Moreover, in order to examine relationships between surgery-induced blood leukocyte redistribution profiles and postoperative recovery at specific weeks, we correlated lymphocyte and monocyte redistribution scores with Lysholm scores at Weeks 1 and 24. These time points were chosen because Week 1 represents the start of the recovery trajectory and Week 24 represents the time by which maximum recovery is attained. Lymphocyte redistribution during surgery was significantly and positively correlated with Lysholm scores at Week 1 (r = 0.45, p < 0.001) and Week 24 (r = 0.46, p < 0.001). Monocyte redistribution during surgery was significantly and positively correlated with Lysholm scores at Week 1 (r = 0.28, p < 0.05) but not at Week 24 (r = 0.17, p = 0.233). Figure 2 shows scatter plots for lymphocyte redistribution during surgery and recovery at Week 1 (Fig. 2, A) and Week 24 (Fig. 2, B).
We also examined relationships between surgery-induced lymphocyte, monocyte, and neutrophil redistribution profiles and preoperative and postoperative effusion that served as an index of local inflammation of the affected joint. Chi-square analyses revealed that there were no associations between preoperative levels of effusion and surgery-induced immune cell redistribution (i.e., preoperative effusion scores were not associated with the classification of the patient as a high or low lymphocyte, monocyte, or neutrophil redistributor) (p > 0.05 for all). Interestingly, for the postoperative effusion measure, analyses revealed that high lymphocyte redistributors were more likely to have a significantly lower effusion at Week 1 following surgery (chi square = 4.94, p = 0.026). This was in agreement with the fact that patients who were high lymphocyte redistributors also showed higher Lysholm scores at Week 1, thus showing better recovery as had been hypothesized.
Differences Between Sexes in Immune Cell Redistribution Profiles
There were significant differences between the sexes in immune cell redistribution such that women showed less adaptive redistribution profiles than men did (Table III). For lymphocytes and monocytes, women showed lower mobilization, trafficking, and overall redistribution (p < 0.05), whereas no significant differences were observed between the sexes in terms of neutrophil redistribution.
Differences Between Sexes in Postoperative Recovery
Differences between the sexes in terms of surgical stress-induced immune cell redistribution corresponded with differences between the sexes in terms of recovery following surgery. Women showed lower knee function at baseline as compared with men. We examined whether there were differences between the sexes in the extent of osteoarthritis, but the correlation between sex and articular surface grading scale scores was not significant. Additional mixed-model analyses examining recovery of knee function in the context of sex by leukocyte redistribution interaction effects revealed significant three-way interaction effects for two leukocyte subpopulations: lymphocyte redistributor group × sex × time (F = 3.29, p = 0.02) and monocyte redistributor group × sex × time (F = 1.94, p = 0.05). Follow-up post hoc tests were conducted to determine the nature of these interactions. Figure 3, A and B, presents the estimated average Lysholm scores over time for high and low lymphocyte redistributors stratified according to sex. Post hoc univariate analyses comparing the four groups in Figure 3, A and B, revealed differences between the sexes in the low lymphocyte redistributor group during the early phases of recovery: women who were low lymphocyte redistributors had significantly worse Lysholm scores through postoperative Week 16 than did men who were low lymphocyte redistributors (p < 0.05 across all time points). Both male and female high lymphocyte redistributors showed similar recovery patterns. Among patients of the same sex, low and high lymphocyte redistributors displayed different patterns of recovery. Women who were high lymphocyte redistributors had significantly higher Lysholm scores than did women who were low lymphocyte redistributors at Weeks 3, 8, and 16 (p < 0.05). Men who were high lymphocyte redistributors had significantly higher Lysholm scores than did men who were low lymphocyte redistributors during later recovery (at Weeks 24 and 48) (p < 0.05) but not at earlier time points. This finding indicates that women who were high lymphocyte redistributors showed enhanced early recovery and that men who were high lymphocyte redistributors showed higher maximum knee function. There were no differences in Lysholm scores between women and men who were high lymphocyte redistributors across all postoperative time points. However, women who were low lymphocyte redistributors had significantly lower Lysholm scores through Week 16 than did men who were low lymphocyte redistributors (p < 0.05 at all time points).
