This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) by interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP (adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed. Patients attending a private medical practice specializing in CFS were diagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the Bell Ability Scale was assigned, and a blood sample was taken for the "ATP profile" test, designed for CFS and other fatigue conditions. Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficiencies of ADP into the mitochondria and ATP into the cytosol where the energy is used. With the consent of each of 71 patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell Ability Scale. The individual numerical factors show that patients have different combinations of biochemical lesions. When the factors are combined, a remarkable correlation is observed between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of the 71 patients overlaps the normal region. The "ATP profile" test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out.

The renin-angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RAS-activated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout'(KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.Laboratory Investigation advance online publicaation, 19 May 2008; doi:10.1038/labinvest.2008.42.

PURPOSE OF REVIEW: Chronic fatigue syndrome is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas. RECENT FINDINGS: The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage. SUMMARY: The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.

The sensitivity of the tuberculin skin test is impaired in HIV-1 infected persons. ELISpot-based detection of immune sensitisation may be less affected. Furthermore, the quantitative response can be related to the CD4 count, potentially improving specificity for active disease.T-SPOT.TB was performed on HIV-1 infected participants, 85 with active tuberculosis (TB) and 81 healthy patients (non-TB). The ratio of summed ESAT-6 and CFP-10 response to the CD4 count (SFC/CD4) was calculated.Using manufacturer's guidelines, active TB was diagnosed with 76% sensitivity and 53% specificity. Using a SFC/CD4 ratio of 0.12, sensitivity (80%) and specificity (62%) improved.The quantitative T-cell response increased with increasing smear positivity in the active TB group (p=0.0008). In the non-TB group, the proportion of persons scored positive by T-SPOT.TB was lower in the CD4<200 group (p=0.029).The ratio of summed T cell response to CD4 count improved diagnostic accuracy of the T-SPOT.TB assay in HIV-infected persons and ratio of SFC/CD4>0.12 should prompt investigation for active disease. A strong association between the degree of sputum positivity and T-SPOT.TB score was found. The sensitivity of T-SPOT.TB in active disease may be less impaired by advanced immunosuppression.

SETTING: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in human immunodeficiency virus type I (HIV-1) infected tuberculosis (TB) patients who start combination antiretroviral treatment (ART). Neurological manifestations occur in more than 10% of TB-IRIS cases. Apart from a few case reports, the radiological features of neurological TB-IRIS have not been described. OBJECTIVE: To describe the neuroradiological findings of patients with paradoxical neurological TB-IRIS. DESIGN: Computed tomography (CT; n = 13) and magnetic resonance imaging (n = 3) findings of 16 patients were reviewed. RESULTS: IRIS manifestations included meningitis (n = 4), intracranial space occupying lesions (SOLs, presumed tuberculomas; n = 5), meningitis and SOLs (n = 5), radiculomyelitis (n = 1) and spondylitis (n = 1). In patients with tuberculoma IRIS, we observed a high prevalence of 1) low density lesions on non-contrast-enhanced CT (all lesions), 2) multiple lesions (in 5/10 patients) and 3) perilesional oedema (17/22 lesions). In patients with meningitis, meningeal enhancement (n = 2) and hydrocephalus (n = 1) were infrequently observed. CONCLUSION: This is the first substantial series to describe the radiological features of paradoxical neurological TB-IRIS. Compared to published radiological findings of tuberculomas in HIV-1-infected patients (not receiving ART), an increased inflammatory response is suggested in tuberculoma IRIS. However, this was not observed in patients with TB meningitis IRIS.

Eosinophilia is an established marker of asthma-related inflammation. We assessed the effect of omalizumab on peripheral blood eosinophil counts using a pooled analysis of data from five randomized, double-blind, placebo-controlled studies in patients with moderate-to-severe persistent allergic asthma receiving moderate-to-high-dose inhaled corticosteroids (omalizumab, n=1136; placebo, n=1100). Relationships between omalizumab, peripheral blood eosinophils, serum free IgE concentrations and clinical outcomes were explored. Baseline mean eosinophil counts were similar in each treatment group. Post-treatment eosinophil counts were significantly reduced from baseline in the omalizumab group (p<0.0001) but were not significantly different in the placebo group. Greater reductions in eosinophil counts were observed in patients who had post-treatment free IgE levels <50ng/mL. Three studies included steroid-stable and steroid-reduction phases. At the end of each phase in these studies, a significantly greater reduction in eosinophil counts was achieved in the omalizumab group compared with the placebo group (p<0.0001). A consistent pattern of improved clinical outcomes/decreased eosinophils and worsened clinical outcomes/increased eosinophils was observed for both omalizumab and placebo treatment groups. The findings from our analysis of a large patient population are consistent with earlier reports of the inhibitory effect of omalizumab on eosinophils.

