Tag: De Meirleir

Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions

Abstract:

OBJECTIVE: In an attempt to examine whether impairments in cardiorespiratory fitness are associated with daily functioning in patients with chronic fatigue syndrome (CFS), this study addresses the correlations between exercise capacity and activity limitations/participation restrictions.

DESIGN: Prospective observational study.

SETTING: An outpatient tertiary care, chronic fatigue clinic at the Vrije Universiteit Brussel (VUB), Belgium.

SUBJECTS: Seventy-seven patients fulfilling the 1994 Centers for Disease Control and Prevention (CDC) case definition for CFS.

INTERVENTIONS: All patients filled in the Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ) and performed a maximal exercise stress test on a bicycle ergometer. Heart rate was monitored continuously by use of an electrocardiograph. Metabolic and ventilatory parameters were measured through spirometry.

RESULTS: A statistically significant correlation between the score obtained with the CFS-APQ and the body weight-adjusted peak oxygen uptake (Spearman rho = -0.32; p = 0.005), functional aerobic impairment (rho = 0.33; p = 0.004), workload/body weight (rho = -0.30; p = 0.009), exercise duration (rho = -0.30; p = 0.008), and the percentage of target heart rate achieved (rho = -0.33; p = 0.004) was observed. The correlations between the remaining exercise capacity parameters and the scores obtained with the CFS-APQ all indicated a trend towards association (0.01 <p<0.05).

CONCLUSIONS: These results suggest a moderate association between exercise capacity and activity limitations/participation restrictions in patients with CFS. The observed correlations lack strength to predict activity limitations/ participation restriction based on exercise capacity parameters. Disability evaluation in CFS should therefore encompass both exercise capacity testing and measurements at the activity/participation dimension.

 

Source: Nijs J, De Meirleir K, Wolfs S, Duquet W. Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions. Clin Rehabil. 2004 Mar;18(2):139-48. http://www.ncbi.nlm.nih.gov/pubmed/15053122

 

Atypical depression as a secondary symptom in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) has gained prominence since 1988 and a substantial amount of research has been done in this domain. However, it is still regarded as a controversial condition. Moreover, most of the symptoms of CFS itself are non-specific, occurring in many illnesses; some of the symptoms are also common in depression. Indeed, an area of continued controversy and debate involves the diagnostic overlap between CFS and psychiatric disorders. Through anecdotal evidence, atypical depression appears to be common in CFS. Recent developments in psychobiology underscore the role of the acute phase response and its associated sickness behavior in affective disorders. Thus, we hypothesize that atypical depression is sickness behavior rather than an affective disorder as shown by anecdotal evidence in CFS.

 

Source: Van Hoof E, Cluydts R, De Meirleir K. Atypical depression as a secondary symptom in chronic fatigue syndrome. Med Hypotheses. 2003 Jul;61(1):52-5. http://www.ncbi.nlm.nih.gov/pubmed/12781640

 

Psychometric properties of the Dutch Chronic Fatigue Syndrome–Activities and Participation Questionnaire (CFS-APQ)

Abstract:

BACKGROUND AND PURPOSE: The Chronic Fatigue Syndrome-Activities and Participation Questionnaire (CFS-APQ) is a recently developed disease-specific assessment tool for monitoring activity limitations and participation restrictions in patients with chronic fatigue syndrome (CFS). In this study, the convergent validity, content validity, and test-retest reliability of data obtained with the Dutch-language version of the questionnaire were examined.

SUBJECTS AND METHODS: One hundred eleven consecutive patients with CFS were enrolled, of whom 47 fulfilled all inclusion criteria. The subjects were first asked to rate their pain, fatigue, and ability to concentrate using 3 visual analog scales, to list at least 5 activities that had become difficult to perform due to their complaints, and to complete the CFS-APQ. Furthermore, subjects were asked to complete a modified version of the CFS-APQ at home and return it to the investigators. The content of the questionnaire was reviewed using the World Health Organization’s International Classification of Impairments, Disability and Health (ICIDH) beta II draft. Spearman rank correlation coefficients (R) were used for the convergent validity analysis, and intraclass correlation coefficients were computed for the assessment of the test-retest data.

