Nathan D. Schilaty

Involvement of reactive oxygen species in cocaine-taking behaviors in rats

Reactive oxygen species (ROS) have been implicated in the development of behavioral sensitization following repeated cocaine exposure. We hypothesized that increased ROS following cocaine exposure would act as signaling molecules in the mesolimbic dopamine (DA) system, which might play an important role in mediating the reinforcing effects of cocaine. The aim of this study was to evaluate cocaine enhancement of brain metabolic activity and the effects of ROS scavengers on cocaine self‐administration behavior, cocaine‐induced ROS production in the nucleus accumbens (NAc) and cocaine enhancement of DA release in the NAc. Metabolic neural activity monitored by temperature and oxidative stress were increased in NAc following cocaine exposure. Systemic administration of the ROS scavenger N‐tert‐butyl‐α‐phenylnitrone (PBN) or 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPOL), either pre‐ or post‐treatment, significantly decreased cocaine self‐administration without affecting food intake. Infusion of TEMPOL into the NAc inhibited cocaine self‐administration. Increased oxidative stress was found mainly on neurons, but not astrocytes, microglia or oligodendrocytes, in NAc of rats self‐administering cocaine. TEMPOL significantly attenuated cocaine‐induced enhancement of DA release in the NAc, compared to saline controls. TEMPOL had no effect on the enhancement of DA release produced by the DA transporter inhibitor GBR12909. Taken together, these findings suggest that enhancement of ROS production in NAc neurons contributes to the reinforcing effect of cocaine.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

Electrophysiology and microdialysis studies have provided compelling evidence that moderate to high ethanol concentrations enhance dopamine (DA) neurotransmission in the nucleus accumbens (NAc) through the mesolimbic DA system. However, with fast-scan cyclic voltammetry, short-term exposure to moderate to high doses of ethanol decreases evoked DA release at terminals in the NAc. The aim of this study was to evaluate the involvement of nicotinic acetylcholine receptors (nAChRs) in modulating the effects of ethanol on DA release in the NAc of C57BL/6 mice ex vivo and in vivo. Local stimulation evoked robust, frequency-dependent DA release in the NAc slice preparation, with maximal release at 40 Hz in the shell and 20 Hz in the core. Nicotine decreased DA release in a concentration-dependent (0.01–10 μM) manner in the shell and core, with an IC50 of 0.1 μM ex vivo and 0.5 mg/kg in vivo. Nicotine and ethanol inhibition of DA release was blocked by the α6*-nAChR antagonist α-conotoxins CtxMII and α-CtxMII [H9A; L15A] ex vivo (100 nM) in the core but not the shell. Furthermore, the nonspecific nAChR antagonist mecamylamine (2 mg/kg) blocked the effects of ethanol in the core in vivo. These findings suggest that DA release is inhibited by ethanol via nAChRs in the NAc and that DA modulation by nAChRs differs in the core versus the shell, with α6*-nAChRs affecting DA release in the core but not in the shell.

Novel mechanical impact simulator designed to generate clinically relevant anterior cruciate ligament ruptures

Background Over 250,000 anterior cruciate ligament ruptures occur each year; therefore, it is important to understand the underlying mechanisms of these injuries. The objective of the current investigation was to develop and analyze an impact test device that consistently produces anterior cruciate ligament failure in a clinically relevant manner. Method A mechanical impact simulator was developed to simulate the ground reaction force impulse generated from landing in a physiologic and clinically relevant manner. External knee abduction moment, anterior shear, and internal tibial rotation loads were applied to the specimen via pneumatic actuators. The magnitudes of applied loads were determined in vivo from a cohort of healthy athletes. Loads were systematically increased until specimen failure was induced. Three cadaveric lower extremity specimens were tested and clinically assessed for failure. Knee specimens were physically and arthroscopically examined at baseline and at post‐injury by a board certified orthopedic surgeon. Findings All three specimens experienced failure at either the midsubstance or the femoral insertion site. The mean peak strain prior to failure was 18.8 (6.2)%, while the mean peak medial collateral ligament strain was 7.9 (5.9)%. Interpretation A board certified orthopedic surgeon confirmed observed rupture patterns were representative of clinical cases. Peak strains were consistent with literature. The novel mechanical impact simulator will allow researchers to assess clinically relevant patterns of rupture and the data generated will inform clinician decisions. This novel machine presents the ability to assess healthy specimens as well as differences in the function of deficient and reconstructed knees. HighlightsSimulator executed physiologic landing forces on cadaveric lower extremities.Applied in vivo knee kinetics to mimic relative anterior cruciate ligament injury risk.Specimens experienced anterior cruciate ligament failure with high risk biomechanics.Ligament failures occurred proximally near femoral insertion (clinical pattern).First ligament injury simulator to consistently generate failure in clinical location.

