Skip Navigation


NDT Advance Access first published online on July 29, 2008
This version published online on October 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn439
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/247    most recent
gfn439v2
gfn439v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Chiu, Y.-L.
Right arrow Articles by Tsai, T.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiu, Y.-L.
Right arrow Articles by Tsai, T.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Higher systemic inflammation is associated with poorer sleep quality in stable haemodialysis patients

Yen-Ling Chiu1,2, Yi-Fang Chuang3, Kai-Chi Fang4, Shih-Kai Liu4, Hung-Yuen Chen1,2, Ju-Yeh Yang1,2, Mei-Fen Pai1, Yu-Sen Peng1, Kwan-Dun Wu2 and Tun-Jun Tsai2

1 Department of Internal Medicine, Far-Eastern Memorial Hospital 2 Department of Medicine, National Taiwan University Hospital 3 Department of Psychiatry, Min-Sheng Hospital 4 Department of Psychiatry, Far-Eastern Memorial Hospital, Taiwan, Republic of China

Correspondence and offprint requests to: Yu-Sen Peng, Department of Medicine, Far-Eastern Memorial Hospital, Taiwan, Republic of China. Tel: +886-2-8966-7000 ext. 1164; Fax: +886-2-8966-7000 ext. 1162; E-mail: yenling.chiu{at}gmail.com



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Increased inflammation has been noted in sleep disorder patients with normal renal function. However, the relationship between sleep quality and circulating inflammatory markers has not been previously studied in haemodialysis (HD) patients.

Methods. A total of 114 HD end-stage renal disease patients receiving maintenance HD for >3 months were included in this study. Pittsburgh Sleep Quality Index (PSQI) was used to measure individual's sleep quality. Based on the global PSQI score, patients were divided into groups of good sleepers (PSQI < 5) and bad sleepers (PSQI ≥ 5).

Results. Twenty-three patients (20.2%) were classified as good sleepers and 91 patients (79.8%) were bad sleepers. Bad sleepers have significantly higher serum hsCRP level and lower serum phosphate level (all P < 0.05). The global PSQI score, or worse sleep quality are positively correlated with serum triglyceride level, high-sensitivity C-reactive protein (hsCRP) level, IL-1β level and negatively correlated with the haemoglobin and phosphate level. In the multi-variable linear regression model, levels of hsCRP (β = 0.209, P = 0.029) and triglyceride (β = 0.212, P = 0.025) were both significant independent predictors for the global PSQI score.

Conclusion. Our study demonstrated severe impairment of sleep quality in HD patients and corroborated the role of inflammation in the pathogenesis of sleep disturbance.

Keywords: haemodialysis; inflammation; sleep quality; triglyceride



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
It is well known that inflammatory indexes are frequently elevated in end-stage renal disease (ESRD) individuals. Persistent inflammation in ESRD population is associated with many clinically important complications, including atherosclerosis [1], malnutrition syndrome [2], higher hospitalization rates [3] and most importantly, cardiovascular mortality [4]. The causes of chronic inflammation in ESRD patients remain controversial, but many studies point to decreased cytokine excretion, uraemia milieu, acidosis, oxidative stress, bio-incompatibility to dialyzer membrane, periodontitis and infection [5].

Insomnia is a common complaint of ESRD patients. Our prior study demonstrated the severity of sleep disturbance in haemodialysis (HD) patients [6]. Another Taiwan-based multi-centre study also showed a very high prevalence of insomnia (66.6%) in ESRD patients and sleep disturbances were associated with restless leg syndrome (RLS) and a high risk for sleep apnoea [7]. In ESRD patients, poorer sleep quality is independently linked to higher mortality rate [8], but the reasons behind this association are unknown. While many studies have shown sleep disturbance with cytokine elevation in patients with normal renal function [9,10], only one small sample size study (n = 18) has been performed in HD patients [11]. It is possible that systemic inflammation is the link between sleep disturbance and reduced survival in ESRD [12]. This study was carried out to investigate the association of systemic inflammation with sleep quality in a cohort of maintenance HD patients.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients
This study was performed within a HD unit of a medical centre located in northern Taiwan. All patients received daytime dialysis, but the total hours per week varied from 8 h to 13.5 h. The inclusion criteria were as follows: (1) received maintenance HD >3 months; (2) age >18 years and (3) provided informed consent. The exclusion criteria were as follows: (1) presence of autoimmune disease, malignancy, active infection, uncontrolled heart failure or significant inflammation; (2) acute medical or surgical condition that required hospitalization or operation within the prior month; (3) patients with depression disorder, anxiety disorder, dementia or psychotic disorder, as diagnosed by psychiatrists; (4) use of immunosuppressants, immunomodulators or steroid that may influence serum cytokine levels. Finally, a total of 114 patients were enrolled. This study was approved by the Far-Eastern Memorial Hospital Research Ethics Review Committee (No. 96060) and informed consent obtained from all participants.

