This study utilised the killing curve method to determine the in vitro effects of all possible two drug combinations of ceftazidine, cefotaxime, cefuroxime, ciprofloxacin, chloramphenicol, imipenem and temocillin against 10 strains of Pseudomonas cepacia isolated from the sputa of cystic fibrosis patients. The incidence of synergy was 21% and that of antagonism was 5.2%. Combinations associated with synergy for 30% of isolates were ceftazidime/cefotaxime, ceftazidime/cefuroxime, cefotaxime/ciprofloxacin, cefotaxime/chloramphenicol, ciprofloxacin/temocillin, and imipenem/ciprofloxacin. Combinations associated with synergy for 40% of isolates were ceftazidime/ciprofloxacin, cefotaximel temocillin, and imipenem/temocillin. The combination of ceftazidime/temocillin was associated with synergy against 70% of isolates. The present study therefore identifies several antibiotic combinations that may prove valuable, if confirmed in clinical studies, for treatment of P. cepacia infections.

David Tyrrell is remembered by physicians and scientists principally for his discovery of the common cold viruses and elucidation of their pathogenesis, but also for his work in various other areas, including influenza, bovine spongiform encephalopathy (BSE) and chronic fatigue syndrome (CFS). David possessed a deep humanity, honesty, perseverance and a vision of collaboration as a means of making discoveries that would contribute meaningfully to the alleviation of human suffering. He also had a warmth and a mischievous sense of humour that was frequently directed at bureaucracy, which he thoroughly disliked.

Summary Since conducting follow-up studies of patients with acute symptomatic parvovirus B19 infection which showed that a significant proportion of patients develop prolonged arthritis and chronic fatigue syndrome (CFS), we have become interested in the mechanisms of this phenomenon. We showed that these cases have high levels of pro-inflammatory cytokines in their circulation and that this correlates with the symptoms. However, the underlying mechanisms were not apparent, and we have used various approaches to begin studying this phenomenon. DNA polymorphisms were looked for and several were shown to be more common in these subjects compared with controls; these occur within genes of both the immune response [human leucocyte antigen (HLA)-DRB1, HLA-B, transforming growth factor (TGF)-beta1] and those involved in several other cellular functions (predominantly the cytoskeleton and cell adhesion). Interestingly, one particular single-nucleotide polymorphism (SNP) which is associated with symptomatic B19 infection occurs in the Ku80 gene which has recently been shown to be a B19 co-receptor. B19 persistence is probably the key to this phenomenon, and some new data are presented on short regions of sequence homology (17-26 bp) between human, mouse and rat parvoviruses and their respective hosts which occur in many host genes. This homology may provide a foothold for virus persistence and may also play a role in the genesis of disease through gene disruption. Finally, we used microarrays and TaqMan real-time polymerase chain reaction in 108 normal persons to study human gene expression in persons who are B19-seropositive versus B19-seronegative (age- and sex-matched) to examine the hypothesis that gene regulation may be altered in subjects harbouring the B19 virus DNA. Six genes were found to be differentially expressed with roles in the cytoskeleton (SKIP, MACF1, SPAG7, FLOT1), integrin signalling (FLOT1, RASSF5), HLA class III (c6orf48), and tumour suppression (RASSF5). These results have implications not only for B19 but also for other persistent viruses as well and confirmation is required. In conclusion, these disparate findings contribute to our understanding of the pathogenesis of B19 disease. We are using these studies as a starting point to study the phenomenon of chronic immune activation following B19 infection.

BACKGROUND: A genetic component to the development of chronic fatigue syndrome (CFS) has been proposed, and a possible association between human leucocyte antigen (HLA) class II antigens and chronic fatigue immune dysfunction has been shown in some, but not all, studies. AIMS: To investigate the role of HLA class II antigens in CFS. METHODS: Forty nine patients with CFS were genotyped for the HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the frequency of these alleles was compared with a control group comprising 102 normal individuals from the UK. All patients and controls were from the same region of England and, apart from two patients, were white. RESULTS: Analysis by 2 x 2 contingency tables revealed an increased frequency of HLA-DQA1*01 alleles in patients with CFS (51.0% v 35%; odds ratio (OR), 1.93; p = 0.008). HLA-DQB1*06 was also increased in the patients with CFS (30.2% v 20.0%; OR, 1.73, p = 0.052). Only the association between HLA-DQA1*01 and CFS was significant in logistic regression models containing HLA-DQA1*01 and HLA-DRQB1*06, and this was independent of HLA-DRB1 alleles. There was a decreased expression of HLA-DRB1*11 in CFS, although this association disappeared after correction for multiple comparisons. CONCLUSIONS: CFS may be associated with HLA-DQA1*01, although a role for other genes in linkage disequilibrium cannot be ruled out.

