Of Mice and Men: On the Origin of XMRV

Abstract:

The novel human retrovirus xenotropic murine leukemia virus-related virus (XMRV) is arguably the most controversial virus of this moment. After its original discovery in prostate cancer tissue from North American patients, it was subsequently detected in individuals with chronic fatigue syndrome from the same continent. However, most other research groups, mainly from Europe, reported negative results.

The positive results could possibly be attributed to contamination with mouse products in a number of cases, as XMRV is nearly identical in nucleotide sequence to endogenous retroviruses in the mouse genome. But the detection of integrated XMRV proviruses in prostate cancer tissue proves it to be a genuine virus that replicates in human cells, leaving the question: how did XMRV enter the human population?

We will discuss two possible routes: either via direct virus transmission from mouse to human, as repeatedly seen for, e.g., Hantaviruses, or via the use of mouse-related products by humans, including vaccines. We hypothesize that mouse cells or human cell lines used for vaccine production could have been contaminated with a replicating variant of the XMRV precursors encoded by the mouse genome.

 

Source: van der Kuyl AC, Cornelissen M, Berkhout B. Of Mice and Men: On the Origin of XMRV. Front Microbiol. 2011 Jan 17;1:147. doi: 10.3389/fmicb.2010.00147. ECollection 2010. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109487/ (Full article)

 

EBV Chronic Infections

Abstract:

The infection from Epstein-Barr virus (EBV) or virus of infectious mononucleosis, together with other herpes viruses’ infections, represents a prototype of persistent viral infections characterized by the property of the latency. Although the reactivations of the latent infection are associated with the resumption of the viral replication and eventually with the “shedding”, it is still not clear if this virus can determine chronic infectious diseases, more or less evolutive.

These diseases could include some pathological conditions actually defined as “idiopathic”and characterized by the “viral persistence” as the more credible pathogenetic factor. Among the so-called idiopathic syndromes, the “chronic fatigue syndrome” (CFS) aroused a great interest around the eighties of the last century when, just for its relationship with EBV, it was called “chronic mononucleosis” or “chronic EBV infection”.

Today CFS, as defined in 1994 by the CDC of Atlanta (USA), really represents a multifactorial syndrome characterized by a chronic course, where reactivation and remission phases alternate, and by a good prognosis. The etiopathogenetic role of EBV is demonstrated only in a well-examined subgroup of patients, while in most of the remaining cases this role should be played by other infectious agents – able to remain in a latent or persistent way in the host – or even by not infectious agents (toxic, neuroendocrine, methabolic, etc.). However, the pathogenetic substrate of the different etiologic forms seems to be the same, much probably represented by the oxidative damage due to the release of pro-inflammatory cytokines as a response to the triggering event (infectious or not infectious).

Anyway, recently the scientists turned their attention to the genetic predisposition of the subjects affected by the syndrome, so that in the last years the genetic studies, together with those of molecular biology, received a great impulse. Thanks to both these studies it was possible to confirm the etiologic links between the syndrome and EBV or other herpesviruses or other persistent infectious agents.

The mechanisms of EBV latency have been carefully examined both because they represent the virus strategy to elude the response of the immune system of the host, and because they are correlated with those oncologic conditions associated to the viral persistence, particularly lymphomas and lymphoproliferative disorders. Just these malignancies, for which a pathogenetic role of EBV is clearly documented, should represent the main clinical expression of a first group of chronic EBV infections characterized by a natural history where the neoplastic event aroused from the viral persistence in the resting B cells for all the life, from the genetic predisposition of the host and from the oncogenic potentialities of the virus that chronically persists and incurs reactivations.

Really, these oncological diseases should be considered more complications than chronic forms of the illness, as well as other malignancies for which a viral – or even infectious – etiology is well recognized. The chronic diseases, in fact, should be linked in a pathogenetic and temporal way to the acute infection, from whom start the natural history of the following disease. So, as for the chronic liver diseases from HBV and HCV, it was coined the acronym of CAEBV (Chronic Active EBV infection), distinguishing within these pathologies the more severe forms (SCAEBV) mostly reported in Far East and among children or adolescents.

Probably only these forms have to be considered expressions of a chronic EBV infection “sensu scrictu”, together with those forms of CFS where the etiopathogenetic and temporal link with the acute EBV infection is well documented. As for CFS, also for CAEBV the criteria for a case definition were defined, even on the basis of serological and virological findings. However, the lymphoproliferative disorders are excluded from these forms and mantain their nosographic (e.g. T or B cell or NK type lymphomas) and pathogenetic collocation, even when they occur within chronic forms of EBV infection. In the pathogenesis, near to the programs of latency of the virus, the genetic and environmental factors, independent from the real natural history of EBV infection, play a crucial role.

