Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) is defined by self-reported symptoms. There are no diagnostic signs or laboratory markers, and the pathophysiology remains inchoate. In part, difficulties identifying and replicating biomarkers and elucidating the pathophysiology reflect the heterogeneous nature of the syndromic illness CFS. We conducted this analysis of people from defined metropolitan, urban, and rural populations to replicate our earlier empirical delineation of medically unexplained chronic fatigue and CFS into discrete endophenotypes. Both the earlier and current analyses utilized quantitative measures of functional impairment and symptoms as well as laboratory data. This study and the earlier one enrolled participants from defined populations and measured the internal milieu, which differentiates them from studies of clinic referrals that examine only clinical phenotypes.</p> <p>Methods</p> <p>This analysis evaluated 386 women identified in a population-based survey of chronic fatigue and unwellness in metropolitan, urban, and rural populations of the state of Georgia, USA. We used variables previously demonstrated to effectively delineate endophenotypes in an attempt to replicate identification of these endophenotypes. Latent class analyses were used to derive the classes, and these were compared and contrasted to those described in the previous study based in Wichita, Kansas.</p> <p>Results</p> <p>We identified five classes in the best fit analysis. Participants in Class 1 (25%) were polysymptomatic, with sleep problems and depressed mood. Class 2 (24%) was also polysymptomatic, with insomnia and depression, but participants were also obese with associated metabolic strain. Class 3 (20%) had more selective symptoms but was equally obese with metabolic strain. Class 4 (20%) and Class 5 (11%) consisted of nonfatigued, less symptomatic individuals, Class 4 being older and Class 5 younger. The classes were generally validated by independent variables. People with CFS fell equally into Classes 1 and 2. Similarities to the Wichita findings included the same four main defining variables of obesity, sleep problems, depression, and the multiplicity of symptoms. Four out of five classes were similar across both studies.</p> <p>Conclusion</p> <p>These data support the hypothesis that chronic medically unexplained fatigue is heterogeneous and can be delineated into discrete endophenotypes that can be replicated. The data do not support the current perception that CFS represents a unique homogeneous disease and suggests broader criteria may be more explanatory. This replication suggests that delineation of endophenotypes of CFS and associated ill health may be necessary in order to better understand etiology and provide more patient-focused treatments.</p

The phosphatase PTEN-mediated control of PI-3 kinase in Tregs cells maintains homeostasis and lineage stability

Foxp3+ regulatory T cells (Tregs) are required for immune homeostasis. One notable distinction between conventional T cells (Tconv) and Tregs is differential phosphatidylinositol 3-kinase (PI3K) activity: only Tconv downregulate PTEN, the primary negative regulator of PI3K, upon activation. Here, we show that control of PI3K in Tregs is essential for lineage homeostasis and stability. Mice lacking Pten in Tregs developed an autoimmune-lymphoproliferative disease characterized by excessive TH1 responses and B cell activation. Diminished control of PI3K activity in Tregs led to reduced CD25 expression, accumulation of Foxp3+CD25− cells and ultimately, loss of Foxp3 expression in these cells. Collectively, these data demonstrate that control of PI3K signaling by PTEN in Tregs is critical to maintain their homeostasis, function and stability

A compendium of ecological knowledge for restoration of freshwater fishes in Australia’s Murray–Darling Basin

Many freshwater fishes are imperilled globally, and there is a need for easily accessible, contemporary ecological knowledge to guide management. This compendium contains knowledge collated from over 600 publications and 27 expert workshops to support the restoration of 9 priority native freshwater fish species, representative of the range of life-history strategies and values in south-eastern Australia’s Murray–Darling Basin. To help prioritise future research investment and restoration actions, ecological knowledge and threats were assessed for each species and life stage. There is considerable new knowledge (80% of publications used were from the past 20 years), but this varied among species and life stages, with most known about adults, then egg, juvenile and larval stages (in that order). The biggest knowledge gaps concerned early life stage requirements, survival, recruitment, growth rates, condition and movements. Key threats include reduced longitudinal and lateral connectivity, altered flows, loss of refugia, reductions in both flowing (lotic) and slackwater riverine habitats, degradation of wetland habitats, alien species interactions and loss of aquatic vegetation. Examples and case studies illustrating the application of this knowledge to underpin effective restoration management are provided. This extensive ecological evidence base for multiple species is presented in a tabular format to assist a range of readers

Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States

<p>Abstract</p> <p>Background</p> <p>XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories.</p> <p>Results</p> <p>Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a <it>gag </it>and a <it>pol </it>nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls.</p> <p>Conclusions</p> <p>We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS.</p

Blood Signature of Pre-Heart Failure: A Microarrays Study

International audienceBACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p&lt;0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p&lt;0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p&lt;0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Long-Term Infection and Vertical Transmission of a Gammaretrovirus in a Foreign Host Species

Increasing evidence has indicated natural transspecies transmission of gammaretroviruses; however, viral-host interactions after initial xeno-exposure remain poorly understood. Potential association of xenotropic murine leukemia virus-related virus (XMRV) in patients with prostate cancer and chronic fatigue syndrome has attracted broad interests in this topic. Although recent studies have indicated that XMRV is unlikely a human pathogen, further understanding of XMRV xenoinfection would allow in vivo modeling of the initial steps of gammaretroviral interspecies transmission, evolution and dissemination in a new host population. In this study, we monitored the long-term consequences of XMRV infection and its possible vertical transmission in a permissive foreign host, wild-derived Mus pahari mice. One year post-infection, XMRV-infected mice showed no notable pathological changes, while proviral DNA was detected in three out of eight mice. XMRV-infected mice remained seropositive throughout the study although the levels of gp70 Env- and p30 capsid-specific antibodies gradually decreased. When vertical XMRV transmission was assessed, no viremia, humoral immune responses nor endogenization were observed in nine offspring from infected mothers, yet one offspring was found PCR-positive for XMRV-specific sequences. Amplified viral sequences from the offspring showed several mutations, including one amino acid deletion in the receptor binding domain of Env SU. Our results therefore demonstrate long-term asymptomatic infection, low incidence of vertical transmission and limited evolution of XMRV upon transspecies infection of a permissive new host, Mus pahari