Some Interesting Facets of Research Science:
by Alan Cocchetto, © 2004
Twenty years after the Lake Tahoe epidemic: Clinical and Biochemical Characteristics
Differentiating Chronic Fatigue Syndrome from Major Depression and Healthy Control
Populations: Dyfunction of the RNase L pathway:
Dr. Robert Suhadolnik reported on the RNase L cleavage characteristics associated with alterations to the 2-5A antiviral pathway in patients with CFS. As has been reported previously, the CFS patients differed significantly from healthy and depression controls regarding abnormalities observed in this pathway and in particular, the RNase L ratio (37/80 kDA) was strongly correlated with many of the changes that are characteristic of CFS (low NK/natural killer cell cytotoxicity, abnormal alpha-interferon levels, RNase L pathway abnormalities, etc).
Syndrome of chronic fatigue in patients receiving interferon-alpha for chronic Hepatitis C
Since CFS patients often report the onset of their symptoms following viral infection, the release of interferon-alpha in viral infections is relevant to CFS symptomology. Dr. Charles Raison reported on a study of 162 patients being treated for hepatitis C viral (HCV) infection. Since HCV treatment included interferon-alpha injections, an extensive self-reported questionnaire aided in the assessment of symptomology associated with this treatment protocol. Prior to HCV treatment, 22% of patients reported moderate to severe fatigue and 3% of patients endorsed symptoms sufficient to meet criteria for CFS. Interestingly, during interferon-alpha treatment, 70% of HCV patients reported moderate to marked fatigue while 30% endorsed symptoms sufficient to meet CFS criteria which was found to be highly statistically significant. The authors concluded that interferon-alpha treated patients provide further support for the role of viruses and/or antiviral immune responses in the pathophysiology of fatiguing illnesses including CFS.
The Dubbo infection outcomes study: Post-infective fatigue as a model for CFS:
Since prolonged fatigue states appear to follow from acute infections, this study aimed to validate
such post-infective fatigue states to serve as a model for the study of the onset and course of CFS as well as to define the symptom characteristics. Dr. Jim Jones reported that post-infective fatigue states following documented infection represent a valid and informative model for CFS.
Furthermore, the symptom characteristics of CFS, including fatigue and mood disturbance, are embedded within those typical of acute infection and are present from the time of onset of the illness. Severity of the illness was the strongest predictor of the subsequent development of post-infective fatigue states. The authors concluded that post-infective fatigue represents an ideal model to determine risk factors for the onset of CFS and to define its pathophysiology.
*Deficiency in the expression of STAT1 protein in a subpopulation of patients with CFS:
See accompanying article on Dr. Konstance Knox's presentation at the conference. Please
note that the data that was published in the AACFS Conference Syllabus was incorrect. The
correct data was presented on overheads by Dr. Knox in her presentation and this information
is included in the accompanying article in this issue of the Forum.
Quantitative fluorescence measures of cytotoxic potential in CFS:
Dr. Kevin Maher reported on NK (natural killer) cell cytotoxicity for CFS patients versus controls and found deficient levels of perforin, granzyme A and granzyme B in patients. These findings suggest that cytotoxic cellular level defects exist in CFS that not only include NK cells but also cytotoxic T-cells.
Chlamydia and mycoplasma infections in patients with CFS and rheumatological diseases:
This study was aimed at searching for a potential role of sexual transmitted diseases (STD) in the
pathogenesis of rheumatologic syndromes characterized by prolonged fatigue. Dr. Racciatti reported that of the 66 CFS patients, 33 patients tested positive for such urogenital infections that included chlamydia trachomatis, ureaplasma urealyticum and mycoplasma spp. The authors concluded that investigations for infectious agents of STD's be recommended as part of the diagnostic protocol for CFS.
CFS: Does science finally meet the clinic?
Dr. Marc Freemont reported on CFS in the clinic. Because CFS etiology and pathogenesis
remain poorly understood, this creates numerous problems due to the existence of several
patient subgroups. Recognition of pathological inhomogeneity among patients led recently
to questioning the accuracy of the 1994 case definition and to the development of a new Canadian clinical working case definition published in 2003. This new working case instrument highlights symptom clusters that reflect specific areas of pathogenesis. Dr. Freemont focused on linking available data to patient subgrouping in order to derive improved diagnosis and patient management strategies. The authors concluded that because of physiological heterogeneity in CFS subgroups, a good understanding of the physiological dysregulations involved for a given clinical subject is of prime importance before making any decision about a therapeutic strategy.