Finally, it was realized a review of cases – not much numerous in literature – of chronic EBV infection associated to chronic liver and neurological diseases, where the modern techniques of molecular biology should be useful to obtain a more exact etiologic definition, not always possible to reach in the past.

The wide variety of clinical forms associated to the EBV chronic infection makes difficult the finding of a univocal pathogenetic link. There is no doubt, however, that a careful examination of the different clinical forms described in this review should be useful to open new horizons to the study of the persistent viral infections and the still not well cleared pathologies that they can induce in the human host.

 

Source: Eligio P, Delia R, Valeria G. EBV Chronic Infections. Mediterr J Hematol Infect Dis. 2010 Aug 10;2(1):e2010022. doi: 10.4084/MJHID.2010.022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033110/ (Full article)

 

Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS

Abstract:

There is evidence that disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways and a lowered antioxidant status are important pathophysiological mechanisms underpinning myalgic encephalomyelitis / chronic fatigue syndrome(ME/CFS). Important precipitating and perpetuating factors for ME/CFS are (amongst others) bacterial and viral infections; bacterial translocation due to an increased gut permeability; and psychological stress.

Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years. These findings implicate that ME/CFS is a risk factor to cardio-vascular disorder.

This review demonstrates that disorders in various IO&NS pathways provide explanations for the earlier mortality due to cardiovascular disorders in ME/CFS. These pathways are: a) chronic low grade inflammation with extended production of nuclear factor kappa B and COX-2 and increased levels of tumour necrosis factor alpha; b) increased O&NS with increased peroxide levels, and phospholipid oxidation including oxidative damage to phosphatidylinositol; c) decreased levels of specific antioxidants, i.e. coenzyme Q10, zinc and dehydroepiandrosterone-sulphate; d) bacterial translocation as a result of leaky gut; e) decreased omega-3 polyunsatutared fatty acids (PUFAs), and increased omega-6 PUFA and saturated fatty acid levels; and f) the presence of viral and bacterial infections and psychological stressors. The mechanisms whereby each of these factors may contribute towards cardio-vascular disorder in ME/CFS are discussed.

ME/CFS is a multisystemic metabolic-inflammatory disorder. The aberrations in IO&NS pathways may increase the risk for cardiovascular disorders.

 

Source: Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-93. https://www.ncbi.nlm.nih.gov/pubmed/20038921

 

Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome

Abstract:

BACKGROUND: There is now evidence that major depression and myalgic encephalomyelitis / chronic fatigue syndrome(ME/CFS) are accompanied by partially overlapping pathophysiological mechanisms, i.e. activation of various inflammatory and oxidative & nitrosative (IO&NS) pathways.

OBJECTIVE: The aim of the present study was to examine the urinary excretion of 8-hydroxy-deoxyguanosine (8-OhdG), a marker of oxidative damage to DNA, in depression; ME/CFS; and depression and ME/CFS.

METHODS: Toward this end, morning urine was sampled for the assays of 8-OHdG and creatinine, in 44 patients with ME/CFS; 25 with major depression; 23 with depression and ME/CFS; and 17 normal controls. Severity of fatigue and somatic symptoms was measured by means of the Fibromyalgia and CFS Rating (FF) scale.

RESULTS: We found that 49.0% of the variance in the urinary excretion of 8-OHdG was predicted by the regression on creatinine. Consequently, the urinary 8-OHdG excretion should be expressed as the residualized 8-OHdG values after partialling out the effects of creatinine and not by computing the 8-OHdG / creatinine ratio. We found that the residualized urinary excretion of 8-OHdG (adjusted for creatinine) was significantly higher in patients with depression and ME/CFS than in normal controls and all other patients. In the patient group, there were significant correlations between the urinary 8-OHdG and the total score on the FF scale and sadness and flu-like malaise.

CONCLUSIONS: The findings show increased oxidatively generated DNA damage in patients with major depression and ME/CFS and, therefore, further extent the role played by IO&NS pathways in the pathophysiology of both disorders. Since oxidatively damage to DNA is a risk factor for atherosclerosis and neurodegeneration, our results also explain previous findings on increased cardiovascular morbidity in depression and ME/CFS, and neurodegenerative processes in depression.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome. Neuro Endocrinol Lett. 2009;30(6):715-22. https://www.ncbi.nlm.nih.gov/pubmed/20035260

 

Serum Cytokine Levels in Postinfective Fatigue Syndrome

TO THE EDITOR—Previous studies have sought evidence for a role of abnormal cytokine activity in patients with chronic fatigue syndrome and have had conflicting results [1–3]. These ambiguous results may reflect heterogeneity in groups of patients considered to have chronic fatigue syndrome and variations in assay systems.

