HomeLarge Type Edition
HOME ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
PubMed
Right arrow PubMed Citation
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:1053-1058 (2006)
© 2006 The Gerontological Society of America

Persistent Changes in Interleukin-6 and Lower Extremity Function Following Hip Fracture

Ram R. Miller, Anne R. Cappola, Michelle D. Shardell, William G. Hawkes, Janet A. Yu-Yahiro, J. Richard Hebel and Jay Magaziner

Divisions of 1 Gerontology and 2 Biostatistics & Bioinformatics of the Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore.
3 Division of Endocrinology, Diabetes, and Metabolism and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia.
4 Department of Orthopedic Surgery, The Union Memorial Hospital, Baltimore, Maryland.

Address correspondence to Ram R Miller, MDCM, MSc, University of Maryland, School of Medicine, Division of Gerontology, Department of Epidemiology and Preventive Medicine, 660 W. Redwood St., Suite 200, Baltimore, MD 21201. E-mail: rrmiller{at}epi.umaryland.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. A hip fracture often heralds a period of functional decline in elderly persons. Although an inflammatory reaction would be expected following a hip fracture, whether the degree of this response is associated with adverse functional outcomes is unknown.

Methods. In a cohort from the Baltimore Hip Studies, women aged 65 years or older with a hip fracture were evaluated at 3 or 10 days (baseline) and 2, 6, and 12 months (follow-up) postfracture. Serum was analyzed for interleukin-6 (IL-6) level. A score of timed performance of 9 tasks, the Lower Extremity Gain Scale (LEGS) was calculated at each evaluation. We divided participants into tertiles based on their cytokine levels at 2, 6, and 12 months, and examined the LEGS score trajectories as a function of IL-6 tertile using generalized estimating equations, adjusting for age, prefracture function, body fat, pain, cognitive function, type of surgical repair, the number of in-hospital complications, and the number of comorbid medical conditions.

Results. At baseline, 2, 6, and 12 months, respectively, 149, 95, 101, and 82 participants provided serum samples; of these participants 65, 78, and 59 also provided a LEGS measure at 2, 6, and 12 months, respectively. At 12 months postfracture the median (interquartile range) of serum IL-6 levels was 7.4 (4.0, 15.9) pg/mL. Participants in the lowest tertile of IL-6 level performed better on the LEGS than did those in the highest tertile (p =.008). At 12 months postfracture, participants in the lowest tertile scored 5.3 points better (95% confidence interval, 2.0-8.6) on the LEGS than did those in the highest tertile (p =.002).

Conclusions. Higher IL-6 levels are adversely associated with recovery of lower extremity function after hip fracture. Factors that predict cytokine response and the potential mechanisms by which this effect is mediated warrant further study.

A hip fracture often portends a period of increased functional decline and disability, in disproportion to what would be expected in frail elderly persons (1). Recently, the association of chronic inflammatory processes with functional decline in the elderly population has garnered increased attention (2,3). Markers of chronic inflammation have been associated with sarcopenia, decreased strength, and the frailty syndrome (4–6). A hallmark of the frailty syndrome is the limited ability to recover from physiologic stressors. Whether persistent changes in inflammatory cytokines that might accompany such stressors influence this recovery is not known. Although an inflammatory reaction would be expected following a traumatic event such as hip fracture, we hypothesized that an exaggerated response would be associated with adverse functional outcomes.

We examined a cohort of women admitted to two Baltimore area hospitals between 1992 and 1995 who were enrolled in the Baltimore Hip Studies (BHS). Women 65 years old and older were followed for a year after hip fracture, to evaluate whether serum levels interleukin-6 (IL-6) after hip fracture are associated with an adverse effect on function.


   METHODS
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Participants were drawn from the third cohort in the BHS (BHS-3). Between 1992 and 1995, 205 Caucasian women, at least 65 years old, admitted to one of two hospitals in Baltimore with a new fracture of the proximal femur agreed to participate in a prospective study. Participants were evaluated at 3 or 10 days (baseline) and at 2, 6, and 12 months posthospitalization for fracture (follow-up). Women with a history of rheumatoid arthritis, systemic lupus erythematosus, or scleroderma were excluded from the analyses as these individuals could have abnormal cytokine levels and poor function unrelated to hip fracture. A more detailed description of this cohort may be found elsewhere (7).