RESULTS: Overall scores on the CFS-APQ correlated with the scores from the visual analog scales for pain (R=.51, P<.001) and fatigue (R=.50, P<.001). The majority of the responses (157 out of 183 answers [85.8%]) to the request to “list difficult activities” matched the content of the CFS-APQ. Using the ICIDH beta II draft, 21 out of 26 questions were found to address activities, and the remaining 5 questions measured the participation level. The Cronbach alpha coefficient was.94, and intraclass correlation coefficients for test-retest reliability of the overall scores were >or= .95 (P<.001).

DISCUSSION AND CONCLUSION: The results substantiate the convergent validity, content validity, and reliability of the CFS-APQ scores for patients with CFS.

 

Source: Nijs J, Vaes P, McGregor N, Van Hoof E, De Meirleir K. Psychometric properties of the Dutch Chronic Fatigue Syndrome–Activities and Participation Questionnaire (CFS-APQ). Phys Ther. 2003 May;83(5):444-54. http://ptjournal.apta.org/content/83/5/444.long (Full article)

 

Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome

Abstract:

STUDY OBJECTIVE: To examine whether bronchial hyperresponsiveness (BHR) in patients with chronic fatigue syndrome (CFS) is caused by immune system abnormalities.

DESIGN: Prospective comparative study.

SETTING: A university-based outpatient clinic (Vrije Universiteit; Brussels, Belgium).

PARTICIPANTS: One hundred thirty-seven CFS patients and 27 healthy volunteers.

MEASUREMENTS: Pulmonary function testing, histamine bronchoprovocation test, immunophenotyping, and ribonuclease (RNase) latent determination.

RESULTS: Seventy-three of 137 patients presented with BHR, of whom 64 had normal results of the histamine bronchoprovocation test. No significant differences were found in age or sex characteristics between the groups. There were no differences in the RNase L ratio, total lung capacity, or FEV(1)/FVC ratio between CFS patients with or without BHR. The group of patients in whom BHR was present (BHR+) differs most significantly from the control group with eight differences in the immunophenotype profile in the cell count analysis and seven differences in the percentage distribution profile. The group of patients in whom no BHR was detected (BHR-) only differed from the control subjects in CD25+ count and in the percentage of CD25+ cells. We observed a significant increase in cytotoxic T-cell count and in the percentage of BHR+ patients compared to BHR- patients, which is consistent with the significant reduction in percentage naïve T cells.

CONCLUSIONS: These results refute any association between the cleaving of 80 kd RNase L and BHR. Immunophenotyping of our sample confirmed earlier reports on (chronic) immune activation in patients with CFS, compared to healthy control subjects. BHR+ CFS patients have more evidence of immune activation compared to BHR- patients. Inflammation and the consequent IgE-mediated activation of mast cells and eosinophils, as seen in asthma patients, is unlikely to be responsible for the presence of BHR in patients with CFS.

 

Source: Nijs J, De Becker P, De Meirleir K, Demanet C, Vincken W, Schuermans D, McGregor N. Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome. Chest. 2003 Apr;123(4):998-1007. http://www.ncbi.nlm.nih.gov/pubmed/12684286

 

Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue

Abstract:

In some patients complaining of chronic fatigue such as those suffering from the chronic fatigue syndrome (CFS), no underlying physical cause can be clearly identified and they typically present a normal thyroid function. Several studies indicate a dysregulation in the type I interferons (IFN-alpha/beta) pathway in CFS resulting in a sustained upregulation of 2(‘),5(‘)-oligoadenylate synthetases (2-5OAS). Likewise, patients treated with IFN-alpha/beta usually complain of severe fatigue as a limiting side effect.

Beside the 2-5OAS, IFN-alpha/beta induce also the expression of three closely related proteins of unknown function termed the 2-5OAS-like (2-5OASL) proteins. The amino acid sequences of the 2-5OASL proteins display 96% identity with the partial sequence of the thyroid receptor interacting protein (TRIP) 14, further contain two typical thyroid hormone receptor (TR) coregulator domains and feature two ubiquitin C-terminal domains.

From these observations, we raise the hypothesis that the 2-5OASL proteins are TRIPs capable of, respectively, repressing TR transactivation and/or signaling the receptor for destruction by the proteasome. Such molecular mechanisms could explain the development of a clinical hypothyroid state in presence of a normal thyroid function.

 

Source: Englebienne P, Verhas M, Herst CV, De Meirleir K. Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue. Med Hypotheses. 2003 Feb;60(2):175-80. http://www.ncbi.nlm.nih.gov/pubmed/12606231

 

Chronic fatigue syndrome: a risk factor for osteopenia?