Figure 3, C and D, presents the estimated average Lysholm scores over time for high and low monocyte redistributors stratified according to sex. Men and women were divided into high and low monocyte redistributor groups. Post hoc univariate analyses comparing male and female high and low monocyte redistributors revealed that women who were high monocyte redistributors showed significantly enhanced recovery compared with women who were low monocyte redistributors. Men who were high monocyte redistributors showed a similar magnitude of recovery compared with men who were low monocyte redistributors. With the exception of Week 16, women who were high redistributors had significantly higher Lysholm scores than did women who were low redistributors (p < 0.05 for all), whereas no significant differences were observed in the Lysholm scores of men who showed high monocyte redistribution as compared with those who showed low monocyte redistribution. Moreover, women who were low monocyte redistributors had significantly lower Lysholm scores than did men who were low monocyte redistributors (p < 0.02 through postoperative Week 16). By Week 24, women and men who were low monocyte redistributors had comparable Lysholm scores. In contrast, women and men who were high monocyte redistributors had comparable Lysholm scores throughout the entire recovery period. Thus, when lymphocyte and monocyte redistribution is high across both sexes, the difference between the sexes in terms of recovery disappears.
The present study represents the first clinical test of the ability of the stress-induced leukocyte redistribution model to predict the rate and magnitude of recovery following surgery. On the basis of the results of preclinical studies, we hypothesized that patients who show an increase in blood lymphocyte or monocyte numbers early during surgery, and/or a decrease later during surgery, will show enhanced recovery. Our results confirmed this hypothesis. The results of the present study showed that surgical stress-induced leukocyte redistribution can predict (and may partially mediate) inter-individual differences in recovery; specifically, individuals who showed the predefined “adaptive” leukocyte redistribution profile during surgical stress showed higher Lysholm scores following surgery (Figs. 1, 2, and 3). These results also suggest that leukocyte redistribution profiles can predict the observed differences between the sexes in terms of recovery: women showed less adaptive leukocyte redistribution during surgical stress and also showed lower Lysholm scores than men did (Fig. 3).
Immune Cell Redistribution and Recovery from Surgery: Biological Mechanisms
While the findings described here need to be validated and examined mechanistically, taken together with results from numerous preclinical studies12-17,20-23, they suggest that patients who show the predefined “adaptive” profiles of stress-induced immune cell redistribution during surgery also show enhanced wound-healing. Enhanced wound-healing and recovery is likely to be mediated by a cascade of biological events launched when a patient mounts an adaptive fight-or-flight stress response at the time of surgery. Initially, the short-term physiological stress response induces a redistribution of immune cells from their “barracks” (e.g., spleen, bone marrow, and marginated pool) into the “boulevards” (bloodstream). This results in an initial increase in blood leukocyte numbers (mediated largely by norepinephrine and epinephrine) that makes more leukocytes available for recruitment at potential sites of immune activation, including the site of surgery21,22,39. As the physiological stress response progresses, the number of immune cells in the blood decreases (mediated by epinephrine and cortisol) as cells begin to move out of the bloodstream and into potential “battle-stations” (e.g., skin, subcutaneous tissues, sentinel lymph nodes) and actual “battle-stations” (e.g., site of surgery)21,22,39. In addition to increasing leukocyte trafficking, it is also likely that acute stress enhances the functional capacity of leukocytes arriving at the site of surgery12,13,21,22. Thus, the immune response at the site of surgery is optimized and enhanced by the activation of acute stress physiology and mediates more efficient clearance of damaged tissue and/or pathogens during the days following surgery. An optimized immune response also facilitates and promotes enhanced tissue proliferation and remodeling that go on for weeks and months, respectively, following surgery. The net long-term result of an optimized immune and wound-healing response is likely to be reduced scar-tissue formation and improved knee function as reflected in the higher Lysholm scores that were observed in patients who showed “adaptive” immune cell redistribution during the stress of surgery.