Measure of Function
Timed performance of 9 lower extremity tasks was assessed at each evaluation: (i) reach for an item on the ground from a sitting position; (ii) put a sock on the fractured-side foot; (iii) put a shoe on the fractured-side foot; (iv) rise from an armless chair; (v) walk 10 feet; (vi) step up four steps; (vii) step down four steps; (viii) get on the toilet; and (ix) get off the toilet. Performance of these tasks was scored on a scale of 0–4 to create a summary score of lower extremity function, the Lower Extremity Gain Scale (LEGS). This score ranges from 0 to 36, with higher scores indicating better performance. It has been shown to be a reliable measure, and the domains that it assesses have been identified by hip fracture patients and their caregivers (surgeons, physical therapists, and family) as important aspects of functioning (8). In the year following hip fracture, 85-year-old participants had LEGS scores that were on average 2.6 points lower than those of participants aged 80–85 years (9).

IL-6 Measurement
The methods for the collection and storage of the serum samples have been described in detail elsewhere (10). IL-6 levels were measured by two-antibody enzyme-linked immunosorbent assay (ELISA) using biotin–streptavidin–peroxidase detection and commercially available human antibodies (Pierce/Endogen, Rockford, IL). The linear range for the IL-6 assay was 1.5–100 pg/mL. Cytokine measurements above the detection limit for the assay were converted to the highest level of the assay, and measurements below the detection limit were scored as zero. One hundred forty-nine participants provided serum samples at baseline; 95, 101, and 82 participants provided serum samples at 2, 6, and 12 months, respectively. Some participants who did not provide a serum sample at baseline provided one during follow-up.

Covariates
Age, type of surgical repair (internal fixation vs arthroplasty), and presence or absence of 20 noninfectious and 3 infectious in-hospital complications were collected from the hospital record. Because infection is associated with elevated inflammatory cytokine levels (11), infectious and noninfectious in-hospital complications were tabulated separately. The list of potential complications appears in the Appendix. The presence, prior to the fracture, of osteoarthritis, coronary artery disease (history of either angina pectoris, cardiovascular disease, or myocardial infarction), congestive heart failure, stroke, dementia, diabetes, chronic obstructive pulmonary disease, and peripheral vascular disease was collected from the hospital record. These conditions were chosen because they have been observed to be associated with an adverse effect on functional recovery in elderly persons (12). Fat tissue mass (FTM) and lean body mass (LBM) were estimated using a method described in detail elsewhere that uses dual-energy x-ray absorptiometry (DXA) (Hologic, Inc., Waltham, MA) (7). Percent body fat was calculated as FTM / (FTM + LBM). At each visit, participants were asked about pain symptoms during the previous week. Mental status was assessed using the Mini-Mental State Examination (MMSE) (13). At the baseline evaluation, participants reported on their prefracture limitations with 11 Activities of Daily Living requiring lower extremity functioning (LE-ADLs). A score of LE-ADL function was calculated as the number of activities in which the person was impaired (required either human or equipment assistance or both or completely unable to perform). The 11 activities included were walking 10 feet or across a room; walking 1 block on a level sidewalk; climbing five stairs; getting into a car; getting into and out of bed; rising from an armless chair; putting on pants; putting socks and shoes on both feet; getting in/out of a bath or shower; taking a bath, shower, or sponge bath; and getting on and off the toilet. The scale thus ranges from 0 to 11, with higher scores representing greater prefracture impairment. Proxy data were used when patient data were unavailable or when the patient was cognitively impaired (MMSE score < 17).


View this table:
[in this window]
[in a new window]
  		APPENDIX .

 
Statistical Analyses
Participants were divided into tertile groups based on their serum IL-6 levels at each time point of the follow-up period (low tertile: IL-6 ≤ 5.63, middle tertile 5.63 < IL-6 ≤ 14.30, and high tertile IL-6 > 14.30 pg/mL), in a manner similar to other cohort studies of elderly persons (14,15).

