Oleg Dolkart

Statins Enhance Rotator Cuff Healing by Stimulating the COX2/PGE2/EP4 Pathway An In Vivo and In Vitro Study

Background: Statins are lipid-lowering drugs with many beneficial pleiotropic effects. Cyclooxygenase (COX2) selective inhibitors that are commonly prescribed in orthopaedic patients may effect healing. Evidence indicates that statins stimulate COX2 activity. Hypothesis: Atorvastatin (ATV) administration will enhance tendon healing by stimulating the acute inflammatory phase via increasing the production of prostaglandin E2 (PGE2). Study Design: Controlled laboratory study. Methods: After experimental rotator cuff (RC) tearing and suturing, 48 Wistar rats were randomly allocated into 4 groups: (1) ATV (20 mg/kg), (2) celecoxib (CEL; COX2 inhibitor) (10 mg/kg), (3) ATV + CEL (20 mg/kg + 10 mg/kg), and (4) saline alone. Animals were sacrificed 3 weeks after RC tears and repair, and tendon integrity was tested biomechanically in tension. To further evaluate the underlying mechanism of action, human and rat primary tenocytes were obtained from the supraspinatus tendon. Cultures were treated with a therapeutic dosage of 5 commonly used statins: CEL, ATV + CEL, PGE2, and a selective antagonist of PGE2 receptor 4 (EP4). Cell proliferation (thymidine incorporation), migration (wound healing assay), and adhesion (iCELLigence) were evaluated. The expression of all PGE2 receptors (EPs) was determined by quantitative reverse transcription polymerase chain reaction. Results: Tension testing of healed tendons demonstrated significantly higher maximal loading and stiffness in the ATV group as compared with the saline (+30% and +20%, respectively; P < .001) and CEL groups (+33% and +50%, respectively; P < .005). Celecoxib alone did not affect tendon healing (P = .88). In line with these in vivo results, tenocytes treated with statins demonstrated significantly higher proliferation rates; CEL abrogated this effect, and PGE2 treatment stimulated tenocyte proliferation even in the presence of CEL. Also, ATV stimulated the migration (wound healing) and adhesion of tenocytes. Among all PGE2 receptors, tenocytes mainly express EP4, and an EP4 selective antagonist blocked the effect of ATV. Conclusion: Results indicate that ATV enhances tendon healing by stimulating tenocyte proliferation, migration, and adhesion via increased COX2 activity and autocrine/paracrine PGE2 signaling. Findings also demonstrate that this effect is mediated by EP4 signaling. Clinical Relevance: Although chronic inflammation contributes to the development of tendinopathy, study results advocate for a positive role of PGE2 in tendon healing during the acute inflammatory phase that follows tendon surgical repair. It is therefore suggested that ATV should be further investigated as a possible modality to improve tendon healing.

Timing matters: NSAIDs interfere with the late proliferation stage of a repaired rotator cuff tendon healing in rats

IntroductionRotator cuff (RC) tear is a common problem that causes pain and can limit shoulder function. Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed for musculoskeletal pain, including the pain subsequent to RC repair. NSAIDs have been reported to affect bone metabolism and fracture healing, but there is little evidence about their effect on tendon healing. We investigated the effect of meloxicam (non-steroidal anti-inflammatory drug) on the healing of RC tendons when given immediately after surgical repair.Materials and methodsThirty-nine rats underwent acute RC tear and repair. Group A (nxa0=xa013) received daily intraperitoneal (IP) injections of meloxicam for the first 10 postoperative days. Group B (nxa0=xa013) received IP injections of meloxicam starting from postoperative day 11. Group C (nxa0=xa013, controls) received daily IP injections of saline for 3xa0weeks. The animals were killed 3xa0weeks after surgery and the RC was evaluated by gross inspection, biomechanical testing and histological examination.ResultsGroup B displayed a significantly lower mean maximal load at 3xa0weeks than group C (Pxa0=xa00.02) and group A (Pxa0=xa00.05). Stiffness was significantly lower in B group as compared to A group (Pxa0=xa00.05). Qualitative examination of histology specimens did not disclose any apparent differences with respect to cellularity, vascularity, healing, and collagen orientation.ConclusionsWe conclude that meloxicam decreases the biomechanical strength of repaired rat RCs when administered between 11 and 20xa0days after the repair.