Incidence of Second Anterior Cruciate Ligament Tears (1990-2000) and Associated Factors in a Specific Geographic Locale:

Background: Second anterior cruciate ligament (ACL) tears after reconstruction occur at a reported rate of 20% to 30%. This high frequency indicates that there may be factors that predispose an athlete to graft failure and ACL tears of the contralateral knee. Purpose: To determine the incidence of second ACL injuries in a geographic population-based cohort over a 10-year observation period. Study Design: Descriptive epidemiological study. Methods: International Classification of Diseases, 9th Revision (ICD-9) codes relevant to the diagnosis of an ACL tear and the procedure code for ACL reconstruction were searched across the Rochester Epidemiology Project, a multidisciplinary county database, between the years of 1990 and 2000. This cohort of patients was tracked for subsequent ACL injuries through December 31, 2015. The authors identified 1041 patients with acute, isolated ACL tears. These patients were stratified by primary and secondary tears, sex, age, activity level, side of injury, sex by side of injury, and graft type. Results: Of the 1041 unique patients with a diagnosed ACL tear in Olmsted County, Minnesota, from 1990 to 2000, there were 66 (6.0%) second ACL tears; 66.7% of these tears occurred on the contralateral side. A second ACL injury was influenced by graft type (P < .0001), election of ACL reconstruction (P = .0060), and sex by side of injury (P = .0072). Nonparametric analysis of graft disruption by graft type demonstrated a higher prevalence of second ACL tears with allografts compared with hamstring (P = .0499) or patellar tendon autografts (P = .0012). Conclusion: The incidence of second ACL tears in this population-based cohort was 6.0%, with 66.7% of these tears occurring on the contralateral side from the original injury. There was a high population incidence of second ACL injuries in female patients younger than age 20 years. The utilization of patellar tendon autografts significantly reduced the risk of second ACL injuries compared with allografts or hamstring autografts in this cohort.

Use of Objective Neurocognitive Measures to Assess the Psychological States that Influence Return to Sport Following Injury

There is growing interest in the effects of psychological states on human performance, especially with those who have suffered debilitating injury and are attempting to return to sport (RTS). Current research methods measure psychological states through validated questionnaires; however, these outcomes only allow for subjective assessment and may be unintentionally biased. Application of objective neurocognitive measures correlated with psychological states will advance understanding of injury outcomes by identifying human behavior and avoiding vague assumptions from subjective measures.

Incidence of Second Anterior Cruciate Ligament Tears and Identification of Associated Risk Factors From 2001 to 2010 Using a Geographic Database

Background: The reported rate of second anterior cruciate ligament (ACL) injuries (20%-30%), including graft failure and contralateral ACL tears, after ACL reconstruction (ACLR) or nonoperative therapy indicates that multiple factors may predispose patients to subsequent ACL injuries. Purpose: To determine the incidence of second ACL injuries in a population-based cohort over a 10-year observation period (2001-2010) and to identify factors that contribute to the risk of second injuries. Study Design: Descriptive epidemiological study. Methods: International Classification of Diseases, 9th Revision (ICD-9) codes relevant to the diagnosis of an ACL tear and the procedure code for ACLR were utilized to search the Rochester Epidemiology Project, a multidisciplinary county database, between the years of 2001 and 2010. The complete medical records for all cases were reviewed to confirm diagnosis and treatment details. A total of 914 unique patients with 1019 acute, isolated ACL tears were identified. These patients were stratified by primary and secondary tears, sex, age, activity level, side of injury, sex × side of injury, and graft type of reconstruction. Results: Second ACL tears were recorded in 141 (13.8%) of the 914 patients diagnosed with an ACL tear in Olmsted County, Minnesota, USA, from 2001 to 2010; 50.4% of these occurred in the contralateral knee. A noncontact mechanism was responsible for 76.4% of all ACL injuries. A second ACL injury was influenced by factors of sex × age group, treatment type × age group, and treatment type × activity level. Nonparametric analysis of graft disruption × graft type demonstrated that a higher prevalence of second ACL tears occurred with allografts compared with hamstring autografts (P = .0054) and patellar tendon autografts (P = .0001). Conclusion: The incidence of second ACL tears in this population-based cohort was 13.8%, and half occurred to the ACL of the contralateral knee. Statistically, second ACL injuries differed by sex, occurring in female patients younger than 25 years and male patients aged 26 to 45 years. Allografts continued to be associated with a greater risk of second ACL injuries compared with hamstring and patellar tendon autografts. Nonoperative treatment carried more risk of contralateral tears than ACLR.

Letter to the editor: Effect of Sagittal Plane Mechanics on ACL Strain during Jump Landing

We read with great interest the article entitled, “Effect of Sagittal Plane Mechanics on ACL Strain During Jump Landing” by Bakker et al.1 We congratulate the authors for their complex study design that utilized the in sim approach2 that is designed to cross-correlate the complex results of in vivo, in vitro, and in silico research approaches. The published study adds information in regards to potential models of the mechanisms of ACL injury to the body of literature. This article is protected by copyright. All rights reserved

Effect of sagittal plane mechanics on ACL strain during jump landing: EFFECT OF SAGITTAL PLANE

We read with great interest the article entitled, “Effect of Sagittal Plane Mechanics on ACL Strain During Jump Landing” by Bakker et al.1 We congratulate the authors for their complex study design that utilized the in sim approach2 that is designed to cross-correlate the complex results of in vivo, in vitro, and in silico research approaches. The published study adds information in regards to potential models of the mechanisms of ACL injury to the body of literature. This article is protected by copyright. All rights reserved