It is also noteworthy that women undergoing major orthopaedic procedures (i.e., total hip or knee arthroplasty, laminectomy) tend to have lower preoperative and postoperative function as compared with men26. However, in spite of the prevalence of minimally invasive surgery, little is known about the influence of sex on the variability of outcome. Our results showed that as with major orthopaedic surgery, women as a group demonstrated slower postoperative recovery than men did, even in the case of arthroscopy. Men showed significantly greater surgery-induced mobilization and trafficking of lymphocytes and monocytes (Table III). Interestingly, men also showed significantly enhanced recovery (Fig. 3). Furthermore, while women on the average had worse recovery than men did, recovery in women who were high lymphocyte and monocyte redistributors was comparable with that in men (Fig. 3). Additional research is needed to determine why women in particular showed worse leukocyte redistribution during surgery and impaired recovery following surgery.
Factors mediating inter-individual and sex-related differences in leukocyte redistribution during short-term stressors such as surgery merit additional investigation. Trait differences in genes and in long-term exposure to stress, sex, and other hormones are likely to be important factors. State-dependent differences in relative concentrations of stress hormones (principally epinephrine, norepinephrine, and cortisol) released during surgery are also likely to be important as it has been shown that stress-induced changes in leukocyte distribution are mediated by glucocorticoid and catecholamine hormones13,19,35,40. Although neutrophils and monocytes/macrophages play a prominent role during early stages of wound-healing, lymphocytes are involved in later stages, regulate postoperative healing and angiogenesis, and are thought to be critical for effective and optimized wound-healing41-47. Our data suggest that lymphocyte redistribution profiles during surgery are significant predictors of recovery. These data also raise the possibility that lymphocyte and monocyte redistribution may be trait-like measures and that individuals who show adaptive leukocyte redistribution during stress may also experience the immunological benefits of more efficient mobilization and trafficking during immune surveillance (before and during surgical wounding) and during the proliferation and remodeling phases of wound-healing (during the weeks to months following surgery) and, as a result, show enhanced recovery. Clearly, additional studies are required to elucidate the mechanisms by which surgical stress-induced changes in leukocyte redistribution predict (and may mediate) recovery.
Immune Cell Redistribution and Preoperative and Postoperative Inflammation
Preoperative inflammation is an index of the extent of tissue damage, and, if chronic, may adversely affect postoperative healing independent of the amount of original tissue damage. However, it is important to note that inflammation is also essential for successful wound-healing. An optimum inflammatory response has three characteristics: (1) it is mounted rapidly and robustly (in terms of the numbers and concentrations of immune cells and factors) following wounding, (2) it quickly removes damaged cells and pathogens, and (3) it is resolved efficiently and effectively, with most immune cells leaving the site of inflammation within days after wounding to pave the way for the proliferative and remodeling phases of the wound-healing cascades. With use of a measure of joint effusion as an index of inflammation, our study revealed that preoperative effusion was not related to immune cell redistribution during surgery, suggesting that the magnitude of preexisting joint inflammation did not affect the magnitude or profile of leukocyte redistribution during surgery. Interestingly, we observed that patients who showed higher lymphocyte redistribution during surgery correspondingly showed lower levels of effusion one week following surgery, suggesting a faster resolution of postoperative inflammation, which may have contributed to the more efficient recovery that was also observed for high lymphocyte redistributors.
Stress and Surgery
At first glance, the results described here may appear to go against the widespread expectation that stress should inhibit rather than enhance postoperative recovery. This expectation is likely to arise because numerous studies have shown that distress suppresses or dysregulates various aspects of immune function8-11 and also impairs wound-healing48,49. It becomes clear that our results complement rather than contradict the well-known immunosuppressive/dysregulatory effects of stress as soon as one distinguishes the short-term, adaptive, fight-or-flight stress response from long-term, maladaptive, chronic stress or distress12. Studies showing stress-induced immunosuppression/dysregulation have examined largely chronic stressors, and studies involving acute stressors have not accounted for stress effects on leukocyte distribution. Acute stressors have been shown to induce large changes in immune cell trafficking and function that lead to robust enhancements in innate, adaptive, primary, and secondary immune responses12,14,16-21,24,25. It has been proposed that the acute stress response is one of nature's fundamental survival mechanisms, without which neither predator nor prey could stay alive12,18. It has been argued that just as this response prepares the musculoskeletal, cardiovascular, and neuroendocrine systems for fight-or-flight situations, it similarly prepares the immune system for responding to challenges such as wounding or infection that may arise due to the actions of a stressor (e.g., an attack by a lion, or a surgical procedure)13,18,20.