Patient characteristics were compared between those observed and those missing at 12 months after hip fracture using Fisher's exact test or the chi-square test (for categorical and dichotomous variables) and two-sample t tests (for continuous variables). Generalized estimating equations (GEE) (16) were used to model the longitudinal relationship between IL-6 category and LEGS using a normal working model and robust standard errors to account for correlations across time within individuals. Generalized F tests were used to compare LEGS trajectories between those in the mid-level and high IL-6 categories to the lowest (reference) IL-6 category, and time-specific t tests were performed when a significant difference (p <.05) between LEGS trajectories was observed. The models were adjusted for age, comorbidity, type of surgical repair, postsurgical complications, infections, percent body fat, prefracture LE-ADL score, MMSE score, and pain.

The validity of GEE results are contingent on missing data being missing completely at random (MCAR) as defined by Rubin (17). A sensitivity analysis of the MCAR assumption using weighted estimating equations (WEEs) was performed (18). The weights were calculated by performing a logistic regression of observing both IL-6 and LEGS (yes or no) on the covariates used in the analysis model for each visit.

Selection into this study by providing serum to assay and subsequent missing data among study participants could potentially lead to a biased subsample relative to the initial 205 BHS-3 participants. To further compare the 149 participants who provided serum at baseline to the 56 who did not, two-sample t tests were performed to contrast 12-month LEGS between participants who did and did not provide serum at baseline in the group of those with a LEGS score at 12 months. Two-sample t tests were also performed to compare baseline LEGS and IL-6 between participants observed and missing at 12 months in the group of those who provided serum at baseline.


   RESULTS
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Characteristics of the study sample appear in Table 1. Mean age (standard deviation) was 81.0 years (7.8 years). All participants were white. Twenty-seven participants died during the follow-up period. Women included in the analysis at 12-month follow-up were, on average, younger and performed better on the MMSE than women with incomplete 12-month data for the analyses presented here. Otherwise, no significant differences existed between participants with complete and missing data at 12 months postfracture.


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics of the Study Population.

 
With respect to LEGS score at baseline (p =.19) and at 12 months (p =.93), additional analyses showed that participants who provided serum for IL-6 analyses did not differ from participants who did not provide serum. Furthermore, IL-6 levels at baseline did not differ between participants who provided serum at 12 months postfracture and participants who did not (p =.89).

The median and interquartile ranges for IL-6 at each evaluation are displayed in Figure 1. Cytokine levels were highest at baseline, declined by the 2-month examination, with a more gradual decline in median levels thereafter. At the baseline, 2-month, 6-month, and 12-month examinations 13%, 7%, 5%, and 5%, respectively, of the IL-6 measurements were above the assay limit and 0%, 1%, 3%, and 5% were below the detection limit for the assay. At 12 months postfracture, the median (interquartile range) of serum IL-6 levels was 7.4 (4.0–15.9) pg/mL.


Figure 01
View larger version (5K):
[in this window]
[in a new window]
  		Figure 1. Median value and inter-quartile range for serum IL-6 concentration at each time point

 
Due to the proximity of the baseline evaluation to the hip fracture surgery, only 56 participants attempted the LEGS measurements at baseline (data not shown). Over the 2- to 12-month follow-up period, the adjusted mean LEGS score was lowest at 2 months for all IL-6 tertile groups, and increased throughout the follow-up period (Figure 2). Participants in the middle IL-6 tertile displayed a marginally significantly (p =.10) worse LEGS performance over the 2- to 12-month follow-up period than did participants in the lowest tertile. Women in the highest IL-6 tertile had a significantly worse LEGS trajectory than did women in the lowest tertile (p =.008). At 12-months after hip fracture, on average, participants in the lowest IL-6 tertile scored 5.3 points better (95% confidence interval, 2.0-8.6) on the LEGS than did participants in the highest tertile (p =.002). The sensitivity analysis yielded similar results and the same conclusions as the GEE analysis (data not shown).


Figure 02
View larger version (11K):
[in this window]
[in a new window]
  		Figure 2. Adjusted* mean Lower Extremity Gain Scale (LEGS) scores at 2, 6, and 12 months by interleukin-6 (IL-6) tertile. *Adjusted for age, the number of comorbid medical conditions at baseline, type of surgical repair, the total number of infectious in-hospital complications, the total number of noninfectious in-hospital complications, percent body fat, prefracture lower extremity function, Mini-Mental State Examination score, and recent pain

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We found that IL-6 levels increase following hip fracture and then decrease over the subsequent year. However, up to 12 months postfracture, serum IL-6 levels appear to remain elevated, with median IL-6 levels of 7.4 pg/mL. Higher levels of these cytokines, especially at 1 year postfracture, are associated with poorer lower extremity function, as measured by timed performance. Results of previous studies have documented a relationship between inflammation and functional decline in elderly persons (2,3,19); however, to our knowledge, this is the first study to examine this relationship following an acute traumatic and debilitating event (hip fracture).