Abstract:

No data documenting a possible depletion of bone mineral density in patients with chronic fatigue syndrome (CFS) are currently available. However, recent pathophysiological observations in CFS patients may have deleterious consequences on bone density.

Firstly, the deregulation of the 2,5A synthetase RNase L antiviral pathway and its associated channelopathy, implicates increased demands for calcium and consequent increased calcium-re-absorption from the skeletal system.

Secondly, Mycoplasma fermentans which has been frequently associated with CFS, produces a lipopeptide, named 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates macrophages. MALP-2 has been shown to enhance bone resorption in a dose-dependent manner, at least in part by stimulating the formation of prostaglandins.

Thirdly, decreased levels of insulin-like growth factor I (IGF-I) have been reported in CFS-patients. IGF-I is critical to the proliferation of osteoblasts. Consequently, depleted levels of IGF-I may shift the balance between osteoclastic and osteoblastic activity towards bone resorption.

 

Source: Nijs J, De Meirleir K, Englebienne P, McGregor N. Chronic fatigue syndrome: a risk factor for osteopenia? Med Hypotheses. 2003 Jan;60(1):65-8. http://www.ncbi.nlm.nih.gov/pubmed/12450768

 

High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients

Abstract:

Prevalence of Mycoplasma species infections in chronic fatigue syndrome (CFS) has been extensively reported in the scientific literature. However, all previous reports highlighted the presence of Mycoplasmas in American patients. In this prospective study, the presence of Mycoplasma fermentans, M. penetrans, M. pneumoniae and M. hominis in the blood of 261 European CFS patients and 36 healthy volunteers was examined using forensic polymerase chain reaction.

One hundred and seventy-nine (68.6%) patients were infected by at least one species of Mycoplasma, compared to two out of 36 (5.6%) in the control sample (P<0.001). Among Mycoplasma-infected patients, M. hominis was the most frequently observed infection (n=96; 36.8% of the overall sample), followed by M. pneumoniae and M. fermentans infections (equal frequencies; n=67; 25.7%). M. penetrans infections were not found. Multiple mycoplasmal infections were detected in 45 patients (17.2%). Compared to American CFS patients (M. pneumoniae>M. hominis>M. penetrans), a slightly different pattern of mycoplasmal infections was found in European CFS patients (M. hominis>M. pneumoniae, M. fermentansz.Gt;M. penetrans).

 

Source: Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med Microbiol. 2002 Nov 15;34(3):209-14. http://femsim.oxfordjournals.org/content/34/3/209.long (Full article)

 

Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients

Abstract:

A 37-kDa binding polypeptide accumulates in peripheral blood mononuclear cell (PBMC) extracts from chronic fatigue syndrome (CFS) patients and is being considered as a potential diagnostic marker (De Meirleir, K., Bisbal, C., Campine, I., De Becker, P., Salehzada, T., Demettre, E., and Lebleu, B. (2000) Am. J. Med. 108, 99-105). We establish here that this low molecular weight 2-5A-binding polypeptide is a truncated form of the native 2-5A-dependent ribonuclease L (RNase L), generated by an increased proteolytic activity in CFS PBMC extracts. RNase L proteolysis in CFS PBMC extracts can be mimicked in a model system in which recombinant RNase L is treated with human leukocyte elastase. RNase L proteolysis leads to the accumulation of two major fragments with molecular masses of 37 and 30 kDa. The 37-kDa fragment includes the 2-5A binding site and the N-terminal end of native RNase L. The 30-kDa fragment includes the catalytic site in the C-terminal part of RNase L. Interestingly, RNase L remains active and 2-5A-dependent when degraded into its 30- and 37-kDa fragments by proteases of CFS PBMC extract or by purified human leukocyte elastase. The 2-5A-dependent nuclease activity of the truncated RNase L could result from the association of these digestion products, as suggested in pull down experiments.

 

Source: Demettre E, Bastide L, D’Haese A, De Smet K, De Meirleir K, Tiev KP, Englebienne P, Lebleu B.Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Biol Chem. 2002 Sep 20;277(38):35746-51. Epub 2002 Jul 12. http://www.ncbi.nlm.nih.gov/pubmed/12118002

 

Structural and functional features of the 37-kDa 2-5A-dependent RNase L in chronic fatigue syndrome

Abstract:

A 2′,5′-oligoadenylate (2-5A)-dependent 37-kDa form of RNase L has been reported in extracts of peripheral blood mononuclear cells (PBMC) from individuals with chronic fatigue syndrome (CFS). In the current study, analytic gel permeation FPLC, azido photoaffinity labeling, two-dimensional (2-D) gel electrophoresis, and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) have been used to examine the biochemical relationship between the 80-kDa RNase L in healthy control PBMC and the 37-kDa RNase L in PBMC from individuals with CFS.