At first glance, these findings may call into question the usefulness of stress-reduction procedures administered prior to surgery. Although additional studies are required, we propose that a reduction in chronic stress levels is likely to have beneficial effects because preclinical studies have suggested that a reduction of chronic stress may increase the magnitude of adaptive, short-term stress responses and their salubrious or health-promoting effects20. In agreement with these findings, clinical studies have shown that, in comparison with controls, patients undergoing abdominal surgery who had been given preoperative relaxation instructions showed decreased anxiety before and after surgery but more robust cortisol and epinephrine responses (physiological indicators of a stronger acute stress response) during surgery50. Importantly, studies have shown that patients who scored higher for trait anxiety or Type-A personality (likely to result in higher levels of chronic stress) showed lower cortisol and epinephrine responses (indicating a weaker acute stress response) during abdominal surgery51. Therefore, interventions that reduce chronic stress and optimize acute stress at the time of surgery or immune activation are likely to be beneficial.
Strengths, Weaknesses, and Future Directions
The strengths of the present study include the widely used surgical model, the prospective longitudinal design, the specific patient population, and the objective measure of recovery. This study also addresses an important gap in research because there has been limited prospective research on musculoskeletal injury and surgical recovery that has taken a comprehensive approach to identifying preoperative determinants of postoperative outcomes. A major strength is the support that the present study provides for the novel idea that the acute stress response is one of nature's fundamental survival mechanisms that may be clinically harnessed (see below) to enhance protective immunity during surgery. A major contribution comes from the fact that the findings described here could lead to the use of patient profiles of leukocyte redistribution during surgery as prognostic indicators of recovery and to the development of biobehavioral and pharmacological interventions designed to manipulate leukocyte redistribution during surgery in a way that maximizes postoperative healing and recovery. A weakness of the present study is the absence of biological measurements at the site of surgery that would help to identify specific cellular and molecular mediators of enhanced recovery. Another weakness involves the correlational nature of our findings because correlation does not prove causation. However, given the substantial amount of preclinical data on which our leukocyte redistribution model was based, it is likely that surgical stress-induced changes in leukocyte distribution at least partially mediate recovery. There are also several issues pertinent to this study that merit future investigation. First, the present study suggests that age may be inversely related to recovery, although the association did not reach significance. Therefore, it would be useful for future studies to be designed to examine the effects of age on acute stress-induced leukocyte redistribution and its relationship to recovery following surgery. However, the important finding of the present study is that when age and immune cell redistribution were included in the model, immune cell redistribution variables were significantly associated with recovery but age was not. Second, although we attempted to keep anesthesia conditions as uniform as possible among patients, future studies should be powered to quantify the potential effects of the type of anesthetic agent and the depth of anesthesia on immune cell redistribution. Third, additional research is required to determine the psychological, physiological, and immunological mediators of acute stress-induced changes in leukocyte redistribution and the acute stress-induced enhancement of postoperative recovery.