Arthroscopic findings of coexisting lesions with greater tuberosity fractures.

Proximal humerus fractures comprise approximately 5% of all fractures, with isolated greater tuberosity fractures accounting for approximately 20% of proximal humerus fractures. Although performing shoulder arthroscopy in situations including a fracture is technically demanding, it allows surgeons the opportunity to identify and treat other coexisting lesions that could have otherwise been missed. The incidence of these pathologies in combination with greater tuberosity fractures has not been established. This study aimed to identify the various types of pathologies that may coexist with greater tuberosity fractures but not be detected before fixation. Displaced 2-part greater tuberosity fractures were treated arthroscopically in the authors department. All patients initially underwent diagnostic arthroscopy during which other coexisting pathologies were detected and assessed, including rotator cuff tears, labral tears (Bankart or superior labral anterior posterior lesions), or long head of the biceps pathologies. Twenty-four patients underwent arthroscopic (n=10) or arthroscopic-assisted (n=14) greater tuberosity reduction and fixation. Thirteen (54.2%) fragments were fully displaced. Four (16.7%) patients had fracture dislocation of the glenohumeral joint. The concomitant soft-tissue pathologies were identified and treated arthroscopically in 22 (92%) patients. Arthroscopic evaluation before greater tuberosity fracture fixation revealed a high percentage of concomitant soft tissue pathologies. These pathologies may be overlooked otherwise, but they are easily detected arthroscopically, enabling their treatment during the same procedure.

Skeletal effect of casein and whey protein intake during catch-up growth in young male Sprague-Dawley rats.

The aim of the present study was to determine whether the type of protein ingested influences the efficiency of catch-up (CU) growth and bone quality in fast-growing male rats. Young male Sprague-Dawley rats were either fed ad libitum (controls) or subjected to 36 d of 40 % food restriction followed by 24 or 40 d of re-feeding with either standard rat chow or iso-energetic, iso-protein diets containing milk proteins - casein or whey. In terms of body weight, CU growth was incomplete in all study groups. Despite their similar food consumption, casein-re-fed rats had a significantly higher body weight and longer humerus than whey-re-fed rats in the long term. The height of the epiphyseal growth plate (EGP) in both casein and whey groups was greater than that of rats re-fed normal chow. Microcomputed tomography yielded significant differences in bone microstructure between the casein and whey groups, with the casein-re-fed animals having greater cortical thickness in both the short and long term in addition to a higher trabecular bone fraction in the short term, although this difference disappeared in the long term. Mechanical testing confirmed the greater bone strength in rats re-fed casein. Bone quality during CU growth significantly depends on the type of protein ingested. The higher EGP in the casein- and whey-re-fed rats suggests a better growth potential with milk-based diets. These results suggest that whey may lead to slower bone growth with reduced weight gain and, as such, may serve to circumvent long-term complications of CU growth.

Incidence and severity of infections after closed reduction and external fixation of proximal humeral fractures.

Objectives: This study aimed to evaluate the incidence and severity of pin tract infections in a series of patients treated by Closed reduction external fixation (CREF) for proximal humeral fractures. Design: Retrospective review of medical charts and radiographs. Setting: Academic level-1 trauma center. Patients: Forty-six consecutive patients (20 males, 26 females, mean age 50 years (range 20–90 years) with proximal humeral fractures treated by CREF were enrolled into the study based on data retrieved from medical charts and radiographs. Intervention: None. Main Outcome Measure: Evaluation of the incidence and severity of post-CREF pin tract infections. Results: All 46 fractures healed after an average of 4 weeks. There were 18 (39.1%) cases of pin tract infections whose most common bacteria colonization was gram-positive. Pin tract infections were significantly higher among patients with multiple fragment fractures and multiple pins. Treatment consisting of oral or intravenous antibiotics was effective in all cases, and the infection was resolved within 2 weeks at most. Conclusions: Most pin tract infections were managed with systemic antibiotics with good results. The occurrence of pin tract infection did not require a change of the stabilization method and none of the patients required revision of their CREF. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The response of cells derived from the supraspinatus tendon to estrogen and calciotropic hormone stimulations: in vitro study.