Sex-Based Differences in Knee Kinetics With Anterior Cruciate Ligament Strain on Cadaveric Impact Simulations

Background: Females are at an increased risk of sustaining noncontact knee ligament injuries as compared with their male counterparts. The kinetics that load the anterior cruciate ligament (ACL) are still under dispute in the literature. Purpose/Hypothesis: The purpose of this study was to determine whether there are differences in knee kinetics between the sexes that lead to greater ACL strain in females when similar external loads are applied during a simulated drop vertical jump landing task. It was hypothesized that female limbs would demonstrate significant differences in knee abduction moment that predispose females to ACL injury when compared with males. Study Design: Controlled laboratory study. Methods: Motion analysis data of 67 athletes who performed a drop vertical jump were collected. The kinematic and kinetic data were used to categorize tertiles of relative risk, and these values were input into a cadaveric impact simulator to assess ligamentous loads during the simulated landing task. Uni- and multiaxial load cells and differential variable reluctance transducer strain sensors were utilized to collect kinetic data and maximum ACL strain for analysis. Conditions of external loads applied to the cadaveric limbs were systematically varied and randomized. Data were analyzed with 2-way repeated-measures analysis of variance and the Fisher exact test. Results: Five kinetic parameters were evaluated. Of the 5 kinetic variables, only knee abduction moment (KAM) demonstrated significant differences in females as compared with males (F 1,136 = 4.398, P = .038). When normalized to height and weight, this difference between males and females increased in significance (F 1,136 = 7.155, P = .008). Compared with males, females exhibited a 10.3-N·m increased knee abduction torque at 66 milliseconds postimpact and a 22.3-N·m increased abduction torque at 100 milliseconds postimpact. For loading condition, the condition of “maximum ACL strain” demonstrated a maximum difference of 54.3-N·m increased abduction torque and 74.5-N·m increased abduction torque at 66 milliseconds postimpact. Conclusion: Under the tested conditions, increased external loads led to increased medial knee translation force, knee abduction moment, and external knee moment. Females exhibited greater forces and moments at the knee, especially at KAM, when loaded in similar conditions. As these KAM loads are associated with increased load and strain on the ACL, the sex-based differences observed in the present study may account for a portion of the underlying mechanics that predispose females to ACL injury as compared with males in a controlled simulated athletic task. Clinical Relevance: KAM increases strain to the ACL under clinically representative loading. Additionally, this work establishes the biomechanical characteristics of knee loading between sexes.

Sex-Based Differences of Medial Collateral Ligament and Anterior Cruciate Ligament Strains With Cadaveric Impact Simulations

Background: Female patients sustain noncontact knee ligament injuries at a greater rate compared with their male counterparts. The cause of these differences in the injury rate and the movements that load the ligaments until failure are still under dispute in the literature. Purpose/Hypotheses: This study was designed to determine differences in anterior cruciate ligament (ACL) and medial collateral ligament (MCL) strains between male and female cadaveric specimens during a simulated athletic task. The primary hypothesis tested was that female limbs would demonstrate significantly greater ACL strain compared with male limbs under similar loading conditions. A secondary hypothesis was that MCL strain would not differ between sexes. Study Design: Controlled laboratory study. Methods: Motion analysis of 67 athletes performing a drop vertical jump was conducted. Kinetic data were used to categorize injury risk according to tertiles, and these values were input into a cadaveric impact simulator to assess ligamentous strain during a simulated landing task. Uniaxial and multiaxial load cells and differential variable reluctance transducer strain sensors were utilized to collect mechanical data for analysis. Conditions of external loads applied to the cadaveric limbs (knee abduction moment, anterior tibial shear, and internal tibial rotation) were varied and randomized. Data were analyzed using 1-way analysis of variance (ANOVA), 2-way repeated-measures ANOVA, and the Fisher exact test. Results: There were no significant differences (P = .184) in maximum ACL strain between male (13.2% ± 8.1%) and female (16.7% ± 8.3%) specimens. Two-way ANOVA demonstrated that across all controlled external load conditions, female specimens consistently attained at least 3.5% increased maximum ACL strain compared with male specimens (F 1,100 = 4.188, P = .043); however, when normalized to initial contact, no significant difference was found. There were no significant differences in MCL strain between sexes for similar parameters. Conclusion: When compared with baseline, female specimens exhibited greater values of ACL strain at maximum, initial contact, and after impact (33, 66, and 100 milliseconds, respectively) than male specimens during similar loading conditions, with a maximum strain difference of at least 3.5%. During these same loading conditions, there were no differences in MCL loading between sexes, and only a minimal increase of MCL loading occurred during the impact forces. Our results indicate that female patients are at an increased risk for ACL strain across all similar conditions compared with male patients. Clinical Relevance: These data demonstrate that female specimens, when loaded similarly to male specimens, experience additional strain on the ACL. As the mechanical environment was similar for both sexes with these simulations, the greater ACL strain of female specimens must be attributed to ligament biology, anatomic differences, or muscular stiffness.