Testosterone Levels Before and After Anterior Cruciate Ligament Reconstruction A Prospective Observational Study.

PURPOSE: Over 200,000 anterior cruciate ligament (ACL) reconstructions are performed in the US each year. The recovery process following surgery can be slow and difficult with patients suffering persistent strength and endurance deficits. Testosterone is an important anabolic hormone responsible for maintenance and development of muscle mass. While the response of the hypothalamic-pituitary axis (HPA) to surgery has been investigated, no studies exist tracking the HPA response, specifically that involved in testosterone homeostasis, to ACL reconstructions. The purpose of this study was to explore the response of endogenous testosterone production after ACL reconstruction and determine a possible correlation between perioperative testosterone levels in males and postoperative strength and clinical outcomes. METHODS: This was a single-center, prospective observational study measuring preoperative and postoperative testosterone levels. Plasma testosterone, follicle stimulating hormone (FSH), and lutenizing hormone (LH) were measured before 10:30 am on the day of surgery. These were then checked at the same time of day at 1 week, 6 weeks, and 12 weeks postoperatively. Patients were also evaluated with the visual analog scale for pain (VAS), Tegner, and Lysholm scales preoperatively and at postoperative visits. Statistical analysis was performed using ANOVA and were considered significant at p < 0.05. RESULTS: Twenty male patients with a mean age of 34.0 ± 9.2 years undergoing ACL reconstruction were enrolled between October 2017 and April 2018. Results showed a decrease in testosterone (3.7 ng/mL vs. 2.9 ng/mL, p = 0.05), free testosterone (8.2 pg/mL vs. 6.8 pg/mL, p = 0.05), and follicle stimulated hormone (1.8 mIU/mL vs. 1.7 mIU/ mL, p = 0.83) between the preoperative plasma draw and 1-week postoperative follow-up visit. Luteinizing hormone (1.1 mIU/mL vs. 1.5 mIU/mL, p = 0.11) increased postoperatively. By week 6, testosterone returned to baseline (3.7 ng/mL vs. 3.9 ng/mL), while free testosterone continued to increase through week 12. Lutenizing hormone peaked at the 1-week postoperative visit and trended downward until week 6 (1.5 mIU/mL vs. 1.4 mIU/mL, p = 0.79). Follicle stimulating hormone continued to increase after the week-1 visit through week 12. Patient reported outcomes exhibited a trend similar to hormone levels, with the lowest patient reported outcome (PRO) scores reported at week 1 and a constant trend upward. Although there were similar trends, there were no significant correlations between change in hormone levels and change in PRO scores. CONCLUSION: Our study emphasizes the crucial period of hormonal decrease and their return to baseline. This knowledge will contribute to the understanding and timing of hormone therapy supplementation. Short-term testosterone replacement may be beneficial to return patients to work and physical activity at a faster rate.

Changes in the Synovial Fluid Cytokine Profile of the Knee Between an Acute Anterior Cruciate Ligament Injury and Surgical Reconstruction.

BACKGROUND: Changes in the intra-articular inflammatory state during the immediate period after an acute anterior cruciate ligament (ACL) rupture are not well defined. PURPOSE: To evaluate changes in the concentration of select proinflammatory and anti-inflammatory synovial fluid cytokines during the interval between an ACL injury and surgical reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: In patients with an acute ACL injury, a synovial fluid sample was obtained from the injured knee during the initial office visit within 2 weeks of the inciting traumatic event. An additional synovial fluid sample was collected at the time of ACL reconstruction just before the surgical incision. Synovial fluid samples from both the acute injury and the surgery time points were processed with a protease inhibitor, and the concentrations of 10 cytokines of interest were measured using a multiplex magnetic bead immunoassay. The primary outcome was the change in cytokine concentrations between time points. RESULTS: A total of 20 patients with a mean age of 30.2 ± 8.3 years were included. The acute injury synovial fluid samples were collected at 6.6 ± 3.8 days after the injury. The surgical synovial fluid samples were collected at 31.6 ± 15.6 days after the acute injury samples. Based on a series of linear mixed-effects models to control for the effect of concomitant meniscal injuries and by-patient variability, there was a statistically significant increase in the concentrations of RANTES and bFGF and a statistically significant decrease in the concentrations of IL-6, MCP-1, MIP-1ß, TIMP-1, IL-1Ra, and VEGF between time points. CONCLUSION: This study demonstrates the ongoing alterations in the intra-articular microenvironment during the initial inflammatory response in the acute postinjury period. We identified 6 synovial fluid cytokines that significantly decreased and 2 that significantly increased between the first clinical presentation shortly after the injury and the time of surgery 1 month later. CLINICAL RELEVANCE: This study describes the molecular profile of the inflammatory changes between the time of an acute ACL injury and the time of surgical reconstruction 1 month later. A greater understanding of the acute inflammatory response within the knee may be helpful in identifying the optimal timing for a surgical intervention that balances the risk of chondral damage with the likelihood of successful, well-healed reconstruction.