Correlations between the multidimensional fatigue inventory (MFI) and the short-form 36
(SF-36) scales in subjects with unexplained chronic fatigue:
This study was aimed at determining the correlations between dimensions of fatigue as measured
by the MFI and the functional impairment measured by SF-36 in subjects with unexplained chronic fatigue. Dr. Rosane Nisenbaum reported that 40 of 68 subjects with unexplained chronic fatigue had been classified with CFS and 28 had idiopathic chronic fatigue. As expected, higher fatigue levels were correlated with lower functioning. The authors concluded that physical fatigue was the only predictor of physical functioning; physical fatigue and mental fatigue were joint predictors of general health; general fatigue and reduced activity were predictors of vitality; and physical fatigue and reduced motivation predicted social functioning.
Using artificial neural networks to classify fatigue:
Artificial neural networks (AANS) were used to help determine which set of survey questions were most effective for accurately classifying those with CFS. Dr. Ashley Morris reported on
the use of AANS for CFS classification by attempting to generate a list of survey questions that would be most useful in accurately diagnosing CFS. There were 26 questions that were found to better distinguish/assist in CFS classification.
Procoagulant genetic factors in a pooled cohort of 582 CFS, FM and related chronic illness cases:
Low level activation of coagulation in patients with active CFS and/or FM has been reported
previously. Dr. Harold Harrison reported on a study of 582 adults screened for suspected CFS/FM or related chronic illness. The study found that 72% of patients had positive ISAC results while 69% were positive for one or more genetic markers. The authors concluded that the data supported the general hypothesis of concerted genetic contributions of coagulation protein abnormalities to CFS/FM and that those were consistent with family histories. Furthermore, genetic testing to identify the type of procoagulant defect may be warranted as effective interventions to prevent or treat CFS/FM become available.
*Heredity and environment as risk factors for CFS - a pilot study:
Dr. Underhill reported on an important study of 219 diagnosed CFS patients. Briefly stated, 20.5% of the CFS patients had family members with CFS and in 18% they were blood relatives. 9.1% of these responders had one or more household members with CFS. Spouses/partners, offspring and blood relatives were calculated as significant. These findings suggest that secondary cases of CFS occurring in genetically unrelated members (spouses/partners) of CFS patients indicates that an infectious agent which can cause CFS may persist in at least some CFS patients and can be shed into the environment. The presence of close household contact and genetic relationship in some families both represent risk factors for the development of CFS.
Regional blood volume and peripheral blood flow in CFS complicated by POTS:
Dr. Julian Stewart reported results that supported the hypothesis that at least three pathophysiologic variants of orthostatic intolerance in CFS patients existed and that this could be distinguished by peripheral blood flow related to characteristic changes in regional circulations. The results demonstrated enhanced thoracic hypovolemia related to inadequate cardiac venous return during orthostasis.
Reduction in density of serotonin transporters in the anterior cingulate of patients with CFS:
Dr. Kuratsune reported that CFS patients were found to have cerebral hypoperfusion in a variety of brain regions. Serotonergic neurotransmission in patient brains were assessed and the 5-HT transporter density in the anterior cingulate cortex was found to be significantly reduced. This density was found to be negatively correlated with pain scores. These results concluded that an alteration in the serotonergic neurons in the anterior cingulate cortex plays a key role in the
pathophysiology of CFS.
Elastase activity is related to impaired exercise capacity in patients with CFS:
Dr. Jo Nijs reported that while previous research had shown that patients with CFS present with an abnormal exercise response and exacerbation of symptoms after physical activity, the exact cause of this abnormal exercise response had yet to be revealled. The results of their study provide evidence for an association between intracellular immune deregulation and impairments in cardio-respiratory fitness in PWC's. The study suggested that the role of increased elastase activity might be related to impairments of lung diffusion and impairments of oxygen delivery in tissues.