Aging is associated with increased levels of circulating inflammatory cytokines (20). In older adults, peak cytokine concentrations following a stimulus are comparable to those in younger individuals (21); however, compared to younger individuals, elderly persons may have a prolonged inflammatory response with slower normalization of cytokine levels (21,22). Inflammatory cytokine levels have been observed to increase following trauma and surgery, including following hip fracture (23,24). In the extreme, this inflammatory response may be associated with serious immediate consequences such as multisystem organ failure, adult respiratory distress syndrome, and sepsis syndrome (25,26). Although comparison of cytokine levels across studies may be problematic due to laboratory technique variations, we observed peak IL-6 levels comparable to those previously reported in younger persons following femoral fracture repair (27) and in elderly patients following abdominal surgery (23). However, in this cohort of older women after hip fracture, IL-6 levels remained higher at 1 year postfracture than levels observed in a cohort of frail elderly women who had not suffered a hip fracture (28). Furthermore, the consequences of this inflammatory response may be long lived, as those individuals whose IL-6 levels remained high also experienced the poorest lower extremity functional recovery over the subsequent year. Based on our analyses, this relationship is unlikely to be due to age, pain, comorbidities, or in-hospital complications. If inflammatory processes do in fact play a role in functional decline and the onset or acceleration of frailty (3,6), then our results would suggest that a persistent inflammatory response might contribute to the decline in health and physical function that is frequently observed following hip fracture (1).

We are beginning to develop a better understanding of the mechanisms by which inflammation might adversely affect physical function in elderly persons. Remote inflammatory processes, such as cancer, congestive heart failure, arthritis, and chronic obstructive pulmonary disease, have long been observed to be associated with muscle catabolism and loss of muscle function, which have been attributed to circulating cytokines (29,30). Inflammation can contribute to muscle weakness by two main mechanisms: accelerated protein loss and contractile dysfunction (29). The catabolic effect on muscle protein has been strongly linked to tumor necrosis factor-alpha (TNF-{alpha}) (31). In addition, the inflammatory response can also suppress insulin-like growth factor 1 (IGF-1) production and activity, which similarly results in decreased muscle mass (32,33). These hormonal changes have been observed to be associated with adverse effects on function in elderly persons (3). Furthermore, muscle weakness has been found to occur without overt loss of muscle protein (34), suggesting that inflammation may result in changes intrinsic to the muscle itself. In fact, inflammatory cytokines have been associated with altered contractile protein composition and contractile dysfunction in laboratory animals and humans (35,36).

Although our results suggest that inflammatory processes may be associated with physical function following hip fracture, what is less clear is whether specific interventions might have an impact on this relationship. Exercise, a mainstay of hip fracture rehabilitation, has been shown to be associated with decreased levels of inflammatory markers (37). In addition to their effect on lipids, hydroxymethylglutaryl-coenzyme A reductase inhibitors have garnered significant attention for their ability to reduce markers of inflammation in vascular disease (38). Observational studies have also suggested that, despite little effect on bone mineral density, hip fracture risk is lower in women taking these medications (39). Whether the anti-inflammatory effects of these agents also offer any promise for enhancing recovery following hip fracture is unknown. There is evidence that certain orthopedic surgical techniques may result in a greater inflammatory response than others (40). It has even been suggested that, despite the superior skeletal stabilization offered by some of these techniques, under certain circumstances they should be avoided to reduce the inflammatory response and possible consequences such as adult respiratory distress syndrome (40). Our data suggest that the reduction in the inflammatory response could potentially offer a longer term benefit for functional recovery and provide another rationale for modification of surgical technique in certain cases.