Like the 80-kDa RNase L, the 37-kDa RNase L is present as a catalytically inactive heterodimer complex with the RNase L inhibitor (RLI). Formation of a 37-kDa RNase L-RLI complex indicates that the 37-kDa RNase L is structurally similar to the 80-kDa RNase L at the N-terminus, which contains the 2-5A binding domain. The enzymatically active monomer form of 37-kDa RNase L resolved by 2-D gel electrophoresis has a pI of 6.1. RT-PCR and Southern blot analyses demonstrated that the 37-kDa RNase L is not formed by alternative splicing. In-gel tryptic digestion of the 37-kDa RNase L that was excised from 2-D gels and subsequent MALDI-MS analysis identified three peptide masses that are identical to three predicted peptide masses in the 80-kDa RNase L. The electrophoretic mobility of 2-5A azido photolabeled/immunoprecipitated 37-kDa RNase L was the same under reducing and nonreducing conditions. The results presented show that the 37-kDa form of RNase L in PBMC shares structural and functional features with the native 80-kDa RNase L, in particular in the 2-5A binding and catalytic domains.

 

Source: Shetzline SE, Martinand-Mari C, Reichenbach NL, Buletic Z, Lebleu B, Pfleiderer W, Charubala R, De Meirleir K, De Becker P, Peterson DL, Herst CV,Englebienne P, Suhadolnik RJ. Structural and functional features of the 37-kDa 2-5A-dependent RNase L in chronic fatigue syndrome.  J Interferon Cytokine Res. 2002 Apr;22(4):443-56. http://www.ncbi.nlm.nih.gov/pubmed/12034027

 

Antiviral pathway activation in chronic fatigue syndrome and acute infection

Comment on: Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. [Clin Infect Dis. 2001]

 

SIR—We read the very engaging report by Gow et al. [1] with the utmost interest. However, we feel that this article raises more questions than clear-cut answers regarding the hypothesis that motivated the study—that is, that the previously reported activation of the antiviral pathway in chronic fatigue syndrome (CFS) might be linked to infection rather than to CFS specifically. To verify their hypothesis, Gow and colleagues used PCR to measure the genetic expression of 3 IFN-regulated genes—namely, the latent ribonuclease (RNase L), RNA-regulated protein kinase (PKR), 2,5 synthetase, and the RNase L inhibitor (RLI)—in patients with acute infection (in their study, severe gastroenteritis; group 1), patients with CFS (group 2), and healthy control subjects (group 3).

First, surprisingly enough, although they recognized that acute infection is supposed to induce the expression of the genes selected for their study (see figure 1 of [1]), Gow and colleagues failed to find any significant increase in the expression of 2 major genes (RNase L and 2,5 synthetase) in group 1, as compared with groups 2 and 3; they observed only increased mRNA for PKR and RLI. Although it is recognized that genetic expression of PKR, RNase L, and 2,5 synthetase is under the control of interferon, RLI is definitely not [2]. Upregulation of RLI genetic expression with a normal genetic expression of both 2,5 synthetase and RNase L (although PKR is overexpressed!) during acute infection, as was observed in the study of Gow et al. [1], would indicate not only that RNase L is not activated (normal expression of RNase L and, more importantly, of 2,5 synthetase), but that it is further inhibited by an overexpressed RLI [2]. Such a scenario, if verified, would be in complete disagreement with the current understanding of the IFN pathway [3]. Therefore, we cannot help but wonder how Gow and colleagues reconcile their observations with the acute infection status of study group 1. In our view, this inconsistency severely undermines their conclusions.

You can read the rest of this comment here:  http://cid.oxfordjournals.org/content/34/10/1420.long

 

Source: De Meirleir K, Suhadolnik RJ, Lebleu B, Englebienne P. Antiviral pathway activation in chronic fatigue syndrome and acute infection. Clin Infect Dis. 2002 May 15;34(10):1420-1; author reply 1421-2. http://cid.oxfordjournals.org/content/34/10/1420.long (Full article)