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Correlating gene expression patterns with biomechanical properties of connective tissues provides insights into the molecular processes underlying the tissue growth and repair. Cadaveric specimens such as human knees are widely considered suitable for biomechanical studies, but their usefulness for gene expression experiments is potentially limited by the unavoidable, nuclease-mediated degradation of RNA. Here, we tested whether valid gene expression profiles can be obtained using degraded RNA from human anterior cruciate ligaments (ACLs). Human ACL RNA (N = 6) degraded in vitro by limited ribonuclease digestion resemble highly degraded RNA isolated from cadaveric tissue. PCR threshold cycle (Ct) values for 90 transcripts (84 extracellular matrix, 6 housekeeping) in degraded RNAs variably ranged higher than values obtained from their corresponding non-degraded RNAs, reflecting both the expected loss of target templates in the degraded preparations as well as differences in the extent of degradation. Relative Ct values obtained for mRNAs in degraded preparations strongly correlated with the corresponding levels in non-degraded RNA, both for each ACL as well as for the pooled results from all six ACLs. Nuclease-mediated degradation produced similar, strongly correlated losses of housekeeping and non-housekeeping gene mRNAs. RNA degraded in situ yielded comparable results, confirming that in vitro digestion effectively modeled degradation by endogenous ribonucleases in frozen and thawed ACL. We conclude that, contrary to conventional wisdom, PCR-based expression analyses can yield valid mRNA profiles even from RNA preparations that are more than 90% degraded, such as those obtained from connective tissues subjected to biomechanical studies. Furthermore, legitimate quantitative comparisons between variably degraded tissues can be made by normalizing data to appropriate housekeeping transcripts.

Considering that an athlete performs at-risk sports activities countless times throughout the course of his or her career prior to the instance of anterior cruciate ligament (ACL) injury, one may conclude that non-contact ACL injury is a rare event. Nevertheless, the overall number of non-contact ACL injuries, both in the US and worldwide, remains alarming due to the growing number of recreational and professional athletes participating in high-risk activities. To date, numerous non-contact ACL injury mechanisms have been proposed, but none provides a detailed picture of sequence of events leading to injury and the exact cause of this injury remains elusive. In this perspective article, we propose a new conception of non-contact ACL injury mechanism that comprehensively integrates risk factors inside and outside the knee joint. The proposed mechanism is robust in the sense that it is biomechanically justifiable and addresses a number of confounding issues related to ACL injury.

Objective Resistance training (RT) can improve whole muscle strength without increasing muscle fiber size or contractility. Neural adaptations, which lead to greater neural activation of muscle, may mediate some of these improvements, particularly in older adults, where motor neuron denervation is common. The purpose of this study was to explore the relationship of neural adaptations, as reflected by neural cell adhesion molecule (NCAM) expression, to improvements in (1) whole muscle strength and (2) muscle fiber size following RT in older adults with knee osteoarthritis. We performed whole muscle strength measurements and immunohistochemical analysis of fiber size, type, and NCAM expression before and after a 14-week RT program. Results RT increased whole-muscle strength as measured by 1-repetition maximum (1-RM) leg press (P = 0.01), leg extension (P = 0.03), and knee extensor peak torque (P = 0.050), but did not alter NCAM expression. Greater NCAM expression in myosin heavy chain (MHC) II fibers was associated with greater whole muscle strength gains (knee extensor peak torque r = 0.93; P < 0.01) and greater MHC II fiber size (r = 0.79; P < 0.01). Our results suggest that training-induced NCAM expression, and neural adaptations more generally, may be important for RT-induced morphological and functional improvements in older adults. Trial registration NCT01190046

Critical to digital medicine is the promise of improved patient monitoring to allow assessment and personalized intervention to occur in real-time. Wearable sensor-enabled observation of physiological data in free-living conditions is integral to this vision. However, few open-source algorithms have been developed for analyzing and interpreting these data which slows development and the realization of digital medicine. There is clear need for open-source tools that analyze free-living wearable sensor data and particularly for gait analysis, which provides important biomarkers in multiple clinical populations. We present an open-source analytical platform for automated free-living gait analysis and use it to investigate a novel, multi-domain (accelerometer and electromyography) asymmetry measure for quantifying rehabilitation progress in patients recovering from surgical reconstruction of the anterior cruciate ligament (ACL). Asymmetry indices extracted from 41,893 strides were more strongly correlated ( r  = −0.87, p  < 0.01) with recovery time than standard step counts ( r  = 0.25, p  = 0.52) and significantly differed between patients 2- and 17-weeks post-op ( p  < 0.01, effect size: 2.20–2.96), and controls ( p  < 0.01, effect size: 1.74–4.20). Results point toward future use of this open-source platform for capturing rehabilitation progress and, more broadly, for free-living gait analysis.