Replicating and validating these findings is a necessary and important step toward clinical application. Once that is done, there are several ways (all of which require additional validation) in which these findings could enhance clinical practice. First, given how inexpensive and straightforward it is to quantify blood leukocyte numbers, surgeons could monitor changes in leukocyte distribution during surgery. This would provide information instantaneously during surgery about whether additional intraoperative or postoperative intervention is indicated to enhance recovery, especially for patients who show a maladaptive immune cell redistribution. Second, the principal stress hormones that are known to mediate stress-induced changes in leukocyte distribution (epinephrine, norepinephrine, and cortisol)13,18,19,21,22,35,52 could be administered at specific times during surgery to induce “adaptive” leukocyte redistribution in patients who fail to show an adaptive response. Third, the identification of mechanisms mediating adaptive as opposed to maladaptive leukocyte redistribution during stress would enable the development of pharmacological or biobehavioral interventions designed to maximize adaptive surgical stress-induced leukocyte redistribution and the related enhancement of postoperative recovery. Fourth, we hypothesize that the ability to mount adaptive immune cell redistribution responses during stress may be a characteristic that is expressed in a similar manner across different stressors. If this hypothesis is confirmed, it would open the possibility of prospectively identifying patients who are likely to show adaptive as opposed to maladaptive stress-induced changes in immune cell distribution through the administration of an appropriately designed stress test before surgery. Such prospective identification coupled with the interventions mentioned above could maximize the probability of a patient showing adaptive leukocyte redistribution during surgery, leading to enhanced recovery following surgery.
The present study identifies potential mediators of the well-known, but hard-to-explain, observation that patients with similar demographic, physical, and clinical characteristics often show large differences in the rate and extent of postoperative recovery. Our results may be applicable to a wide range of surgical procedures because the physiological stress response that is known to drive stress-induced changes in immune cell distribution13,14,16,19,21,22,35,40 is likely to be similar during different types of surgery. The present study lays the foundation for prospectively identifying patients who are likely to show low as opposed to high leukocyte redistribution during surgery and for designing psychological, biobehavioral, and pharmacological interventions to maximize the rate and extent of recovery. The important personal and economic benefits of enhanced recovery include reduced morbidity, fewer days lost from work or sports activities, more complete and long-lasting return to sports and life activities, reduced risk of reinjury, and reduced individual and societal health-care costs.
NOTE: Firdaus S. Dhabhar designed the immunological aspects of the study, formulated and operationalized leukocyte redistribution concepts, guided and interpreted analyses, and wrote the manuscript. Patricia H. Rosenberger was Project Director, conducted and interpreted statistical analyses with guidance from Trace Kershaw, and wrote the initial draft of the manuscript. Jeannette R. Ickovics was Principal Investigator and oversaw study design and conduct. Jean M. Tillie and Firdaus S. Dhabhar made all immunological measurements. Elissa Epel played a substantial role in study design, operationalization of leukocyte redistribution concepts, data analyses, interpretation, and writing. Eric Nadler assisted with initial data analysis. Peter Jokl was the Medical Director of the study, performed operations, evaluated patients in the immunology sub-study as well as the parent study, and was centrally responsible for implementation and clinical oversight. John P. Fulkerson performed operations and evaluated patients for the parent study. All authors contributed to manuscript review and editing. Funding for this research came from NIAMS (RO1-AR-46299). The authors are grateful to Dr. Trace Kershaw for help and guidance with statistical analyses.
A commentary by Martin I. Boyer, MD, MSc, FRCS(C), is available at www.jbjs.org/commentary and as supplemental material to the online version of this article.
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from NIH-NIAMS RO1-AR-46299. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Department of Orthopaedics and Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut; Department of Psychiatry, University of California San Francisco, San Francisco; and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
1. Schappert SM. Ambulatory care visits of physician offices, hospital outpatient departments, and emergency departments: United States, 1995. Vital Health Stat 13. 1997;129:1-38.
2. Rosenberger PH, Jokl P, Ickovics JR. Psychosocial factors and surgical outcome: an evidence-based literature review. J Am Acad Orthop Surg. 2006;14:397-405.
3. Schimmer RC, Brülhart KB, Duff C, Glinz W. Arthroscopic partial meniscectomy: a 12-year follow-up and two-step evaluation of the long-term course. Arthroscopy. 1998;14:136-42.
4. Daniel DM. Selecting patients for ACL surgery. In: Jackson DW, Arnoczky SP, Woo SL-Y, Frank CB, Simon TM. The anterior cruciate ligament. Current and future concepts. New York: Raven Press; 1993. p 251-8.
5. McConville OR, Kipnis JM, Richmond JC, Rockett SE, Michaud MJ. The effect of meniscal status on knee stability and function after anterior cruciate ligament reconstruction. Arthroscopy. 1993;9:431-9.
