Friday, March 18, 2005


Medical Journal Summaries by Lucy Dechene, Ph.D.


“Influence of Melatonin on Quality of Life in Patients with Chronic Fatigue and Late Melatonin Onset,” Smits et al. (J CFS 10 (3/4): 25-36, 2002). 

38 CFIDS patients with delayed Dim Light Melatonin Onset (DLMO) were given the Medical Outcome Study Short Form questionnaire before and after treatment with 5 mg melatonin given 5 hours before DLMO daily for 13 weeks. Results of the questionnaires were compared to those of 43 patients with Delayed Sleep Phase Syndrome and 1063 healthy controls. Before treatment, CFIDS patients were similar to the Delayed Sleep Phase patients, except for worse physical functioning, lower energy/vitality and general health perception. After treatment, the CFIDS patients had significant improvement on “physical functioning,” “energy/vitality,” “bodily pain,” and “general health perception.”


“Levels of Nitric Oxide Synthase Product Citrulline Are Elevated in Sera of Chronic Fatigue Syndrome Patients,” Pall. (J CFS 10 (3/4): 37-41, 2002).

Serum levels of citrulline, a product of nitric oxide synthase activity, were measured in 36 CFIDS patients and 16 controls. Serum citrulline levels were significantly elevated in CFIDS patients and there was a trend towards higher levels in CFIDS patients with stronger symptoms. Dr. Pall concludes, “These results provide support for the inference that overall nitric oxide synthesis is elevated in CFS as compared to controls. They confirm an important prediction of the elevated nitric oxide/peroxynitrite theory of CFS. They also suggest that similar serum studies should not only be repeated in CFS, but also performed in multiple chemical sensitivity, fibromyalgia and post traumatic stress disorder, other conditions also proposed to be caused by elevated levels of nitric oxide and its oxidant product, peroxynitrite.”


“Toxins and Immunity in Chronic Fatigue Syndrome,” Richardson. (J CFS 10 (3/4): 43-50, 2002).

This was, unfortunately, probably Dr. Richardson’s last paper on CFIDS, since he died in July.  Dr. Richardson illustrates links between exposure, absorption and effects of viruses, bacteria, and inorganic toxins and their toll on the immune and endocrine systems as potential causes of chronic symptomatology as seen in CFS. One of the oddest cases was that of a young female who had what at first appeared to be epilepsy, but instead was found to have times of severe low blood sugar brought upon by excessive use of products with the sweetener aspartame. Most of the paper relates cases of pesticide poisoning which at first appeared to be CFIDS. He points out that while these cases have many similar symptoms to CFIDS, there are many common symptoms missing that occur in CFIDS caused by reactions to pathogens.

“NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as mechanism of chemical sensitivity in multiple chemical sensitivity,” Pall. (FASEB J 16: 1407-1417, 2002). This is a highly technical paper which explains Dr. Pall’s peroxynitrite hypothesis applied to MCS. A few of his arguments are: 1. Several organic solvents known to induce MCS all induce increases in nitric oxide levels, 2. Neopterin, a marker of the induction of the iNOS, is elevated in MCS, 3. Increased oxidative stress exists in MCS and antioxidant therapy may lead to improvement in MCS, 4. Intramuscular injections of B-12 sometimes improve symptoms and B-12 is a potent scavenger of nitric oxide.


 “Ribonuclease L Proteolysis in Peripheral Blood Mononuclear Cells of Chronic Fatigue Syndrome Patients,” Demettre et al. (J Biological Chem 277 (38): 35746-35751, 2002).

This highly technical paper from Dr. De Meirleir’s lab reports on attempts to find out the relationship of the 37-kDa and 30-kDa fragments found in CFIDS peripheral blood mononuclear cells to RNase-L. The researchers found that both fragments did come from RNase-L. The 37-kDa fragment includes the 2-5A binding site and the N terminal end of native RNase-L and the 30-kDa fragment includes the catalytic site in the C-terminal part of RNase-L. Interestingly enough, the fragments remain active. The researchers conclude, “RNase-L proteolysis removes the Cys-rich region (in the protein kinase homology domain) of RNase-L, which is believed to be involved in protein-protein interactions. It is, therefore, conceivable that the proteolysis of RNase-L might alter its interaction with regulatory proteins or its compartmentalization. Such dysregulation could in turn lead to the degradation of cellular mRNA species, which are not normal targets of native RNase-L.” [Commentary: This would suggest that it is possible that the active fragments of RNase-L found in some CFIDS patients are actively degrading messenger RNA in cells. This would greatly interfere in the manufacture of important cellular proteins, mitochondrial function and general cellular functioning. This would certainly explain the strange symptoms CFIDS patients have, as well as the difficulty in detecting the reasons for them, since the cause is intracellular disruption.—L.D.]

“Markers of Viral Infection in Monozygotic Twins Discordant for Chronic Fatigue Syndrome,” Koelle, et al. (Clin Infect Dis 35: 518-25, 2002).