Although these results are interesting, they must be viewed with the following limitations in mind. We have no data on the inflammatory cytokine levels prior to the hip fracture, and were therefore unable to assess whether prefracture cytokine levels are predictive of the postfracture response and the associations we observed. In addition, a proportion of study participants had cytokine levels beyond the range of the assays used. Also, due to selective forces, serum samples at later evaluations were obtained from younger women with less comorbidity, compared to the cohort as a whole at baseline. Participants with incomplete data had greater prefracture functional limitations and cognitive impairment at baseline; therefore, participants included in the analysis represent the healthiest subset of the initial cohort, suggesting that, if anything, our estimates are attenuated relative to the true association between IL-6 and LEGS. Also, we had limited information on medical and surgical complications after the initial hospitalization for hip fracture; therefore, we are unable to assess whether the associations that we observed are mediated by a more complicated recovery course. Finally, all of the participants included in these analyses were white women; thus we are unable to assess whether similar associations exist in men or in women of other ethnicities.

Summary
We have found that serum levels of the inflammatory cytokine IL-6 remain high up to 1 year after hip fracture and that higher levels of IL-6 12 months postfracture are associated with poorer recovery in lower extremity function. These results suggest that persistent inflammation might contribute to the decline in health and physical function that is frequently observed following hip fracture. Factors that predict an adverse cytokine response and the potential mechanisms by which this response is mediated warrant further study.


   Acknowledgments
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
This work was supported by grants from the National Institutes of Health (R37 AG09901, K23 AG019161, and P60 AG12583 -Claude D. Pepper Older Americans Independence Center (OAIC) Junior Faculty Award to Dr. Miller.) Cytokine assay analyses were supported by a University of Maryland School of Medicine Intramural Award.

This work was presented in abstract form at the 2005 meeting of The American Geriatrics Society.


   Footnotes
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Decision Editor: Luigi Ferrucci, MD, PhD