BACKGROUND: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. AIMS: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. METHODS: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. RESULTS: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. CONCLUSION: These results suggest that patients with CFS have reproducible alterations in gene regulation.

This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1-D2 region of the large ribosomal subunit revealed 100% homology with Aspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.

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.

Patients with chronic fatigue syndrome (CFS) frequently associate the disease onset with a period of high physical and/or emotional stress. Alterations in hypothalamic-pituitary adrenal axis (HPA) function have been demonstrated. Although Cortisol production in patients with CFS has proven to be low, Dehydroepiandrosterone (DHEA) production has not been measured. DHEA output may be altered in this population. The purpose of this uncontrolled, prospective, 6 month study of 23 white women, ages 35-55 was to identify CFS patients with suboptimal serum levels of DHEA-sulphate (DHEA-S), defined as DHEA-S <2.0mug/mL, and to treat those patients with oral DHEA. DHEA-S levels were re-measured after 4-6 weeks of oral DHEA therapy (25 mg). If DHEA-S remained <2.0mug/ mL, or if no clinical response was achieved after 4-6 weeks of therapy, then an increased dose of DHEA was given. Physical and psychological impairment and disability status were measured by the MHAQII before DHEA intervention and at 3-month intervals. Of initially screened patients with CFS, 76%(116 of 153) were ages 35-55, and 89%(103 of 116) had suboptimal (<2.0mug/mL) production of DHEA-S.Supplementation with DHEA to CFS patients lead to a significant reduction in the symptoms of CFS: pain (improved by 18%, p = 0.035), fatigue (decreased by 21%, p = 0.009)), activities of daily living (improved by 8.5%, p = 0.058), helplessness (decreased by 11%, p = 0.015), anxiety (decreased by 35%, p < 0.01), thinking (improved by 26%, p < 0.01), memory (improved by 17%, p < 0.05), and sexual problems (improved by 22%, p = 0.06) over the period of the trial. Further study is necessary to determine the safety and efficacy of supplementation of DHEA to this population in a controlled setting.

THE AIM OF THE STUDY: To evaluate the chronic fatigue and its relation to the function of hypothalamus-pituitary-adrenal axis in patients with New York Heart Association (NYHA) functional class III-IV chronic heart failure. MATERIAL AND METHODS: A total of 170 patients with NYHA functional class III-IV chronic heart failure completed MFI-20L, DUFS, and DEFS questionnaires assessing chronic fatigue and underwent echocardiography. Blood cortisol concentration was assessed at 8:00 am and 3:00 pm, and plasma N-terminal brain natriuretic pro-peptide (NT-proBNP) concentration was measured at 8:00 am. Neurohumoral investigations were repeated before cardiopulmonary exercise test and after it. RESULTS: The results of all questionnaires showed that 100% of patients with NYHA functional class III-IV heart failure complained of chronic fatigue. The level of overall fatigue was 54.5+/-31.5 points; physical fatigue - 56.8+/-24.6 points. Blood cortisol concentration at 8:00 am was normal (410.1+/-175.1 mmol/L) in majority of patients. Decreased concentration was only in four patients (122.4+/-15.5 mmol/L); one of these patients underwent heart transplantation. In the afternoon, blood cortisol concentration was insufficiently decreased (355.6+/-160.3 mmol/L); reaction to a physical stress was attenuated (Delta 92.9 mmol/L). Plasma NT-proBNP concentration was 2188.9+/-1852.2 pg/L; reaction to a physical stress was diminished (Delta 490.3 pg/L). CONCLUSION: All patients with NYHA class III-IV heart failure complained of daily chronic fatigue. Insufficiently decreased blood cortisol concentration in the afternoon showed that in the presence of chronic fatigue in long-term cardiovascular organic disease, disorder of a hypothalamus-pituitary-adrenal axis is involved.