BackgroundMost lesions of articular cartilage do not heal spontaneously and may lead to secondary osteoarthritis. It is not known whether the optimistic reports on the short and long-term results of several different cartilage repair techniques are based on sound methodological quality.MethodsWe performed a literature search in MEDLINE, CINAHL, the Cochrane Central Register, and EMBASE and included studies in which the primary aim of the investigation was to report the outcome after cartilage repair in the knee with use of microfracture, autologous osteochondral transplantation, autologous periosteal transplantation, or autologous chondrocyte implantation. We scored the quality of the studies using a modified Coleman Methodology Score with ten criteria, which results in a final score between 0 and 100. Studies were also assessed with use of the level-of-evidence rating used in the American Volume of The Journal of Bone and Joint Surgery. We collected data on the year of publication, the reported postoperative results, and the outcome measures used to assess the results.ResultsSixty-one studies involving a total of 3987 surgical procedures were included. The average methodology score was 43.5 of 100. Methodological deficiencies were found with respect to five criteriathe type of study, description of the rehabilitation protocol, outcome criteria, outcome assessment, and subject selection process. Large variations in the reported outcome were seen within each treatment modality, and no significant differences were found between each kind of therapy (p = 0.11). The methodology score correlated positively with the level-of-evidence rating (r = 0.668, p < 0.0001), but there were large variations in the methodology score within each level. The linear regression analysis weighted by the number of patients demonstrated a negative yet not significant correlation between the methodology score and the results reported in nineteen studies with use of the Lysholm Scale (r = -0.29, p = 0.19). A total of twenty-seven different clinical outcome measurement scales were used to assess outcome.ConclusionsThe generally low methodological quality found in the studies included in this analysis indicates that caution is required when interpreting results after surgical cartilage repair. Firm recommendations on which procedure to choose cannot be given at this time on the basis of these studies. More attention should be paid to methodological quality when designing, performing, and reporting clinical studies.Level of EvidenceTherapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

Women are 2 to 8 times more likely to sustain an anterior cruciate ligament (ACL) injury than men, and previous studies indicated an increased risk for injury during the preovulatory phase of the menstrual cycle (MC). However, investigations of risk rely on retrospective classification of MC phase, and no tools for this have been validated. To evaluate the accuracy of an algorithm for retrospectively classifying MC phase at the time of a mock injury based on MC history and salivary progesterone (P4) concentration. Descriptive laboratory study. Research laboratory. Thirty-one healthy female collegiate athletes (age range, 18-24 years) provided serum or saliva (or both) samples at 8 visits over 1 complete MC. Self-reported MC information was obtained on a randomized date (1-45 days) after mock injury, which is the typical timeframe in which researchers have access to ACL-injured study participants. The MC phase was classified using the algorithm as applied in a stand-alone computational fashion and also by 4 clinical experts using the algorithm and additional subjective hormonal history information to help inform their decision. To assess algorithm accuracy, phase classifications were compared with the actual MC phase at the time of mock injury (ascertained using urinary luteinizing hormone tests and serial serum P4 samples). Clinical expert and computed classifications were compared using κ statistics. Fourteen participants (45%) experienced anovulatory cycles. The algorithm correctly classified MC phase for 23 participants (74%): 22 (76%) of 29 who were preovulatory/anovulatory and 1 (50%) of 2 who were postovulatory. Agreement between expert and algorithm classifications ranged from 80.6% (κ = 0.50) to 93% (κ = 0.83). Classifications based on same-day saliva sample and optimal P4 threshold were the same as those based on MC history alone (87.1% correct). Algorithm accuracy varied during the MC but at no time were both sensitivity and specificity levels acceptable. These findings raise concerns about the accuracy of previous retrospective MC-phase classification systems, particularly in a population with a high occurrence of anovulatory cycles.

This keynote presentation provided a summary of findings from the authors' previous and ongoing research efforts that have focused on identifying the factors associated with increased risk of anterior cruciate ligament (ACL) injury. The epidemiology investigation evaluated the independent effects of athlete sex, level of competition, and sport on the risk of sustaining an ACL injury. The authors prospectively followed athletes from 26 institutions over 4 years to determine the incidence of first-time, noncontact ACL injuries. After controlling for differences in level of play and sport, they found that an athlete's sex had an independent influence on the risk of injury: female athletes' risk of experiencing a noncontact ACL injury was 2.10 times greater than that of their male counterparts. When controlling for athlete sex and level of play, the authors observed that the risk of sustaining a noncontact ACL injury was greatest in soccer and rugby compared with all other sports studied.