Patients with CFS have reduced cerebral blood flow:
Dr. Kazuhiro Yoshiuchi reported on a study of 25 CFS patients and 7 controls for cerebral blood flow (CBF) using xenon CT scans. Results showed that CFS patients as a group had lower total CBF than controls while statisically significant decreases in regional CBF were found for the left and right temporoparietal regions, right inferior frontal cortex, and left and right inferior occipital lobes. The authors also concluded that psychiatric status and illness severity do not play a role in this reduced brain blood flow.
Analysis of the Metabolic Features of CFS using multislice 1H MRSI:
Dr Susan Levine reported on a study that sought to determine the relationship between disease
severity in a given individual and the degree of mitochondrial energy metabolism dysfunction or
neuronal damage in the brain using 1H MR spectral characteristics. A total of 31 patients were
tested and of those, 20% showed elevated ventricular lactate production suggesting the possibility of mitochondrial metabolism dysfunction as has been noted in patients with mitochondrial encephalopathy and in myoclonus epilepsy. These other disorders are thought to arise from a point mutation in the mitochondrial DNA which results in the accumulation of large amounts of lactate in the CSF and parenchyma. The authors concluded that the magnitude of the metabolic energy dysfunction in CFS is most likely less than that seen in the encephalopathies.
Possible role of beta-alanine and gamma-amino butyric acid (GABA) in CFS:
Disabling fatigue and neurocognitive symptoms of CFS may be caused by disturbances in
neurotransmitter systems in the central nervous system (CNS). GABA is the most important
inhibitory neurotransmitter in the CNS while beta-alanine is a structural analog of GABA.
Dr. Ulf Hannestad reported on a study of 6 patients and 12 controls for the measurement of
24 hour urinary GABA and beta-alanine. The authors concluded that some CFS patients
do indeed excrete a significantly increased amount of beta-alanine in the urine and that this
finding confirmed earlier findings by other researchers. The authors suggested that this urinary
abnormality reflects high concentrations of beta-alanine or GABA in the CNS. They suggested
that many symptoms that are characteristic of CFS are also seen as side effects when treating
epileptic patients with antiepileptic drugs since these drugs increase GABA activity in CNS
and can give side-effects that are typical of CFS.
*Heightened prevalence of normocytic normochromic anemia in CFS: The epoetin alpha
Since a previous study of severely affected CFS patients had noted diminished red blood cell (RBC) volume, this study attempted to replicate this finding. For this study, 30 women and 12 men were tested for RBC volume. Dr. Barry Hurwitz reported that 33% of the men and 77% of the women displayed low RBC volume. Interestingly, 100% of low RBC subjects displayed normocytic normochromic anemia. The authors concluded that a high prevalence of CFS subjects were found to have low RBC volume and that this deficit may be characterized as normocytic normochromic anemia. This type of anemia is associated with chronic conditions and is linked to impaired bone marrow response due to a suppression of endogenous erythropoietin.
Interactions between RNase L ankyrin-like domain and ABC transporters: A mechanism
affecting the activity of the multidrug-resistance protein 1:
This study investigated the possibility of an interaction between the ankyrin-like RNase L fragment and the multidrug-resistance protein 1 (MRP-1), an ABC transporter involved in the regulation of immune cell activation and in the resistance of cells to chemicals, including heavy metals. Dr. Marc Fremont reported on the study results that concluded that the alteration of MRP-1 activity by interactions with the ankyrin fragment of RNase L could be a mechanism explaining the high sensitivity of patients to different chemicals including heavy metals. Furthermore, MRP-1 is also involved in the maintenance of the Th1/Th2 balance which is relevant in CFS.
Elevated nitric oxide/peroxynitrite mechanism of CFS and related conditions: Mechanisms
of symptoms and other correlate generation:
CFS overlaps with other multisystem illnesses including multiple chemical sensitivity (MCS)
and fibromyalgia (FM). They have high comorbidity with each other and they have overlapping
symptoms as well. Dr. Martin Pall described the etiologic mechanism of elevated nitric oxide/
peroxynitrite to explain the properties of these illness including symptom generation. The author
concluded that this mechanism provided an explanation for most if not all of the dominant symptoms and other correlates of these illnesses. Dr. Pall further stated that this mechanism provided a challenge to those who had claimed that these illnesses were unexplained or that their symptoms were also unexplained.
* Presentations that we found the most interesting.
The National CFIDS Foundation* 103 Aletha Rd, Needham Ma 02492 * (781) 449-3535 Fax (781) 449-8606