This paper points out that the sub-health state is not equal to chronic fatigue syndrome (CFS) on basis of elaborating the concept and category of sub-health. And the present understanding on concepts of fatigue, chronic fatigue and CFS, as well as the diagnosis criteria and differential diagnosis of CFS are discussed systematically.

Complex chronic diseases require an increasing proportion of society's resources and represent a growing challenge. Valid biomedical models of etiology, pathogenesis, treatment and prognosis are inadequate for understanding these diseases. The article discusses current knowledge about the impact of stress on the immune-, hormonal - and central nervous systems, and integrates this knowledge with a phenomenological understanding of the body in an attempt to explain the complex chronic fatigue syndrome. The medical significance of the individual's biography is highlighted, and the inadequacy of statistically grounded biomedical research when aiming to understand complex disease is presented. By regarding human beings as persons who experience bodily and who both create and convey meaning, we claim to have transgressed the mind-body-dichotomy in complex disease development. The dichotomy converges in the living body.

Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) is a disease characterised by severe and debilitating fatigue, sleep abnormalities, impaired memory and concentration, and musculoskeletal pain. In the Western world, the population prevalence is estimated to be of the order of 0.5%. Research studies have identified various features relevant to the pathogenesis of CFS/ME such as viral infection, immune abnormalities and immune activation, exposure to toxins, chemicals and pesticides, stress, hypotension, lymphocyte abnormalities and neuroendocrine dysfunction. However, the precise underlying disease mechanisms and means by which these abnormalities inter-relate in CFS/ME patients, remain to be clarified. Various viruses have been shown to play a triggering or perpetuating role, or both, in this complex disease. Microbes which have been shown to trigger CFS/ME include enteroviruses, Epstein-Barr virus, Chlamydia pneumoniae, parvovirus B19, Coxiella burnetii, Borna disease virus, Varicella Zoster virus, cytomegalovirus, and human herpesvirus type 6 (HHV-6). Chronic microbial infections which have been documented in CFS/ME patients include Coxiella burnetii, parvovirus B19, Chlamydia pneumoniae, hepatitis C, enteroviruses and human retroviruses. Virus reactivations in CFS/ME include Varicella-Zoster virus, Herpes Simplex virus (HSV)(increased frequency of cold sores) and EBV.

Chronic fatigue syndrome (CFS) is now recognized as a medial disorder. In contrast to recent related reports, the present review focuses primarily on aetiological aspects of CFS. Four major hypotheses are reviewed.(1) Although CFS is often associated with viral infection, the presence of viruses has as yet not consistently been detected.(2) It is not clear whether anomalies of the HPA axis often observed in CFS, are cause or the consequences of the disorder.(3) Immune dysfunction as the cause of CFS is thus far the weakest hypothesis.(4) The psychiatric and psychosocial hypothesis denies the existence of CFS as a disease entity. Accordingly, the fatigue symptoms are assumed to be the consequence of other (somatic) diseases. Other possible causes of CFS are oxidative stress and genetic predisposition. In CFS cognitive behavioural therapy is most commonly used. This therapy, however, appears to be ineffective in many patients. The suggested causes of CFS and the divergent reactions to therapy may be explained by the lack of recognition of subgroups. Identification of subtypes may lead to more effective therapeutic interventions.

Fatigue and lack of energy are frequent symptoms in children and adolescents. A diagnosis of chronic fatigue syndrome should be considered in children and adolescents who complain of chronic fatigue associated with other symptoms without a demonstrable physical cause. Lack of knowledge about this syndrome and late diagnosis may have a negative impact on the normal development of affected children and adolescents. Treatment should be based on a rehabilitation program with cognitive behavioral therapy and a gradual increase in activities.

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS. Copyright (c) 2007 S. Karger AG, Basel.

Though patients with chronic fatigue syndrome (CFS) have lots of complaints, abnormal findings cannot be detected by biochemical screening tests. However, some specialized blood tests have revealed neuroendocrine immune axis abnormalities, which is closely associated with each other. Recent studies indicate that CFS can be understood as a special condition based on abnormality of the psycho-neuro-endocrino-immunological system, with the distinguishing feature of CFS seeming to be the secondary brain dysfunction caused by several cytokines and/or autoantibodies. In this paper, we summarize these abnormalities found in CFS and show the neuro-molecular mechanism leading to chronic fatigue.