We established postinfective fatigue syndrome as the only well-characterized model of the onset and evolution of chronic fatigue syndrome in a prospective cohort of individuals followed up from the onset of acute infection (Dubbo Infection Outcomes Study [DIOS]) [4]. Longitudinally collected clinical data and blood samples from participants in DIOS provide a unique opportunity for nested case-control studies examining the pathophysiology of chronic fatigue syndrome.

We previously reported the lack of association between cytokine production from cultured peripheral blood mononuclear cells and the postinfective fatigue syndrome- related illness in participants in DIOS [5]. We now report a masked analysis of a longitudinal case-control series from DIOS that extended the number of cytokines tested and focused on serum levels.

Twenty patients with acute infection were selected, including 5 patients with serologically confirmed acute Epstein-Barr virus (EBV) infection followed by postinfective fatigue syndrome lasting ⩾6 months, 5 patients with acute infection (not primary EBV but seropositive for EBV) followed by postinfective fatigue syndrome, and 10 matched control subjects with acute EBV infection followed by prompt recovery. Serum samples and clinical data from baseline and from 3–6 months and 9–12 months after onset of infection were analyzed. Serum samples were coded according to case-control status before transfer to the cytokine analysis laboratory.

Thirty-five analytes were measured in serum samples with use of amultiplex immunoassay, including the chemokines leptin, epithelial cell-derived neutrophil-activating peptide 78, eotaxin, growth-regulated oncogene α, interleukin (IL)-8, interferon (IFN)-inducible protein 10, monocyte chemotactic protein 3, monokine induced by gamma IFN, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, and regulated upon activation normal T cell expressed and secreted; the cytokines IFN-γ, IL-1α, IL-1β, IL-1Ra, IL-4, IL-5, IL-6, IL-7, IL-2, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17F, tumor necrosis factor α, tumor necrosis factor β; and the growth factors nerve growth factor, plate-let-derived growth factor β, transforming growth factor β, vascular endothelial growth factor, fibroblast growth factor β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

All of the study groups were predominantly female and were matched for both sex distribution (by χ2 test, P = .670) and age (by analysis of variance, P = .597). Cytokine data were analyzed by 2-way analysis of variance examining the effects of time and type of case (EBV postinfective fatigue syndrome, non-EBV postinfective fatigue syndrome, or control) and by Spearman’s correlation between symptom scores and cytokine levels. Because of the number of parameters tested, a conservative threshold for statistical significance (P < .005) was used. Results are shown in Table 1

You can read the rest of this article here: http://cid.oxfordjournals.org/content/50/2/278.full

 

Source: Cameron B, Hirschberg DL, Rosenberg-Hassan Y, Ablashi D, Lloyd AR. Serum cytokine levels in postinfective fatigue syndrome. Clin Infect Dis. 2010 Jan 15;50(2):278-9. doi: 10.1086/649546. http://cid.oxfordjournals.org/content/50/2/278.full (Full article)

 

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?

Abstract:

Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided.

Special emphasis is given to the relationship between immune dysfunctions and fatigue. Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-kappaB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients.

The dysregulation of the RNase L pathway, hyperactive NF-kappaB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied. Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-kappaB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases.

These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.

 

Source: Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov;29(11):4717-26. http://ar.iiarjournals.org/content/29/11/4717.long (Full article)

 

Web usage data as a means of evaluating public health messaging and outreach

Abstract:

BACKGROUND: The Internet is increasingly utilized by researchers, health care providers, and the public to seek medical information. The Internet also provides a powerful tool for public health messaging. Understanding the needs of the intended audience and how they use websites is critical for website developers to provide better services to the intended users.

OBJECTIVE: The aim of the study was to examine the utilization of the chronic fatigue syndrome (CFS) website at the Centers for Disease Control and Prevention (CDC). We evaluated (1) CFS website utilization, (2) outcomes of a CDC CFS public awareness campaign, and (3) user behavior related to public awareness campaign materials and CFS continuing medical education courses.

METHODS: To describe and evaluate Web utilization, we collected Web usage data over an 18-month period and extracted page views, visits, referring domains, and geographic locations. We used page views as the primary measure for the CFS awareness outreach effort. We utilized market basket analysis and Markov chain model techniques to describe user behavior related to utilization of campaign materials and continuing medical education courses.

RESULTS: The CDC CFS website received 3,647,736 views from more than 50 countries over the 18-month period and was the 33rd most popular CDC website. States with formal CFS programs had higher visiting density, such as Washington, DC; Georgia; and New Jersey. Most visits (71%) were from Web search engines, with 16% from non-search-engine sites and 12% from visitors who had bookmarked the site. The public awareness campaign was associated with a sharp increase and subsequent quick drop in Web traffic. Following the campaign, user interest shifted from information targeting consumer basic knowledge to information for health care professionals. The market basket analysis showed that visitors preferred the 60-second radio clip public service announcement over the 30-second one. Markov chain model results revealed that most visitors took the online continuing education courses in sequential order and were less likely to drop out after they reached the Introduction pages of the courses.