ABSTRACT Purpose: The most frequent complications after rotator cuff repair (RCR) are non-healing and re-tear. Age and gender are both proven risk factors for faulty RCR. This study analyzed the effects of female sex steroids and calciotropic hormones on tendon-derived cell characteristics. Methods: Tendon-derived cells from rat supraspinatus were treated with estradiol-17β (E2); soy isoflavones (daidzein, genistein, biochainin A); raloxifene and estrogen receptors α and β agonists and antagonists; and less-calcemic vitamin-D analog, parathyroid hormone, and vehicle control for 24 h. Cell proliferation and mRNA expression of estrogen receptor α and β, vitamin-D receptor (VDR), scleraxis, and collagen-1 were assessed. Results: E2, Biochainin A, raloxifene, and vitamin-D significantly increased tendon-derived cell proliferation. Estrogen receptor α antagonists neutralized tendon-derived cells response to estradiol 17-β; however, estrogen receptor β antagonists did not have an effect. Scleraxis expression decreased following estradiol 17-β and vitamin-D treatments. Vitamin-D significantly reduced collagen-1 expression, while estradiol 17-β had no effect. Vitamin-D and estradiol 17-β upregulated VDR expression. Conclusions: Significant tendon-derived cell proliferation can be achieved with commonly prescribed female sex and calciotropic hormones. However, collagen-1 expression remained constant or decreased following the administration of these hormones. Female sex steroids and vitamin-D promoted tendon-derived cell proliferation via estrogen receptor α and VDR, not estrogen receptor β. Amplified cell proliferation was not associated with increased scleraxis and collagen-1 expression. These results have important implications to the properties of healing tendon and possible pharmaceutical therapies for patients with torn RC. Further research is warranted to expose the underling mechanisms of these effects.

Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study

BackgroundRotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24–48xa0h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline.MethodsIn this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20xa0mg/10xa0ml), ketamine (50xa0mgxa0+xa0morphine 10xa0mg/10xa0ml), or saline (0.9xa0% 10xa0ml) (nxa0=xa015/group), were administered to all patients. First 24xa0h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000xa0mg or oxycodone 5xa0mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented.ResultsPatients’ demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (pxa0<xa00.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases.ConclusionsPre-incisional intra-articular morphine reduced pain in the first 2xa0weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.

Repeated closed reduction attempts of distal radius fractures in the emergency department

IntroductionRepeated attempts of closed reduction of distal radius fractures (DRF) are performed in the emergency department setting to optimize fracture alignment and avoid surgery. The additional manipulation of the fracture may, however, increase dorsal comminution and lead to loss of reduction in the cast. This retrospective cohort study has investigated the effect of second reduction attempt on fracture alignment and comminution.Materials and methodsSix-hundred-eighteen patients with DRF were treated in the medical center in 2007–2010. Seventy-six (12.3%) DRF who underwent two reductions were included in the study. Radiographs taken after the first and second reduction attempts were reviewed for changes in fracture alignment parameters (radial height, radial inclination, volar tilt) and dorsal comminution length. Patients were also followed retrospectively to determine the rates of secondary displacement in a cast.ResultsA second closed reduction attempt improved mean radial height by 1.43xa0mm, mean radial inclination by 1.62° and mean volar tilt by 8.75°. Mean dorsal comminution length increased by 1.6xa0mm. Of the 19 (25%) patients with acceptable alignments after two reduction attempts, follow-up radiographs were available for 12, which showed successful reduction in four cases (33.3 or 5.2% of total 76 patients).ConclusionsA second closed reduction attempt improved immediate fracture alignment, but also worsened dorsal comminution. Only 5.2% of patients who underwent two reduction attempts had an acceptable final alignment and did not require surgery. Increased dorsal comminution may further compromise fracture stability, complicate surgery and have negative effect on the postoperative course.