Measurement of sleep quality
Sleep quality was measured by Pittsburgh Sleep Quality Index (PSQI). This 19-question questionnaire measures the sleep quality of the previous month. From the answers seven components (each scored from 0 to 3) were calculated: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, use of sleep medications and daytime dysfunction. From the sum of seven component scores the global PSQI score was calculated (0–21). A patient with a global PSQI score ≥ 5 is considered to be a bad sleeper and a patient having a value of <5 is considered to be a good sleeper. The Chinese version of the PSQI had been used extensively for the study of sleep quality in Taiwan's dialysis patients [6]. In this study, patients completed this questionnaire by themselves or under the assistance of research nurses at the time when the blood examination was performed.

Measurement of serum cytokine level and other laboratory data
Blood samples were obtained from all patients fasting for at least 8 h just before the mid-week dialysis treatment. The biochemical data were taken at the central lab of Far-Eastern Memorial Hospital. Kt/V was calculated using the single pool Kt/V Daugirdas method. Remaining blood samples were centrifuged and the supernatant was frozen at –80°C. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor {alpha} (TNF-{alpha}) levels were determined by commercial ELISA (enzyme-linked immunosorbent assay) kits (R&D Systems, Inc., Minneapolis, MN, USA).

Statistical analyses
The Kolomogorov–Smirnov test was applied for testing each variable's normality. Continuous variables are presented as mean ± SD if normally distributed. Non-normally distributed continuous variables, such as hsCRP (high-sensitivity C-reactive protein) and cytokine levels, are presented as median (1st and 3rd quartiles). Comparisons of normally distributed continuous variables between good and bad sleepers were performed using Student's t-test. For non-normally distributed continuous variables, the Mann–Whitney U-test was used. Categorical and nominal data were compared using the chi-square test. The bivariate correlation test was performed to determine the association of demographic, biochemical and cytokine data with the PSQI score. For normally distributed variables, Pearson's correlation test was used; for non-normally distributed variables, Spearman's correlation test was used. Factors that reached statistical significance were selected for further multivariable analyses. Age and gender were forced into multiple regression to adjust for potential unidentified confounders. The exploration of significant risk factors to sleep quality was performed by the linear regression model. All analyses were performed with SPSS, version 13.0 (SPSS Inc., Chicago, IL, USA). P-values <0.05 were considered to be significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
One hundred and fourteen patients participated in this study. The average age was 56.8 years old, and 52.3% were male. The average dialysis vintage was 3.64 years. Twenty-three patients (20.2%) were classified as good sleepers (PSQI<5) and 91 patients (79.8%) were bad sleepers (PSQI≥ 5). For all patients, the median level of hsCRP, IL-1β, IL-6 and TNF-{alpha} was 3.83 mg/L, 0.21 pg/mL, 0.22 pg/mL and 6.36 pg/mL, respectively. Table 1 shows the comparison of demographic and clinical characteristics between good sleepers and bad sleepers. The average levels of PSQI of good sleepers and bad sleepers were 3.46 and 10.42, respectively. The rates of regular hypnotics use in good sleepers and bad sleepers were 0% and 41.8%, respectively. Compared with good sleepers, bad sleepers had a significantly lower serum phosphate level (P = 0.012) and higher serum hsCRP level (P = 0.005).


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

  		Table 1 Comparison of demographic and laboratory data between good sleepers and bad sleepers

 
By correlation tests, lower haemoglobin level (β = –0.267, P = 0.005), higher triglyceride level (β = 0.197, P = 0.038), lower phosphate level (β = –0.268, P = 0.004), higher hsCRP level (β = 0.218, P = 0.023) and IL-1β level (β = 0.203, P = 0.030) are significantly associated with the higher global PSQI score (Table 2). Serum levels of IL-6, TNF-{alpha} and ferritin are also positively correlated with the global PSQI score but did not reach statistical significance. The serum albumin level is negatively correlated with the global PSQI score.