22 pairs of monozygotic twins discordant for CFS were studied for evidence of infections with a long list of viruses including EBV, CMV, HHV-6, HHV-7, and HHV-8. While some twins were infected with the various viruses (most commonly CMV and herpes-1), the researchers found no differences between the CFS twins and healthy twins. The researchers conclude, “This co-twin control study of 22 monozygotic twin pairs discordant for CFS did not demonstrate a major contribution for viral infection in perpetuating CFS. This study does not exclude the possibility that infectious agents trigger the illness.”

“Evidence for the Presence of Immune Dysfunction in Chronic Fatigue Syndrome,” Natelson et al. (Clin Diagnostic Laboratory Immun 9 (4): 747-752, 2002).

Dr. Natelson’s group did a careful and thoughtful review of the medical literature on immune dysfunction in CFS. There was one oddity in their approach—if a group published more than one paper, they only “counted” the one done with the largest group of patients. This may have skewed the results. Most useful is the group’s conclusion: “ In summary, any further studies seeking to identify immunological abnormalities in CFS patients require careful attention to methodological issues. First, efforts should be made to reduce the heterogeneity of the patient sample; alternatively, large sample sizes are required in order to evaluate the importance of subgroups within the overall CFS population. Similarly, efforts must be made to reduce any potential major differences between patients and controls in areas such as the level of fitness and the presence of psychiatric disorders. Next, samples should be coded [for blind analysis] and, perhaps, provided as split samples to evaluate within-assay variability in a laboratory. Finally, appropriate statistical methods are required if differences between patients and controls are done on more than one immunological parameter. Our conclusion is that the available evidence does not support chronic fatigue syndrome as being due to any consistent immunological dysfunction. Until that evidence is better documented, we believe that the term ‘chronic fatigue syndrome’ is preferable to the older ‘chronic fatigue and immune dysfunction syndrome.’”

Lyme Disease

“A 58-Year-Old Man with a Diagnosis of Chronic Lyme Disease, Steere. (JAMA 288 (8): 1002-1010). 

This is a report of a Grand Rounds that occurred at Beth Israel Deaconess Medical Center in Boston.  It gives a good overview of chronic Lyme disease.


“Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome,” Arnold et al. (Psychological Med 32: 1075-1089, 2002).

This is a strange study done at NIH with Dr. Straus as a co-author.  19 CFIDS patients (1994 definition) and 10 controls were given neuropsych tests before, during and 24 hours after being given Interleukin-6 to induce flu-like symptoms. The researchers conclude that IL-6 exacerbated the patients’ self-reported symptoms, but did not reveal notable cognitive impairments or differences between patients and controls during cytokine-induced acute influenza-like symptoms. [Commentary: This was a strange study because 5 of the 19 patients had histories of chemical dependence (throwing their CFIDS diagnosis in doubt), the one type of test most likely to show neurocognitive problems in CFIDS patients—the Task Switching Test—was thrown out because some patients messed it up, and there is no evidence that IL-6 is one of the cytokines that influences alertness and cognitive functioning. In addition, in spite of the claim the “follow-up” tests were done 24 hours later, it was admitted in the paper that many of the participants actually didn’t complete those tests until 2 or more days later. So I am less than impressed with the results.—L.D.]


“Cluster Analysis to Define Typology of CFS,” Jason et al. (Psychology Health 17 (3): 323-337, 2002).

165 subjects with chronic fatigue medically evaluated as part of Dr. Jason’s large Chicago study participated in this analysis. 31 participants had been diagnosed with CFIDS, 45 had idiopathic chronic fatigue, 33 had chronic fatigue explained by a medical condition, and 56 had chronic fatigue explained by a psychiatric condition. Factor analysis done earlier separated this group of 166 from the other fatigue groups on the basis of three of four factors—Lack of Energy, Physical Exertion symptoms, and Cognitive Problems. For this analysis, each subject had a factor scale score for the three factors and also one for Fatigue and Rest. The statistical technique of cluster analysis was done to group subjects with similar factor scores. Three clusters were found: 35 people in Cluster 1, 45 in Cluster 2, and 85 in Cluster 3.  1 CFIDS patient was in Cluster 1, 8 were in Cluster 2, and 22 were in Cluster 3. Cluster 3 subjects had high post-exertional fatigue that was not alleviated by rest, severe lack of energy and severe cognitive problems. The researchers concluded that “Findings for comparable levels of post-exertional fatigue severity among CFS and medically-explained chronic fatigue groups suggest that post-exertional fatigue represents a key symptom that differentiates individuals with CFS and other medical explanations for chronic fatigue from those with idiopathic and psychiatrically-explained types of chronic fatigue…One key characteristic that distinguished Clusters 2 and 3 (containing all but 1 CFIDS subject) from Cluster 1 was markedly high severity of post-exertional fatigue. This symptom has been designated as a major criterion for the London definition of myalgic encephalomyelitis (CFS), but as one of the minor criteria for the US definition of CFS. Results from the present investigation highlight the relative importance of this symptom as a diagnostic marker for CFS and point to the potential utility in designating post-exertional fatigue as a major criteria for CFS in future attempts to define this syndrome.”


“Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls,” Barron et al. (J Pediatr 141: 421-5, 2002).

This was a matched case-control study comparing the Beighton joint hypermobility scores in 58 consecutive new cases of children with CFIDS, 58 otherwise healthy controls referred to a dermatology clinic, and 58 previously diagnosed CFIDS cases. The Beighton scores were significantly higher for both CFIDS patient groups compared to the healthy controls. The odds ratio for hypermobility in all CFS patients versus healthy controls was 3.5. The researchers explain the possible significance of this. “ Joint hypermobility may be the most visible reflection of a generalized connective tissue hyperextensibility, and an etiologic association with CFS symptoms may rely on circulatory or neural reflexive changes that accompany such connective tissue abnormalities.” So this could cause neurally mediated hypotension and related symptoms.

Gulf War Syndrome

“Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients,” Skowera et al. (Clin Exp Immunol 129:354-358, 2002).

This British study examined 130 symptomatic GW vets, 90 well GW vets, 128 symptomatic Bosnia vets, 100 CFS patients and 111 healthy controls matched for age and sex for antinuclear antibodies, in particular the novel ones against the nuclear envelope found in one study of CFIDS patients. While some of the vets had ANA antibodies, no participant in the study had ANAs to the nuclear envelope.



“Effects of Strength Training on Muscle Strength, Cross-Sectional Area, Maximal Electromyographic Activity, and Serum Hormones in Premenopausal Women with Fibromyalgia,” Hakkinen et al. (J Rheumatol 29: 1287-95, 2002.). 

This Finnish study randomized 11 female FM patients into a 21-week strength-training program and 10 female FM patients into a control group, and used 12 premenopausal sedentary women as controls in the strength-training program. The researchers found that the magnitude and time course adaptations of the neuromuscular system to resistance training in women with FM were completely comparable to those taking place in healthy women. They concluded, “Observations recorded during the acute loading conditions might be considered an indication of the training induced adaptation of the endocrine system, showing that the acute growth hormone response may become systematic after strength training in both women with FM and controls.”


 “Impaired growth hormone secretion in fibromyalgia patients: Evidence for augmented hypothalamic somatostatin tone,” Paiva et al. (Arthritis Rheum 46(5): 1344-50, 2002). 

Twenty female FM patients were compared with 10 healthy female controls. All subjects exercised to volitional exhaustion on a treadmill. A standard metabolic cart was used to monitor pulse, blood pressure, electrocardiography, oxygen uptake, carbon dioxide output, anaerobic threshold, and maximal workload. Blood was drawn for growth hormone (GH) and cortisol measurements 1 hour before exercise, immediately before exercise, immediately after exercise, and 1 hour after exercise. One month later, testing that was exactly similar was performed, except all subjects were given pyridostigmine bromide (Mestinon; 30 mg orally) 1 hour before exercise. Compared with controls, FM patients failed to exhibit a GH or cortisol response to acute exercise (P = 0.003). After administration of pyridostigmine, 1 hour before exercise, the GH levels of FM patients increased 8-fold (P = 0.001), to a value comparable with that of controls. Pyridostigmine did not increase the cortisol response to exercise in FM patients. Pyridostigmine alone did not stimulate GH secretion in FM patients, nor did it improve exercise-induced GH secretion in controls. FM patients with normal insulin-like growth factor 1 (IGF-1) levels had an impaired GH response to exercise. The researchers concluded, “1) FM patients have a reduced GH response to exercise, 2) pyridostigmine reverses this impaired response, and 3) defective GH secretion in FM can occur in patients with normal IGF-1 levels. Because pyridostigmine is known to reduce somatostatin tone, it is surmised that the defective GH response to exercise in FM patients probably results from increased levels of somatostatin, a hypothalamic hormone that inhibits GH secretion.”


 “Latent class analysis of symptoms associated with chronic fatigue syndrome and fibromyalgia,” Sullivan et al. (Psycholog Med 32: 881-888, 2002). 

Latent class analysis (a statistical technique) was applied to data from 646 patients who had CFIDS, FM or both. The major defining symptoms of CFIDS (fatigue) and FM (widespread pain) were not considered in the analysis. Of the large amount of symptoms in the database, the researchers chose 32 which were common to one or both syndromes. The latent class analysis showed that there was little difference in CFIDS and FM when these symptoms were considered. The researchers found a four-class solution. The classes seemed to differ in a gradual fashion (rather than qualitatively) for symptom endorsements, pre-morbid characteristics, and co-morbidity with panic disorder and major depression. The researchers conclude, “These results were unexpected given the usual assumption of the distinctiveness of chronic fatigue syndrome and fibromyalgia. These results support a conceptualization of chronic fatigue syndrome and fibromyalgia as being characterized by greater similarities than differences.”


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