Correlation Between Synovial Fluid Biomarkers and Leg-Fat Area Ratios in Patients Undergoing ACL Reconstruction With or Without an Associated Meniscectomy.

PURPOSE: This study attempts to establish whether local adiposity of the knee at the level of the joint line is associated with alterations in synovial fluid biomarker concentrations in patients undergoing ACL reconstruction with or without an associated meniscectomy. METHODS: Patients undergoing ACL reconstruction were prospectively enrolled at the time of surgery from July 2011 to January 2015. Synovial fluid samples were collected just prior to incision and the concentrations of 10 biomarkers of interest were determined using a multiplex magnetic bead immunoassay. Knee adiposity was assessed via measures of leg fat area using magnetic resonance axial T2 images at the level of the joint line. Measurement was determined by subtracting the sum of the joint area, consisting of bony and muscle areas, from the total leg area with six different ratios assessed. Groups were evaluated by injury type (isolated ACL, ACL + meniscal injury, and total cohort). The correlation between synovial fluid biomarker levels and leg fat area ratios was evaluated using Spearman's correlation. RESULTS: There were 22 females and 26 males, with a mean age of 33.8 years (± 10.5) and a mean BMI of 25.3 (± 4.0). In the setting of isolated ACL injury, there was a statistically significant correlation between leg fat ratios and interleukin- 6, vascular endothelial growth factor, and interleukin-1 receptor antagonist. In patients with concomitant meniscal tears, there was an inverse correlation between leg fat ratios and monocyte chemoattractant protein-1. CONCLUSION: The leg fat to total leg volume ratio and leg fat to joint space volume ratio were the most consistent measures for alterations in post-injury synovial fluid biomarker concentrations. Analysis of synovial fluid at the time of ACL reconstruction demonstrated significant correlations between specific leg-fat area ratios and synovial fluid biomarker concentrations. Local adiposity around the knee joint appears to modulate the biochemical environment of the joint and can clinically help guide prognostic discussions with the patient.

Changes in Synovial Fluid Biomarker Concentration Before and After ACL Reconstruction.

BACKGROUND: Synovial fluid biomarkers can highlight the molecular milieu associated with knee pathology and have been shown to be significantly different in patients with anterior cruciate ligament (ACL) injuries compared to uninjured controls. The purpose of the current study was to establish how synovial fluid biomarker concentrations change in patients undergoing ACL reconstruction between the immediate preoperative period to the acute postoperative period. METHODS: Patients were prospectively enrolled at the time of surgery from September 2016 to March 2017. Patients who had an operative knee synovial fluid sample obtained at the time of ACL reconstruction and provided a synovial fluid sample at their first postoperative appointment were included. The concentrations of 10 biomarkers were determined using a multiplex magnetic bead immunoassay. Biomarker concentrations before and after surgery were compared using a paired sample t-test. RESULTS: Eight patients with mean age of 33.4 years who underwent isolated ACL reconstruction using a bonepatellar tendon-bone autograft were included. The mean time between surgery and postoperative office visit was 10.4 days. There was a statistically significant increase in the concentrations of interleukin-6 (IL-6, p = 0.014), monocyte chemoattractant protein-1 (MCP-1, p = 0.024), human matrix metalloproteinase 3 (MMP-3, p = 0.00002), macrophage inflammatory protein-1 beta (MIP-1ß, p = 0.006), human interleukin-1 receptor antagonist (IL-1Ra, p = 0.017), and vascular endothelial growth factor (VEGF, p = 0.023) between the time of surgery and the first postoperative visit and a decrease in the concentration of tissue inhibitor of metalloproteinase-2 (p = 0.050). CONCLUSION: The molecular profile of the synovial fluid changes in the early postoperative period following arthroscopic ACL reconstruction. The concentration of proinflammatory markers (such as IL-6, MCP-1, MMP-3, and MIP-1ß) and growth factors including VEGF increases. The concentration of the anti-inflammatory marker tissue inhibitor of metalloproteinase-2 (TIMP-2) appears to decrease postoperatively.

Alterations in Synovial Fluid Biomarker Levels in Knees With Meniscal Injury as Compared With Asymptomatic Contralateral Knees.