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

  		Table 2 Variables correlation with global PSQI score

 
Four variables, including haemoglobin, triglyceride, phosphate and hsCRP, were investigated further in an age- and sex-adjusted multivariable linear regression model (Table 3). The levels of hsCRP and triglyceride remained independent predictors of the higher global PSQI score in the multivariable regression model (P = 0.029 and 0.025, respectively).


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

  		Table 3 Multivariable-adjusted linear regression analysis for the global PSQI score

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study demonstrates that higher systemic inflammation, as demonstrated by serum hsCRP and IL-1β levels, is associated with poorer sleep quality in stable HD patients. Other inflammatory markers, such as IL-6 and TNF-{alpha}, are also positively correlated with poorer sleep quality; nevertheless the results did not reach statistical significance. Our study also demonstrates the independent roles of systemic inflammation and hypertriglyceridaemia in ESRD patients’ sleep disturbance in a multivariable-adjusted regression model.

Sleep problems in the ESRD population are frequently overlooked despite its high prevalence [13] and negative impact on patients’ perceived health-related quality of life [14]. Most importantly, the international DOPPS study found an independent role of sleep disturbance in predicting cardiovascular mortality in a large, multinational population of HD patients [8]. Our study confirms previous studies about the heavy burden of sleep problems in HD patients [7,12,15]. Possible factors affecting sleep have been extensively studied, but some controversy existed. One study suggested that old age, cigarette smoking, alcohol consumption and neuropathy were related to dialysis patients’ insomnia [16]. Our prior study performed by Pai et al. indicated that poorer sleep quality is related to depression and lower haemoglobin level in HD patients [6]. Unruh et al. found that poorer sleep quality is related to black race, higher serum phosphate, current smoking and restless leg syndrome [17]. However, in that study, younger age was associated with decreases in sleep quality.

An inflammatory state has been linked to insomnia in patients without renal disease [18,19]. Both acute total and short-term partial sleep deprivation resulted in elevated hsCRP levels, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity [20]. Elevation of CRP may be due to increased vascular inflammation due to sleep deprivation-related hypertension [21]. Besides, synthesis of CRP in the liver is largely controlled by IL-6, TNF-alpha and IL-1β, and the production of CRP is thought to reflect the activity of these pro-inflammatory cytokines [22]. In contrast to IL-6 levels that display circadian variability, CRP levels have been shown to be quite stable across 24 h and, in the absence of disease, are quite reproducible, even over weeks and months [23]. It has been reported that, in ESRD patients, hsCRP is much more reliable compared with other inflammatory markers because it is associated with least intra-individual variability over time [24].

While systemic inflammation is widely recognized as a non-traditional risk factor for cardiovascular disease in ESRD patients, the relevance between sleep disturbance and inflammation in ESRD patients is much less studied. Eaton et al. were the first to investigate the link between inflammation and sleep complaints in ESRD patients [11]. In that study, patients with sleep-related complaints had significantly higher pre-dialysis IL-1β levels compared with those without and healthy controls (P = 0.004 and P < 0.001, respectively). Another study from our group showed that higher serum level interleukin-18 is associated with poorer sleep quality in peritoneal dialysis (PD) patients [25]. Furthermore, our group also found that cognitive behaviour therapy (CBT) improves PD patients’ sleep quality and decreases serum cytokine level concurrently. Accumulating evidence, including the present study, indicates that increased inflammatory parameters in renal failure patients are linked to poorer sleep quality.

Sleep deprivation induces significant elevation of serum IL-1β and IL-6 levels in healthy volunteers [18,26]. Furthermore, IL-1β and TNF-{alpha} are considered sleep regulatory cytokines because data derived from electrophysiological and biochemical studies demonstrate constant effect on sleep-wake behaviour [27]. IL-1β acts on hypothalamic neurons to alter GABAergic neurotransmission in a Ca2+-dependent manner [28]. Local application of TNF-{alpha} to the surface of the somatosensory cortex increases slow wave activity during non-rapid eye movement sleep (NREMS) in rats [29]. Given the somnolence effect of these cytokines, elevation of IL-1β and TNF-{alpha} levels are related to excessive daytime sleepiness and fatigue during infection or inflammation [30].

We found significant association between the serum triglyceride level and the global PSQI score. In the Hordaland Health Study [31], individuals with shorter sleep duration had significant higher body mass index, total cholesterol and triglyceride level. Our prior study performed in PD patients also found such association [25]. Because metabolic syndrome and its components are implicated in sleep-related breathing disorders [32] and poorer sleep quality [33], it is suggested that sleep apnoea might predispose patients to the development of metabolic syndrome. However, this notion definitely needs further confirmation in dialysis patients.