CONCLUSIONS: The utilization of the CFS website reflects a high level of interest in the illness by visitors to the site. The high utilization shows the website to be an important online resource for people seeking basic information about CFS and for those looking for professional health care and research information. Public health programs should consider analytic methods to further public health by understanding the characteristics of those seeking information and by evaluating the outcomes of public health campaigns. The website was an effective means to provide health information about CFS and serves as an important public health tool for community outreach.

 

Source: Tian H, Brimmer DJ, Lin JM, Tumpey AJ, Reeves WC. Web usage data as a means of evaluating public health messaging and outreach. J Med Internet Res. 2009 Dec 21;11(4):e52. doi: 10.2196/jmir.1278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802568/ (Full article)

 

Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder

Abstract:

INTRODUCTION: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical illness characterized by disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways.

METHODS: This paper examines the role of Coenzyme Q10 (CoQ10), a mitochondrial nutrient which acts as an essential cofactor for the production of ATP in mitochondria and which displays significant antioxidant activities. Plasma CoQ10 has been assayed in 58 patients with ME/CFS and in 22 normal controls; the relationships between CoQ10 and the severity of ME/CFS as measured by means of the FibroFatigue (FF) scale were measured.

RESULTS: Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances.

DISCUSSION: The results show that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders. The findings that lower CoQ10 is an independent predictor of chronic heart failure (CHF) and mortality due to CHF may explain previous reports that the mean age of ME/CFS patients dying from CHF is 25 years younger than the age of those dying from CHF in the general population. Since statins significantly decrease plasma CoQ10, ME/CFS should be regarded as a relative contraindication for treatment with statins without CoQ10 supplementation.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6. https://www.ncbi.nlm.nih.gov/pubmed/20010505

 

Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness

Abstract:

INTRODUCTION: There is now evidence that major depression is accompanied by an induction of inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that has anti-inflammatory effects.

METHODS: This paper examines the plasma concentrations of CoQ10 in 35 depressed patients and 22 normal volunteers and the relationships between plasma CoQ10 and treatment resistant depression (TRD), the severity of illness as measured by means of the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue syndrome (CFS).

RESULTS: We found that plasma CoQ10 was significantly (p=0.0002) lower in depressed patients than in normal controls. 51.4% of the depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls. Plasma CoQ10 was significantly lower in patients with TRD and with CFS than in the other depressed patients. There were no significant correlations between plasma CoQ10 and the HDRS.

DISCUSSION: The results show that lower CoQ10 plays a role in the pathophysiology of depression and in particular in TRD and CFS accompanying depression. It is suggested that depressed patients may benefit from CoQ10 supplementation. The findings that lower CoQ10 is a risk factor to coronary artery disease and chronic heart failure (CHF) and mortality due to CHF suggest that low CoQ10 is another factor explaining the risk to cardiovascular disorder in depression. Since statins significantly lower plasma CoQ10, depressed patients and in particular those with TRD and CFS represent populations at risk to statin treatment.

 

Source: Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 2009;30(4):462-9. https://www.ncbi.nlm.nih.gov/pubmed/20010493

 

Sleep is not disrupted by exercise in patients with chronic fatigue syndromes

Abstract:

PURPOSE: Patients with chronic fatigue syndrome (CFS) report that exertion produces dramatic symptom worsening. We hypothesized this might be due to the exacerbation of an underlying sleep disorder, which we have previously demonstrated to exist.

METHODS: Female patients with CFS and matched healthy controls with no evidence of major depressive disorder were studied with overnight polysomnography on a baseline night and on a night after their performance of a maximal exercise test.

RESULTS: CFS patients as a group had evidence for disturbed sleep compared with controls. Although exercise improved sleep for healthy subjects, it did not do this for the group as a whole. When we stratified the sample on the basis of self-reported sleepiness after a night’s sleep, the patient group with reduced morning sleepiness showed improvement in sleep structure, whereas those with increased morning sleepiness continued to show evidence for sleep disruption.

CONCLUSIONS: Sleep is disturbed in CFS patients as a group, but exercise does not exacerbate this sleep disturbance. Approximately half the patients studied actually sleep better after exercise. Therefore, activity-related symptom worsening is not caused by worsened sleep.

 

Source: Togo F, Natelson BH, Cherniack NS, Klapholz M, Rapoport DM, Cook DB. Sleep is not disrupted by exercise in patients with chronic fatigue syndromes. Med Sci Sports Exerc. 2010 Jan;42(1):16-22. doi: 10.1249/MSS.0b013e3181b11bc7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796587/ (Full article)