Received September 14, 2005

Accepted April 18, 2006


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Magaziner J, Fredman L, Hawkes W, et al. Changes in functional status attributable to hip fracture: a comparison of hip fracture patients to community-dwelling aged. Am J Epidemiol. 2003;157:1023-1031.[Abstract/Free Full Text]
  2. Reuben DB, Cheh AI, Harris TB, et al. Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. J Am Geriatr Soc. 2002;50:638-644.[Medline]
  3. Cappola AR, Xue QL, Ferrucci L, Guralnik JM, Volpato S, Fried LP. Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab. 2003;88:2019-2025.[Abstract/Free Full Text]
  4. Payette H, Roubenoff R, Jacques PF, et al. Insulin-like growth factor-1 and interleukin-6 predict sarcopenia in very old community-living men and women: the Framingham Study. J Am Geriatr Soc. 2003;51:1237-1243.[Medline]
  5. Cesari M, Penninx BWJH, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol Biol Sci Med Sci. 2004;59A:242-248.
  6. Walston J, McBurnie MA, Newman A, et al. Frailty and activation of inflammation and coagulation systems with and without clinical comorbidities. Arch Intern Med. 2002;162:2333-2341.[Abstract/Free Full Text]
  7. Fox KM, Magaziner J, Hawkes WG, et al. Loss of bone density and lean body mass after hip fracture. Osteoporos Int. 2000;11:31-35.[Medline]
  8. Zimmerman S, Hawkes WG, Hebel JR, Fox KM, Lydick E, Magaziner J. The Lower Extremity Gain Scale: a performance-based measure to assess recovery after hip fracture. Arch Phys Med Rehabil. 2006;87:430-436.[Medline]
  9. Hawkes WG, Williams GR, Zimmerman S, et al. A clinically meaningful difference was generated for a performance measure of recovery from hip fracture. J Clin Epidemiol. 2004;57:1019-1024.[Medline]
  10. YuYahiro J, Michael RH, Dubin NH, et al. Serum and urine markers of bone metabolism during the year after hip fracture. J Am Geriatr Soc. 2001;49:877-883.[Medline]
  11. Scherer MA, Neumaier M, von Gumppenberg S. C-reactive protein in patients who had operative fracture treatment. Clin Orthop. 2001;393:287-293.
  12. Miller RR, Zhang Y, Silliman RA, et al. Effect of medical conditions on improvement in self-reported and observed functional performance of elders. J Am Geriatr Soc. 2004;52:217-223.[Medline]
  13. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental state" – A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.[Medline]
  14. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506-512.[Medline]
  15. Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol. 2001;8:131-136.[Medline]
  16. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13-22.[Abstract/Free Full Text]
  17. Rubin DB. Inference and missing data. Biometrika. 1976;63:581-592.[Abstract/Free Full Text]
  18. Robins JM, Rotnitzky A, Zhao LP. Analysis of semiparametric regression models for repeated outcomes in the presence of missing data. J Am Stat Assoc. 1995;90:106-121.
  19. Ferrucci L, Harris TB, Guralnik JM, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47:639-646.[Medline]
  20. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol Med Sci. 1999;54A:M357-M364.[Abstract]
  21. Krabbe KS, Bruunsgaard H, Hansen CM, et al. Ageing is associated with a prolonged fever response in human endotoxemia. Clin Diagn Lab Immunol. 2001;8:333-338.
  22. Bruunsgaard H, Skinhoj P, Qvist J, Pedersen BK. Elderly humans show prolonged in vivo inflammatory activity during pneumococcal infections. J Infect Dis. 1999;180:551-554.[Medline]
  23. Kudoh A, Katagai H, Takazawa T, Matsuki A. Plasma proinflammatory cytokine response to surgical stress in elderly patients. Cytokine. 2001;15:270-273.[Medline]
  24. Beloosesky Y, Grinblat J, Pirotsky A, Weiss A, Hendel D. Different C-reactive protein kinetics in post-operative hip-fractured geriatrics patients with and without complication. Gerontology. 2004;50:216-222.[Medline]
  25. Lobo SMA, Lobo FRM, Bota DP, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest. 2003;123:2043-2049.[Abstract/Free Full Text]
  26. Bauer TT, Monton C, Torres A, et al. Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia and controls. Thorax. 2000;55:46-52.[Abstract/Free Full Text]
  27. Pape HC, Schmidt RS, Rice J, et al. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000;28:3441-3448.[Medline]
  28. Walston J, Xue Q, Semba RD, et al. Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol. 2006;163:18-26.[Abstract/Free Full Text]
  29. Reid MB, Li YP. Cytokines and oxidative signalling in skeletal muscle. Acta Physiol Scand. 2001;171:225-232.[Medline]
  30. Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;22:280-285.[Abstract/Free Full Text]
  31. Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin induced raw 264.7 cells. J Exp Med. 1985;161:984-995.[Abstract/Free Full Text]
  32. Fernandez-Celemin L, Pasko N, Blomart V, Thissen JP. Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab. 2002;283:E1279-E1290.[Abstract/Free Full Text]
  33. Barbieri M, Ferrucci L, Ragno E, et al. Chronic inflammation and the effect of IGF-1 on muscle strength and power in older persons. Am J Physiol Endocrinol Metab. 2002;284:E481-E487.[Medline]
  34. Budgett R. Fatigue and underperformance in athletes: the overtraining syndrome. Br J Sports Med. 1998;32:107-110.[Abstract/Free Full Text]
  35. Li X, Moody MR, Engel D, et al. Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation. 2000;102:1690-1696.[Abstract/Free Full Text]
  36. Vescovo G, Volterrani M, Zennaro R, et al. Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart. 2000;84:431-437.[Abstract/Free Full Text]
  37. Colbert LH, Visser M, Simonsick EM, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2004;52:1098-1104.[Medline]
  38. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28.[Abstract/Free Full Text]
  39. Bauer CD, Mundy GR, Jamal SA, et al. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. J Clin Endocrinol Metab. 2004;89:1217-1221.[Abstract/Free Full Text]
  40. Giannoudis PV, Pape HC, Cohen AP, Krettek C, Smith RM. Review of systemic effects of femoral nailing. Clin Orthop. 2002;404:378-386.



This article has been cited by other articles:


Home page
 Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
R. R. Miller, G. E. Hicks, M. D. Shardell, A. R. Cappola, W. G. Hawkes, J. A. Yu-Yahiro, A. Keegan, and J. Magaziner
Association of Serum Vitamin D Levels With Inflammatory Response Following Hip Fracture: The Baltimore Hip Studies
J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2007; 62(12): 1402 - 1406.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
PubMed
Right arrow PubMed Citation

HOME ARCHIVE SEARCH TABLE OF CONTENTS