Gc variants of vitamin D binding protein differ in their affinity for vitamin D metabolites that modulate antimycobacterial immunity. We conducted studies to determine whether Gc genotype associates with susceptibility to tuberculosis.123 adult tuberculosis patients and 140 controls of Gujarati Asian ethnic origin in the United Kingdom, 130 adult tuberculosis patients and 78 controls in Brazil, and 281 children with tuberculosis and 182 controls in South Africa were recruited to case-control studies. Gc genotypes were determined and their frequency was compared between cases vs. controls. Serum 25-hydroxyvitamin D (25[OH]D) concentrations were obtained retrospectively for 139 Gujarati Asians, and case-control analysis was stratified by vitamin D status. Interferon-gamma release assays were also performed on 36 Gujarati tuberculosis contacts.The Gc2/2 genotype was strongly associated with susceptibility to active tuberculosis in Gujarati Asians, compared with Gc1/1 genotype (OR 2.81, 95% CI 1.19 to 6.66, P=0.009). This association was preserved if serum 25(OH)D was <20 nmol.l(-1)(P=0.01), but not if serum 25(OH)D was >/=20 nmol.l(-1)(P=0.36). Carriage of the Gc2 allele associated with increased PPD-stimulated Interferon-gamma release in Gujarati Asian tuberculosis contacts (P=0.02). No association between Gc genotype and susceptibility to tuberculosis was observed in other ethnic groups studied.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

AimsMutations in the FERM domain containing 7 (FRMD7) genes are known to cause a significant number of cases of congenital idiopathic nystagmus (CIN). Only limited expression data exist suggesting low levels of expression in all tissues. In this study, we assess the expression profile of the murine homologue of FRMD7(Frmd7) in tissue from three murine organs during development.MethodscDNA was extracted from heart, lung, and brain tissues of MF-1 mice at 12 developmental time points, embryonic days 11-19, postnatal days 1 and 8, and from adult mice. Relative expression of Frmd7mRNA was calculated using quantitative real-time PCR techniques with two normalising genes (Gapdhand Actb).ResultsExpression of Frmd7was low in all tissues consistent with earlier reports. In heart and lung tissues, expression remained very low with an increase only in adult samples. In brain tissue, expression levels were higher at all time points with a significant increase at embryonic day 18, with no gender-specific influence on Frmd7expression.ConclusionsFrmd7is expressed at low levels in all tissues studied suggesting a role in many tissue types. However, higher overall expression and a sharp increase at ED18 in the murine brain suggest a different role in this tissue.Earlier studies have shown that genes expressed in the murine brain during development exhibit temporal functional clustering. The temporal pattern of Frmd7 expression found in this study mirrors that of genes involved in synapse formation/function, and genes related to axon growth/guidance. This suggests a role for Frmd7 in these processes and should direct further expression studies.Eye advance online publication, 6 March 2009; doi:10.1038/eye.2009.44.

Ciliated Bronchial Epithelium (CBE) 1 is a novel gene, expressed in ciliated cells. As cilia are important during embryogenesis, we have characterized the murine homologue of CBE1 (Cbe1) and compared its temporal expression during murine and human lung development.Cbe1 cDNA was cloned and characterised using sequencing, standard PCR and Western blotting. Mouse and human embryonic/foetal lungs (HELs) were harvested for mRNA analysis and protein localisation in vivo and in vitro using RT-PCR and immunohistochemistry.Cbe1 amino acid sequence was >75% identical with CBE1 and its alternative splicing and tissue distribution were highly conserved. Pulmonary expression of Cbe1 mRNA was increased at embryonic day 16 (E16), one day later than Foxj1, consistent with a role in ciliogenesis. In HELs, CBE1 mRNA was detectable at 8-9 weeks post conception and increased in explant culture. CBE1 protein expression was weak at 10 weeks post conception but strong at 12.3 weeks post conception, in parallel with cilia formation. Additionally, Cbe1 mRNA was expressed at E11 (4-5 weeks post conception in HELs) in the absence of Foxj1, implying a distinct role in early development.Chronological regulation of CBE1/Cbe1 expression during pulmonary differentiation suggests involvement in ciliogenesis, with an additional role during early lung development.