Compared with previous studies, our study used strict inclusion and exclusion criteria and a widely accepted tool to measure sleep quality. The significant association of inflammation and sleep quality was further demonstrated by multiple regression analysis. However, there are still several limitations to this study that should be addressed. First, we only examined a panel of four inflammatory markers based on a single blood sample taken at the initiation of dialysis treatment. The lack of association of certain inflammatory markers with sleep quality might reflect the difficulty to accurately assess the status of inflammation in HD patients by a single cytokine measurement. A better design that involves multiple testing would be more ideal especially for certain cytokines, such as IL-6, which exhibits a circadian rhythm. Similarly, plasma concentrations of IL-1β are known to peak at sleep onset [30]. Second, our study only used PSQI as a subjective measurement of sleep quality, and comprehensive polysomongraphy was not performed. Further study including survey for sleep apnoea syndrome and restless leg syndrome, and longitudinal follow-up will be more informative. Thirdly, certain medications such as beta-blockers, sleep medications, anti-epileptics and statins may have influenced sleep quality, but the use of these drugs was not controlled. Finally, our population is from a single HD centre in Taiwan, and the result may not be generalized to other races or populations. Further large-scale, longitudinal studies are required to confirm our observations and establish the causal and temporal relationships between sleep quality, inflammation and mortality.

Sleep is gradually regarded as a restorative process important for proper immune system functioning [34]. Recognizing the extremely heavy burden of insomnia and related complications in the ESRD population, more aggressive action to survey patients with sleep disorders and adequate intervention is increasing important. Although definite evidence is still lacking at present, treatments to improve renal failure patients’ sleep quality are likely to improve patients’ systemic inflammation and have the potential benefit of alleviating cardiovascular mortality.

Conflict of interest statement. None declared.