BACKGROUND: Changes in the joint microenvironment after an injury to the articular surface of the knee have been implicated in the pathogenesis of osteoarthritis. While prior studies focused on changes in this microenvironment after anterior cruciate ligament ruptures, few have explored the biomarker changes that occur in the setting of meniscal injuries. PURPOSE: To determine whether meniscal injury results in significant alterations to synovial fluid biomarker concentrations as compared with noninjured contralateral knees. Additionally, to explore the relationship between synovial fluid biomarkers and the degree of cartilage injury seen in these patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients undergoing surgery for unilateral meniscal injury were prospectively enrolled from October 2011 to December 2016, forming a cohort that had synovial fluid samples collected from both the injured knee and the contralateral uninjured knee at the time of meniscal surgery. Synovial fluid samples were collected just before incision, and the concentrations of 10 biomarkers of interest were determined with a multiplex magnetic bead immunoassay. The concentrations of synovial fluid biomarkers from the operative and contralateral knees were compared. Additionally, the synovial fluid biomarker concentrations of operative knees from patients with associated high-grade cartilage lesions were compared with those with low-grade lesions. RESULTS: The current analysis included synovial fluid samples from 82 knees (41 operative and 41 contralateral) from 41 patients undergoing arthroscopic surgery to treat a symptomatic meniscal injury. The mean ± SD age of patients was 49.86 ± 11.75 years. There were significantly greater concentrations of 4 of the 5 proinflammatory biomarkers (IL-6, MCP-1, MIP-1ß, and MMP-3) in symptomatic knees as compared with asymptomatic knees when controlling for the duration of symptoms, body mass index, age, and the random effects of by-patient variability. In the injured knees, associated high-grade cartilage lesions were predictive of elevated MCP-1, MIP-1ß, and VEGF levels. Low synovial fluid concentration of TIMP-1 or a greater ratio of MMP-3 to TIMP-1 was associated with the presence of synovitis. Increasing age was found to be an independent predictor of increased IL-6, MCP-1, and VEGF concentrations in the setting of symptomatic meniscal injury. CONCLUSION: The authors identified 4 proinflammatory synovial fluid biomarkers whose concentrations were significantly different after meniscal injury as compared with uninjured contralateral knees. Furthermore, they describe the effects of associated cartilage damage, synovitis, and patient age on biomarker concentrations.

Effects of mechanical loading on cortical defect repair using a novel mechanobiological model of bone healing.

Mechanical loading is an important aspect of post-surgical fracture care. The timing of load application relative to the injury event may differentially regulate repair depending on the stage of healing. Here, we used a novel mechanobiological model of cortical defect repair that offers several advantages including its technical simplicity and spatially confined repair program, making effects of both physical and biological interventions more easily assessed. Using this model, we showed that daily loading (5N peak load, 2Hz, 60 cycles, 4 consecutive days) during hematoma consolidation and inflammation disrupted the injury site and activated cartilage formation on the periosteal surface adjacent to the defect. We also showed that daily loading during the matrix deposition phase enhanced both bone and cartilage formation at the defect site, while loading during the remodeling phase resulted in an enlarged woven bone regenerate. All loading regimens resulted in abundant cellular proliferation throughout the regenerate and fibrous tissue formation directly above the defect demonstrating that all phases of cortical defect healing are sensitive to physical stimulation. Stress was concentrated at the edges of the defect during exogenous loading, and finite element (FE)-modeled longitudinal strain (εzz) values along the anterior and posterior borders of the defect (~2200µÎµ) was an order of magnitude larger than strain values on the proximal and distal borders (~50-100µÎµ). It is concluded that loading during the early stages of repair may impede stabilization of the injury site important for early bone matrix deposition, whereas loading while matrix deposition and remodeling are ongoing may enhance stabilization through the formation of additional cartilage and bone.

Mumps outbreaks in a highly vaccinated population: Investigation of a neutralization titre against the current circulating wildtype genotype G5 mumps virus.

BACKGROUND: Mumps outbreaks continue to occur globally, despite high levels of uptake of the mumps vaccine. OBJECTIVES: In order to address immunity to the current circulating wildtype virus, we sought to determine a mumps G5 specific IgG quantitative value which correlates with genotype G5 specific neutralization ability in vitro. STUDY DESIGN: Sera from 199 individuals including controls and acute mumps cases were assessed for mumps specific IgG titres using five different enzyme immunoassays coated with antigen from different mumps virus strains. A subset of 66 sera was also assessed for in vitro neutralizing antibody against a contemporary circulating genotype G5 mumps virus. RESULTS: For all the different antigenic targets, mumps specific IgG titres were higher in patients following acute mumps infection compared to controls. In acute mumps infected patients, females showed significantly higher serum titres of anti-G5 IgG compared to males (p<0.05). Furthermore, control males did not show any change in G5 specific IgG with increasing age whereas females show a progressive rise in titre. Linear regression analysis revealed a significant association between the mumps G5 specific IgG levels in the EIA and the in vitro neutralization titres (r(2)=0.59). CONCLUSIONS: Specific IgG to the current circulating genotype G5 mumps strain showed significantly lower titres in males which supports our previous observation that there is a male gender bias in cases of acute mumps infection. Furthermore, in this preliminary study, the data indicate that genotype G5 specific IgG levels of >40 RU/ml are required for neutralization capability to be observed in vitro.