6. Swenson TM, Harner CD. Knee ligament and meniscal injuries. Current concepts. Orthop Clin North Am. 1995;26:529-46.
7. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171-9.
8. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243-51.
9. Coe CL, Laudenslager ML. Psychosocial influences on immunity, including effects on immune maturation and senescence. Brain Behav Immun. 2007;21:1000-8.
10. Irwin MR. Human psychoneuroimmunology: 20 years of discovery. Brain Behav Immun. 2008;22:129-39.
11. Butts CL, Sternberg EM. Neuroendocrine factors alter host defense by modulating immune function. Cell Immunol. 2008;252:7-15.
12. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16:300-17.
13. Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Effects of stress on immune cell distribution. Dynamics and hormonal mechanisms. J Immunol. 1995;154:5511-27.
14. Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol. 1996;156:2608-15.
15. Viswanathan K, Dhabhar FS. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Natl Acad Sci U S A. 2005;102:5808-13.
16. Dhabhar FS, Viswanathan K. Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory. Am J Physiol Regul Integr Comp Physiol. 2005;289:R738-44.
17. Viswanathan K, Daugherty C, Dhabhar FS. Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity. Int Immunol. 2005;17:1059-69.
18. Dhabhar FS, McEwen BS. Bidirectional effects of stress on immune function: possible explanations for salubrious as well as harmful effects. In: Ader R, editor. Psychoneuroimmunology. 4th ed. Boston: Elsevier; 2007. p 723-60.
19. Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Stress-induced changes in blood leukocyte distribution. Role of adrenal steroid hormones. J Immunol. 1996;157:1638-44.
20. Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses immune function in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11:286-306.
21. Dhabhar FS. Stress-induced enhancement of cell-mediated immunity. Ann N Y Acad Sci. 1998;840:359-72.
22. Dhabhar FS, McEwen BS. Bidirectional effects of stress and glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology. 3rd ed. San Diego: Academic Press; 2001. p 301-38.
23. Dhabhar FS, McEwen BS, Spencer RL. Adaptation to prolonged or repeated stress—comparison between rat strains showing intrinsic differences in reactivity to acute stress. Neuroendocrinology. 1997;65:360-8.
24. Bilbo SD, Dhabhar FS, Viswanathan K, Saul A, Yellon SM, Nelson RJ. Short day lengths augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune function. Proc Natl Acad Sci U S A. 2002;99:4067-72.
25. Saint-Mezard P, Chavagnac C, Bosset S, Ionescu M, Peyron E, Kaiserlian D, Nicolas JF, Bérard F. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol. 2003;171:4073-80.
26. Katz JN, Wright EA, Guadagnoli E, Liang MH, Karlson EW, Cleary PD. Differences between men and women undergoing major orthopedic surgery for degenerative arthritis. Arthritis Rheum. 1994;37:687-94.
27. Cameron ML, Briggs KK, Steadman JR. Reproducibility and reliability of the Outerbridge classification for grading chondral lesions of the knee arthroscopically. Am J Sports Med. 2003;31:83-6.
28. Tegner Y, Lysholm J. Rating systems in the evaluation of knee ligament injuries. Clin Orthop Relat Res. 1985;198:43-9.
29. Weitzel PP, Richmond JC. Critical evaluation of different scoring systems of the knee. Sports Med Arthrosc. 2002;10:183-90.
30. Hoser C, Fink C, Brown C, Reichkendler M, Hackl W, Bartlett J. Long-term results of arthroscopic partial lateral meniscectomy in knees without associated damage. J Bone Joint Surg Br. 2001;83:513-6.
31. Kartus JT, Russell VJ, Salmon LJ, Magnusson LC, Brandsson S, Pehrsson NG, Pinczewski LA. Concomitant partial meniscectomy worsens outcome after arthroscopic anterior cruciate ligament reconstruction. Acta Orthop Scand. 2002;73:179-85.