SETTING: Newham Chest Clinic, London, UK. OBJECTIVE: To determine the safety and efficacy of the administration of bolus-dose vitamin D(2) in elevating serum 25-hydroxyvitamin D (25[OH]D) concentrations in tuberculosis (TB) patients. DESIGN: A multi-ethnic cohort of TB patients was randomised to receive a single oral dose of 2.5 mg vitamin D(2)(n = 11) or placebo (n = 14). Serum 25(OH)D and corrected calcium concentrations were determined at baseline and 1 week and 8 weeks post-dose, and compared to those of a multi-ethnic cohort of 56 healthy adults receiving an identical dose of vitamin D(2). RESULTS: Hypovitaminosis D (serum 25[OH]D < 75nmol/l) was present in all patients at baseline. A single oral dose of 2.5 mg vitamin D2 corrected hypovitaminosis D in all patients in the intervention arm of the study at 1 week post-dose, and induced a 109.5 nmol/l mean increase in their serum 25(OH)D concentration. Hypovitaminosis D recurred in 10/11 patients at 8 weeks post-dose. No patient receiving vitamin D(2) experienced hypercalcaemia. Patients receiving 2.5 mg vitamin D(2) experienced a greater mean increase in serum 25(OH)D at 1 week post-dose than healthy adults receiving 2.5 mg vitamin D(2). CONCLUSION: A single oral dose of 2.5 mg vitamin D(2) corrects hypovitaminosis D at 1 week but not at 8 weeks post-dose in TB patients.

One of the main aims of system biology is to understand the structure and dynamics of genomic systems. A computational approach, facilitated by new technologies for high-throughput quantitative experimental data, is put forward to investigate the regulatory system of dynamic interaction among genes in Kaposi's sarcoma-associated herpesvirus network after induction of lytic replication. A reconstruction of transcription factor activity and gene-regulatory kinetics using data from a time-course microarray experiment is proposed. The computational approach uses nonlinear differential equations. In particular, the quantitative Michaelis-Menten model of gene-regulatory kinetics is extended to allow for post-transcriptional modifications and synergic interactions between target genes and the Rta transcription factor. The kinetic method is developed within a Bayesian inferential framework using Markov chain Monte Carlo. The profile of the Rta transcriptional regulator, other post-transcriptional regulatory genes and gene-specific kinetic parameters are inferred from the gene expression data of the target genes. The method described here provides an example of a principled approach to handle a wide range of transcriptional network architectures and regulatory activation mechanisms to reconstruct the activity of several transcription factors and activation kinetic parameters in a single regulatory network.

We have previously reported genomic subtypes of CFS/ME based on expression of 88 human genes. In this study we attempted to reproduce these findings, determine specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection. We determined expression levels of 88 human genes in blood of 61 new patients with idiopathic CFS/ME (according to Fukuda criteria), 6 patients with Q-fever associated CFS/ME form the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 18 normal blood donors. In patients with CFS/ME differential expression was confirmed for all 88 genes. Q-CFS/ME patients had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in endogenous depression patients was similar to that in the normal controls, except for upregulation of five genes (APP, CREBBP, GNAS, PDCD2, PDCD6). Clustering of combined gene data in CFS/ME patients for this and our previous study (n=117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF-36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus (EBV), enterovirus, Coxiella burnetii and parvovirus B19 revealed subtype-specific relationships for EBV and enterovirus, the two most common infectious triggers of CFS/ME.

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines following exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

OBJECTIVE: To determine the bioinformatical characteristics of differential gene expression in patients with chronic superficial gastritis (CSG) with the Pi-deficiency syndrome (PDS) and those of the non-Pi-deficiency syndrome (non-PDS), i.e. patients of CSG with Pi-Wei dampnese-heat syndrome and healthy persons. METHODS: With the BRB-Array Tools software package, original data collection and bioinformatic: analysis of gene arrays were conducted in 6 CSG patients of PDS (CSG-PDS), 6 CSG patients of non-PDS (CSG-nPDS), and 6 healthy volunteers (Normal). RESULTS: Compared with non-PDS, the gene expressions: in PDS with regards to protein synthesis, energy metabolism, immune reaction and ionic transport tended to be down-regulated, while those concerning secretion, cytoskeleton and ubiquitinization were up-regulated dominantly. CONCLUSIONS: The two kinds of samples, CSG-PDS/Normal and CSG-PDS/CSG-nPDS, have their respective gene expression profiles with different characteristics. Gene expression profile has certain referential significance in syndrome classification.

ABSTRACT: BACKGROUND: At present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. The hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with CFS and so provide biomarkers for the condition. METHODS: Human genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of patients with post-viral chronic fatigue (n=8) and healthy control subjects (n=7). RESULTS: Patients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significance CONCLUSIONS: Differential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for differential diagnosis and treatment.

BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes. METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays. FINDINGS: There were no significant differences in gene expression for any transcript. CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.