Rotator interval closure has no additional effect on shoulder stability compared to Bankart repair alone

PurposeArthroscopic Bankart repair (ABR) provides satisfactory results for recurrent anterior shoulder instability, but the high recurrence rate post-ABR remain a concern. One of the adjunct procedures proposed to improve ABR results is arthroscopic rotator interval closure (ARIC). This study prospectively evaluated the outcomes of ABRs alone compared to combined ABRu2009+u2009ARIC and identified risk factors related to failure of each procedure.MethodsThirty-nine consecutive patients (mean age 23.1 (18.3–37.5)xa0years; 37 males) underwent arthroscopic stabilization for recurrent anterior traumatic shoulder instability. Twenty patients underwent ABR alone and 19 underwent ABRu2009+u2009ARIC. Remplissage was added when glenoid engagement was observed during surgery. All patients were prospectively followed, and their postoperative courses were reviewed and functionally assessed at the last visit.ResultsThe re-dislocation rate was higher in the ABRu2009+u2009ARIC group compared to the ABR only group at a mean follow-up of 4.2 (2–5.6)xa0years (3 vs. 0, Pu2009=u20090.06). More subluxations were found in the ABR only group (2 vs. 1, respectively; Pu2009=u20090.58). The final limitation of range of motion (ROM) compared with the preoperative ROM was similar in both groups. Remplissage procedures were performed more often in the ABR only group [12 (60%) vs. 4 (21%), Pu2009=u20090.013].ConclusionsARIC performed as an adjunct to ABR showed no superiority in attaining value-added stability compared to ABR alone. Adding a remplissage procedure may achieve better stability.Level of evidenceLevel 2.

Lower risk of stress fractures in young adults with ADHD under chronic treatment with methylphenidate

INTRODUCTIONnMethylphenidate (MP) use is highly prevalent among children and young adults. Previous basic and epidemiological research demonstrated an adverse effect of MP on bone mass. Studies in military recruits have shown that history of MP use before conscription was a risk factor for stress fractures (SF) during the service.nnnMETHODSnThis study is part of the project in which the association between MP use and incidence of SF was retrospectively investigated in a cohort of healthy conscripts aged 18-25, who served for at least 12u202fmonths between 2008 and 2017. Baseline information included sex, age, weight, height, geographic origin, socioeconomic status, and education. Subjects were divided into five groups: subjects without ADHD; untreated subjects with ADHD; and subjects with ADHD and prescriptions of 1-90, 91-180, or 181+ tablets during the study period. The primary outcome was at least one diagnosis of stress fracture during the study.nnnRESULTSnAmong 682,110 subjects (409,175 men [60%]), 29,888 (4.4%) had fractures. MP was used by 1681 (0.4%) men and 2828 (1%) women. In both men and women, SF incidence was significantly higher among subjects with untreated ADHD (7.9% and 5.4%, respectively) and significantly lower in subjects with treated ADHD (1.9-3%; 0.3-4.3%), compared to healthy controls (5.3% and 2.9%). After multivariate adjustment, subjects with untreated ADHD remained at an increased risk of fracture (men ORu202f=u202f1.66, pu202f<u202f0.001 and women ORu202f=u202f1.33, pu202f=u202f0.007), whereas only subjects with highest exposure to MP (180+ tablets) had significantly lower chances for fracture (men ORu202f=u202f0.49, pu202f=u202f0.08 and women ORu202f=u202f0.09, pu202f=u202f0.02), compared to healthy controls.nnnDISCUSSIONnThe study has demonstrated lower risk of stress fractures with concurrent MP use. The findings in this population challenge our understanding of the MP effect on bone integrity and prompt further basic research.