32. Rosenberger PH, Ickovics JR, Epel ES, D'Entremont D, Jokl P. Physical recovery in arthroscopic knee surgery: unique contributions of coping behaviors to clinical outcomes and stress reactivity. Psychol Health. 2004;19:307-20.
33. Marx RG, Jones EC, Allen AA, Altchek DW, O'Brien SJ, Rodeo SA, Williams RJ, Warren RF, Wickiewicz TL. Reliability, validity, and responsiveness of four knee outcome scales for athletic patients. J Bone Joint Surg Am. 2001;83:1459-69.
34. Ceddia MA, Price EA, Kohlmeier CK, Evans JK, Lu Q, McAuley E, Woods JA. Differential leukocytosis and lymphocyte mitogenic response to acute maximal exercise in the young and old. Med Sci Sports Exerc. 1999;31:829-36.
35. Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996;10:77-91.
36. Gibbons RD, Hedeker D, Elkin I, Waternaux C, Kraemer HC, Greenhouse JB, Shea MT, Imber SD, Sotsky SM, Watkins JT. Some conceptual and statistical issues in analysis of longitudinal psychiatric data. Application to the NIMH treatment of Depression Collaborative Research Program dataset. Arch Gen Psychiatry. 1993;50:739-50.
37. Donner A, Klar N. Statistical considerations in the design and analysis of community intervention trials. J Clin Epidemiol. 1996;49:435-9.
38. Murray DM. Design and analysis of group-randomized trials. New York: Oxford University Press; 1998.
39. Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking. Ann N Y Acad Sci. 2000;917:876-93.
40. Miller AH, Spencer RL, Hassett J, Kim C, Rhee R, Ciurea D, Dhabhar F, McEwen B, Stein M. Effects of selective type I and II adrenal steroid agonists on immune cell distribution. Endocrinology. 1994;135:1934-44.
41. Fishel RS, Barbul A, Beschorner WE, Wasserkrug HL, Efron G. Lymphocyte participation in wound healing. Morphologic assessment using monoclonal antibodies. Ann Surg. 1987;206:25-9.
42. Schäffer M, Barbul A. Lymphocyte function in wound healing and following injury. Br J Surg. 1998;85:444-60.
43. Shimaoka M, Hosotsubo K, Sugimoto M, Sakaue G, Taenaka N, Yoshiya I, Kiyono H. The influence of surgical stress on T cells: enhancement of early phase lymphocyte activation. Anesth Analg. 1998;87:1431-5.
44. Stabile E, Kinnaird T, la Sala A, Hanson SK, Watkins C, Campia U, Shou M, Zbinden S, Fuchs S, Kornfeld H, Epstein SE, Burnett MS. CD8+ T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4+ mononuclear cells through the expression of interleukin-16. Circulation. 2006;113:118-24. Erratum in: Circulation. 2006;113:e711.
45. Efron JE, Frankel HL, Lazarou SA, Wasserkrug HL, Barbul A. Wound healing and T-lymphocytes. J Surg Res. 1990;48:460-3.
46. Kloth LC, McCulloch JM. Wound healing: alternatives in management. 3rd ed. Philadelphia: FA Davis; 2002. p 568.
47. Boyce DE, Jones WD, Ruge F, Harding KG, Moore K. The role of lymphocytes in human dermal wound healing. Br J Dermatol. 2000;143:59-65.
48. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R. Slowing of wound healing by psychological stress. Lancet. 1995;346:1194-6.
49. Broadbent E, Petrie KJ, Alley PG, Booth RJ. Psychological stress impairs early wound repair following surgery. Psychosom Med. 2003;65:865-9.
50. Manyande A, Chayen S, Priyakumar P, Smith CC, Hayes M, Higgins D, Kee S, Phillips S, Salmon P. Anxiety and endocrine responses to surgery: paradoxical effects of preoperative relaxation training. Psychosom Med. 1992;54:275-87.
51. Salmon P, Pearce S, Smith CC, Manyande A, Heys A, Peters N, Rashid J. Anxiety, type A personality and endocrine responses to surgery. Br J Clin Psychol. 1989;28(Pt 3):279-80.
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52. Fauci AS, Dale DC. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest. 1974;53:240-6.