OBJECTIVE: To investigate the differential gene expression profiles in coronary heart disease (CHD) patients of blood-stasis syndrome (BSS) by oligonucleotide microarray technique, and the clinical significance of target gene. METHODS: Subjects were assigned to CHD patients with BSS (n=8), CHD patients without BSS (n=8), and BSS patients without CHD (n=8) based on coronary angiography and the diagnostic criteria of BSS. The sex- and age-matched healthy volunteers (n=8) were enrolled as the control group. Venous blood samples were collected for RNA extraction; Test-3 chip was employed to examine the quality of samples. Then, the samples were hybridized with Affymetrix U133 Plus 2.0 array to compare the gene expression profiles among the four groups. Gene-array scanner and gene chip operating software were applied to screen out hybridization signals and analyze gene expression, respectively. Based on the comparison of the samples of the four groups, the differential genes related with CHD and BSS were analyzed with Gene Ontology (GO) and pathway, and target genes selected were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Thirty CHD patients with BSS were selected according to the former criteria and 40 healthy as controls. The serum concentration of interleukin-8 (IL-8) was determined by double-antibody sandwich avidin-biotin peroxidase complex enzyme-linked (ABC-ELISA). RESULTS: A total of 107 differential genes were found being associated with CHD, including 48 up-regulated genes and 59 down-regulated genes. Among these 107 differential genes, 14 genes (13.1%) were found related to inflammatory reaction and immune response through GO analysis. In the pathway analysis, 4 of 15 conspicuous pathways were referred to the inflammation and immune response. Among 48 differential genes related to BSS, 26 genes were up-regulated, and 22 were down-regulated. Five of the 48 genes (10.4%) and 5 of 10 signficant pathways were involved in inflammation and immunity. The results of real-time RT-PCR proved the accuracy of the gene chip. The patients have markedly higher level of serum IL-8 compared to the controls (P<0.05). CONCLUSION: The correlation of inflammatory- and immune-related genes with CHD patients of BSS was revealed at the level of nucleic acid, and the target gene IL-8 may play a role in the pathobiology of CHD with BSS.

BACKGROUND: Leukapheresis has commonly been used to obtain the cell products intended for clinical cell therapy. Hypocalcemia related to citrate toxicity and some circulatory effects such as hypovolemia and hypotension are well-known complications of leukapheresis. In this study, we analyzed the gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained before and after leukapheresis to determine if the hemodynamic changes can affect the gene expression profiles of leukocytes. METHODS: PBMCs were isolated from EDTA blood from 5 healthy donors collected before and immediately after apheresis. RNA was isolated, amplified, and analyzed using a cDNA microarray with 17,500 genes. Hierarchical clustering analysis was performed to evaluate the differences of gene expression profiling. RESULTS: Hierarchical clustering separated PBMCs from different donors with each other, but did not separate PBMCs collected before and after leukapheresis. Comparison of gene expression by PBMCs collected before and after leukapheresis found only 25 genes were differentially expressed (15 were up-regulated and 10 were down-regulated after leukapheresis)(F-test, P<0.005). Stress induced apoptosis-related genes, ANXA3, DEDD, and ATXN2L, and cytokine-related genes, IL13RA1 and IK, which were also related to stress, were up-regulated after leukapheresis. Genes involved in DNA and protein binding, such as CLSTN3, LRBA, SATB2, and HSPA8, were down-regulated. CONCLUSIONS: Leukapheresis had little effect on gene expression of PBMCs. Some genes showing differences between before and after leukapheresis were mainly involved in stress-related reactions.

Chronic Fatigue Syndrome / myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We have recently reported a study of gene expression which identified differential expression of 88 human genes in patients with CFS/ME. Clustering of QPCR data from CFS/ME patients revealed 7 distinct subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity. In this study, for each CFS/ME subtype, we determined those genes whose expression differed significantly from that of normal blood donors, and then determined gene interactions, disease associations and molecular and cellular functions of those gene sets. Genomic analysis was then related to clinical data for each CFS/ME subtype. Genomic analysis revealed some common (neurological, cancer, immunological, inflammatory, haematological) and some distinct (metabolic, endocrine, dermatological, cardiovascular, connective tissue) disease associations among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was the mildest. Clinical features of each subtype were as follows: subtype 1 (cognitive, musculoskeletal, sleep, anxiety / depression); subtype 2 (musculoskeletal, pain, anxiety / depression); subtype 3 (mild); subtype 4 (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6 (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, anxiety / depression). It is particularly interesting that in these genomically derived subtypes, there were distinct clinical syndromes and that those which were most severe were also those with anxiety / depression, as would be expected in a disease with a biological basis.

In this paper, we introduce a method to detect pathological pathways of a disease. We aim to identify biological processes rather than single genes affected by the chronic fatigue syndrome (CFS). So far, CFS has neither diagnostic clinical signals nor abnormalities that could be diagnosed by laboratory examinations. It is also unclear if the CFS represents one disease or can be subdivided in different categories. We use information from clinical trials, the gene ontology (GO) database as well as gene expression data to identify undirected dependency graphs (UDGs) representing biological processes according to the GO database. The structural comparison of UDGs of sick versus non-sick patients allows us to make predictions about the modification of pathways due to pathogenesis.