OBJECTIVE: To determine if anterior cruciate ligament (ACL) injuries in female athletes occur randomly or correlate with a specific phase of the menstrual cycle. DESIGN AND SETTING: Female athletes who sustained ACL injuries reported the days of their menstrual cycles and provided saliva samples for sex-hormone determination. Salivary sex-hormone profiles were assessed to confirm the self-reported menstrual histories. SUBJECTS: A total of 38 female athletes (20 college, 15 high school, 1 middle school, 2 recreational) with recent ACL injuries participated in the study over a 3-year period. MEASUREMENTS: Athletes with recent ACL injuries completed a questionnaire defining the injury, the last menstrual cycle, prior knee injury, school, and type of birth control used (if any). Each subject provided a 30-cc saliva sample within 72 hours of injury. Saliva samples were placed into sealed containers and frozen at -20 degrees C. We obtained 13 additional control samples from uninjured females to test the correlation between saliva and serum sex-hormone levels. Progesterone and estrogen were assayed by radioimmunoassay. Physical examination, magnetic resonance imaging, or surgery confirmed the injury in all subjects. RESULTS: The correlations between saliva and serum estrogen and progesterone were 0.73 (alpha =.01) and 0.72 (alpha =.01), respectively. Ten of 27 athletes who reported their cycle day at time of injury sustained an ACL injury immediately before or 1 to 2 days after the onset of menses. We rejected the null hypothesis that such high frequency was due to random chance. CONCLUSIONS: A significantly greater number of ACL injuries occurred on days 1 and 2 of the menstrual cycle. Salivary sex-hormone levels correlated with the reported cycle day.

Most lesions of articular cartilage do not heal spontaneously and may lead to secondary osteoarthritis. It is not known whether the optimistic reports on the short and long-term results of several different cartilage repair techniques are based on sound methodological quality. We performed a literature search in MEDLINE, CINAHL, the Cochrane Central Register, and EMBASE and included studies in which the primary aim of the investigation was to report the outcome after cartilage repair in the knee with use of microfracture, autologous osteochondral transplantation, autologous periosteal transplantation, or autologous chondrocyte implantation. We scored the quality of the studies using a modified Coleman Methodology Score with ten criteria, which results in a final score between 0 and 100. Studies were also assessed with use of the level-of-evidence rating used in the American Volume of The Journal of Bone and Joint Surgery. We collected data on the year of publication, the reported postoperative results, and the outcome measures used to assess the results. Sixty-one studies involving a total of 3987 surgical procedures were included. The average methodology score was 43.5 of 100. Methodological deficiencies were found with respect to five criteria: the type of study, description of the rehabilitation protocol, outcome criteria, outcome assessment, and subject selection process. Large variations in the reported outcome were seen within each treatment modality, and no significant differences were found between each kind of therapy (p = 0.11). The methodology score correlated positively with the level-of-evidence rating (r = 0.668, p < 0.0001), but there were large variations in the methodology score within each level. The linear regression analysis weighted by the number of patients demonstrated a negative yet not significant correlation between the methodology score and the results reported in nineteen studies with use of the Lysholm Scale (r = -0.29, p = 0.19). A total of twenty-seven different clinical outcome measurement scales were used to assess outcome. The generally low methodological quality found in the studies included in this analysis indicates that caution is required when interpreting results after surgical cartilage repair. Firm recommendations on which procedure to choose cannot be given at this time on the basis of these studies. More attention should be paid to methodological quality when designing, performing, and reporting clinical studies. Therapeutic Level III.

Women are more susceptible to anterior cruciate ligament (ACL) injuries than men performing similar athletic activities. Because tissue remodeling may affect ligament strength, we assessed expression of tissue remodeling effector genes in the human ACL. Specifically, we surveyed ACL for RNAs encoding all known matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) by reverse transcription/polymerase chain reaction (RT-PCR). These experiments revealed that mRNAs encoding nine of sixteen MMPs and all four TIMPs are present in the normal ACL. The nine expressed proteases were MMPs 1–3, 7, 9, 11, 14, and 17 (collagenase 1, gelatinase A, stromelysin 1, matrilysin, gelatinase B, stromelysin 3, and membrane types 1 and 4, respectively), and MMP-18. Genes for MMPs 8, 10, 12, 13, 15, and 16 appeared not to be expressed in ACL, as their mRNAs were not detected using RT-PCR conditions that did yield positive signals from other tissues (testis or bone). We conclude that numerous genes encoding tissue remodeling effector proteins are expressed in the human ACL.