterior malleolar fixation used to treat adult patients with ankle fractures involving the posterior malleolus at our level I trauma center were retrospectively assessed (N = 198). Specifically, both bimalleolar and trimalleolar fractures were included. Exclusion criteria included pilon fractures, trimalleolar fractures with Chaput fragments, and neurologic injury. Demographics, fracture classification, initial operative position, medial clear space, and posterior malleolar fragment size were recorded for each fracture. RESULTS: In total, 151 patients (76.3%) were initially positioned supine, 27.2% of whom had syndesmotic instability requiring operative stabilization. Almost 25% of supine patients also underwent posterior malleolar stabilization for posterior instability. Overall, 73 (48.3%) patients who were initially treated in the supine position needed some form of additional stabilization. Forty-seven patients (23.7%) were initially positioned prone. Syndesmotic stability was restored in 97.9% of these patients. This 2.1% rate of instability vastly differs from the 13-fold higher syndesmotic instability rate observed in the supine group ( P < .001). CONCLUSION: Our data demonstrate that the rate of syndesmotic instability was reduced in trimalleolar and trimalleolar equivalent fractures when prone positioning and direct fixation of the posterior malleolus were first performed. Using traditional preoperative estimates of posterior stability to determine the need for posterior malleolar fixation may be inadequate since almost a quarter of patients treated supine received posterior stabilization. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Synthetic Modification within the "RPRL" Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation.

Apelin is an important mammalian peptide hormone with a range of physiological roles, especially in the cardiovascular system. The apelinergic system is a promising target for treatment of disease, but this remains to be realized due to rapid proteolysis of apelin-derived peptides by proteases, including neprilysin (NEP). The synthetic analogues modified within the NEP degradation site ("RPRL" motif) showed improved in vitro proteolytic stability while maintaining receptor-binding affinities, with three candidate peptides retaining full cardiovascular activities for potential therapeutic application. Many such analogues proved physiologically inactive even with relatively conservative modifications, highlighting the importance of this region for full agonist activity of this peptide hormone.

Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart.

How does the close surgical margin impact recurrence and survival when treating oral squamous cell carcinoma?

PURPOSE: The surgical margin is the main prognostic factor over which the surgeon has control during resection of oral squamous cell carcinoma (OSCC). This study examined the association between surgical excision margins of patients with OSCC and outcomes of disease-free and overall survival. MATERIALS AND METHODS: The authors implemented a retrospective cohort study. The sample was composed of patients with OSCC having resection as their initial treatment. The predictor variable was the pathologic surgical margin, defined as clear (>5 mm), close (1 to 5 mm), or involved (<1 mm). The outcome variables were disease-free (absence of locoregional recurrence) and overall survival. Data were analyzed using Kaplan-Meier survival curves and Cox regression hazard model. RESULTS: The sample was composed of 54 patients with a mean age of 60.5 years (range, 19 to 85 yr) and 26% were women. The 2- and 5-year overall survival rates were 59 and 50%, respectively. The clear surgical margin group showed higher disease-free survival rates than patients with close and involved margins (5-yr probability, 0.78 vs 0.43 and 0.29; P = .014) and a trend toward increased overall survival at 2 and 5 years (P = .093). CONCLUSION: The results suggest that the presence of a close surgical margin (1 to 5 mm) is an adverse risk feature comparable to an involved margin and therefore is associated with decreased disease-free and overall survival. Future studies are needed to replicate these findings before they can be used as a basis for clinical recommendations.