   Notes
 
The original version of this paper was incorrect. A mistake in an author name has been corrected.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Zoccali C, Benedetto FA, Maas R, et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol (2002) 13:490–496.[Abstract/Free Full Text]
  2. Kalantar-Zadeh K, Balakrishnan VS. The kidney disease wasting: inflammation, oxidative stress, and diet-gene interaction. Hemodial Int (2006) 10:315–325.[CrossRef][Medline]
  3. Chiang CK, Hsu SP, Pai MF, et al. Interleukin-18 is a strong predictor of hospitalization in haemodialysis patients. Nephrol Dial Transplant (2004) 19:2810–2815.[Abstract/Free Full Text]
  4. Menon V, Greene T, Wang X, et al. C-reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease. Kidney Int (2005) 68:766–772.[CrossRef][Web of Science][Medline]
  5. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia—the good, the bad, and the ugly. Kidney Int (2005) 67:1216–1233.[CrossRef][Web of Science][Medline]
  6. Pai MF, Hsu SP, Yang SY, et al. Sleep disturbance in chronic hemodialysis patients: the impact of depression and anemia. Ren Fail (2007) 29:673–677.[CrossRef][Web of Science][Medline]
  7. Chen WC, Lim PS, Wu WC, et al. Sleep behavior disorders in a large cohort of Chinese (Taiwanese) patients maintained by long-term hemodialysis. Am J Kidney Dis (2006) 48:277–284.[CrossRef][Web of Science][Medline]
  8. Elder SJ, Pisoni RL, Akizawa T, et al. Sleep quality predicts quality of life and mortality risk in haemodialysis patients: results from the dialysis outcomes and practice patterns study (dopps). Nephrol Dial Transplant (2008) 23:998–1004.[Abstract/Free Full Text]
  9. Mehra R, Storfer-Isser A, Kirchner HL, et al. Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med (2006) 166:1725–1731.[Abstract/Free Full Text]
  10. Motivala SJ, Sarfatti A, Olmos L, et al. Inflammatory markers and sleep disturbance in major depression. Psychosom Med (2005) 67:187–194.[Abstract/Free Full Text]
  11. Erten Y, Kokturk O, Yuksel A, et al. Relationship between sleep complaints and proinflammatory cytokines in haemodialysis patients. Nephrology (Carlton) (2005) 10:330–335.[CrossRef][Medline]
  12. Parker KP. Sleep disturbances in dialysis patients. Sleep Med Rev (2003) 7:131–143.[CrossRef][Web of Science][Medline]
  13. Mahowald MW, Bornemann MA. Sleep and ESRD: a wake-up call. Am J Kidney Dis (2006) 48:332–334.[CrossRef][Web of Science][Medline]
  14. Iliescu EA, Coo H, McMurray MH, et al. Quality of sleep and health-related quality of life in haemodialysis patients. Nephrol Dial Transplant (2003) 18:126–132.[Abstract/Free Full Text]
  15. Walker S, Fine A, Kryger MH. Sleep complaints are common in a dialysis unit. Am J Kidney Dis (1995) 26:751–756.[Web of Science][Medline]
  16. Merlino G, Piani A, Dolso P, et al. Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy. Nephrol Dial Transplant (2006) 21:184–190.[Abstract/Free Full Text]
  17. Unruh ML, Buysse DJ, Dew MA, et al. Sleep quality and its correlates in the first year of dialysis. Clin J Am Soc Nephrol (2006) 1:802–810.[Abstract/Free Full Text]
  18. Moldofsky H, Lue FA, Davidson JR, et al. Effects of sleep deprivation on human immune functions. FASEB J (1989) 3:1972–1977.[Abstract]
  19. Mills PJ, von Kanel R, Norman D, et al. Inflammation and sleep in healthy individuals. Sleep (2007) 30:729–735.[Web of Science][Medline]
  20. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol (2004) 43:678–683.[Abstract/Free Full Text]
  21. Desideri G, Croce G, Ferri C. Does nondipping blood pressure profile contribute to vascular inflammation during sleep deprivation? J Am Coll Cardiol (2004) 44:1529–1530. author reply 1530– 1521.[Free Full Text]
  22. Castell JV, Gomez-Lechon MJ, David M, et al. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology (1990) 12:1179–1186.[Web of Science][Medline]
  23. Meier-Ewert HK, Ridker PM, Rifai N, et al. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem (2001) 47:426–430.[Abstract/Free Full Text]
  24. Tsirpanlis G, Bagos P, Ioannou D, et al. The variability and accurate assessment of microinflammation in haemodialysis patients. Nephrol Dial Transplant (2004) 19:150–157.[Abstract/Free Full Text]
  25. Yang JY, Huang JW, Chiang CK, et al. Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients. Nephrol Dial Transplant (2007) 22:3606–3609.[Abstract/Free Full Text]
  26. Vgontzas AN, Zoumakis E, Bixler EO, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab (2004) 89:2119–2126.[Abstract/Free Full Text]
  27. Opp MR. Cytokines and sleep. Sleep Med Rev (2005) 9:355–364.[CrossRef][Web of Science][Medline]
  28. De A, Churchill L, Obal F Jr, et al. GHRH and IL1beta increase cytoplasmic Ca(2+) levels in cultured hypothalamic GABAergic neurons. Brain Res (2002) 949:209–212.[CrossRef][Web of Science][Medline]
  29. Yoshida H, Peterfi Z, Garcia-Garcia F, et al. State-specific asymmetries in EEG slow wave activity induced by local application of TNF-{alpha}. Brain Res (2004) 1009:129–136.[CrossRef][Web of Science][Medline]
  30. Kapsimalis F, Basta M, Varouchakis G, et al. Cytokines and pathological sleep. Sleep Med (2007) [Epub ahead of print].
  31. Bjorvatn B, Sagen IM, Oyane N, et al. The association between sleep duration, body mass index and metabolic measures in the Hordaland Health Study. J Sleep Res (2007) 16:66–76.[CrossRef][Web of Science][Medline]
  32. Kono M, Tatsumi K, Saibara T, et al. Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest (2007) 131:1387–1392.[CrossRef][Web of Science][Medline]
  33. Jennings JR, Muldoon MF, Hall M, et al. Self-reported sleep quality is associated with the metabolic syndrome. Sleep (2007) 30:219–223.[Web of Science][Medline]
  34. Ziemssen T, Kern S. Psychoneuroimmunology—cross-talk between the immune and nervous systems. J Neurol (2007) 254(Suppl_2):II8–II11.[CrossRef][Medline]
Received for publication: 13. 5.08
Accepted in revised form: 8. 7.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/247    most recent
gfn439v2
gfn439v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Chiu, Y.-L.
Right arrow Articles by Tsai, T.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiu, Y.-L.
Right arrow Articles by Tsai, T.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?