Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis

Epstein-Barr virus (EBV) has been associated with multiple sclerosis (MS), however, most studies examining the relationship between the virus and the disease have been based on serologies, and if EBV is linked to MS, CD8+ T cells are likely to be involved as they are important both in MS pathogenesis and in controlling viruses. We hypothesized that valuable information on the link between MS and EBV would be ascertained from the study of frequency and activation levels of EBV-specific CD8+ T cells in different categories of MS patients and control subjects. We investigated EBV-specific cellular immune responses using proliferation and enzyme linked immunospot assays, and humoral immune responses by analysis of anti-EBV antibodies, in a cohort of 164 subjects, including 108 patients with different stages of MS, 35 with other neurological diseases and 21 healthy control subjects. Additionally, the cohort were all tested against cytomegalovirus (CMV), another neurotropic herpes virus not convincingly associated with MS, nor thought to be deleterious to the disease. We corrected all data for age using linear regression analysis over the total cohorts of EBV- and CMV-infected subjects. In the whole cohort, the rate of EBV and CMV infections were 99% and 51%, respectively. The frequency of IFN-gamma secreting EBV-specific CD8+ T cells in patients with clinically isolated syndrome (CIS) was significantly higher than that found in patients with relapsing-remitting MS (RR-MS), secondary-progressive MS, primary-progressive MS, patients with other neurological diseases and healthy controls. The shorter the interval between MS onset and our assays, the more intense was the EBV-specific CD8+ T-cell response. Confirming the above results, we found that EBV-specific CD8+ T-cell responses decreased in 12/13 patients with CIS followed prospectively for 1.0 +/- 0.2 years. In contrast, there was no difference between categories for EBV-specific CD4+ T cell, or for CMV-specific CD4+ and CD8+ T-cell responses. Anti-EBV-encoded nuclear antigen-1 (EBNA-1)-specific antibodies correlated with EBV-specific CD8+ T cells in patients with CIS and RR-MS. However, whereas EBV-specific CD8+ T cells were increased the most in early MS, EBNA-1-specific antibodies were increased in early as well as in progressive forms of MS. Our data show high levels of CD8+ T-cell activation against EBV--but not CMV--early in the course of MS, which support the hypothesis that EBV might be associated with the onset of this disease.

Neuroanatomical and neuropsychological features of elderly euthymic depressed patients with early- and late-onset.

BACKGROUND: Whether or not cognitive impairment and brain structure changes are trait characteristics of late-life depression is still disputed. Previous studies led to conflicting data possibly because of the difference in the age of depression onset. In fact, several lines of evidence suggest that late-onset depression (LOD) is more frequently associated with neuropsychological deficits and brain pathology than early-onset depression (EOD). To date, no study explored concomitantly the cognitive profile and brain magnetic resonance imaging (MRI) patterns in euthymic EOD and LOD patients. METHOD: Using a cross-sectional design, 41 remitted outpatients (30 with EOD and 11 with LOD) were compared to 30 healthy controls. Neuropsychological evaluation concerned working memory, episodic memory, processing speed, naming capacity and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. White matter hyperintensities were assessed semiquantitatively. RESULTS: Both cognitive performance and brain volumes were preserved in euthymic EOD patients whereas LOD patients showed a significant reduction of episodic memory capacity and a higher rate of periventricular hyperintensities compared to both controls and EOD patients. CONCLUSION: Our results support the dissociation between EOD thought to be mainly related to psychosocial factors and LOD that is characterized by increasing vascular burden and episodic memory decline.

First day of an oil spill on the open sea: early mass transfers of hydrocarbons to air and water.

During the first hours after release of petroleum at sea, crude oil hydrocarbons partition rapidly into air and water. However, limited information is available about very early evaporation and dissolution processes. We report on the composition of the oil slick during the first day after a permitted, unrestrained 4.3 m(3) oil release conducted on the North Sea. Rapid mass transfers of volatile and soluble hydrocarbons were observed, with >50% of ≤C17 hydrocarbons disappearing within 25 h from this oil slick of <10 km(2) area and <10 μm thickness. For oil sheen, >50% losses of ≤C16 hydrocarbons were observed after 1 h. We developed a mass transfer model to describe the evolution of oil slick chemical composition and water column hydrocarbon concentrations. The model was parametrized based on environmental conditions and hydrocarbon partitioning properties estimated from comprehensive two-dimensional gas chromatography (GC×GC) retention data. The model correctly predicted the observed fractionation of petroleum hydrocarbons in the oil slick resulting from evaporation and dissolution. This is the first report on the broad-spectrum compositional changes in oil during the first day of a spill at the sea surface. Expected outcomes under other environmental conditions are discussed, as well as comparisons to other models.

The hourglass and the early conservation models--co-existing patterns of developmental constraints in vertebrates.

Developmental constraints have been postulated to limit the space of feasible phenotypes and thus shape animal evolution. These constraints have been suggested to be the strongest during either early or mid-embryogenesis, which corresponds to the early conservation model or the hourglass model, respectively. Conflicting results have been reported, but in recent studies of animal transcriptomes the hourglass model has been favored. Studies usually report descriptive statistics calculated for all genes over all developmental time points. This introduces dependencies between the sets of compared genes and may lead to biased results. Here we overcome this problem using an alternative modular analysis. We used the Iterative Signature Algorithm to identify distinct modules of genes co-expressed specifically in consecutive stages of zebrafish development. We then performed a detailed comparison of several gene properties between modules, allowing for a less biased and more powerful analysis. Notably, our analysis corroborated the hourglass pattern at the regulatory level, with sequences of regulatory regions being most conserved for genes expressed in mid-development but not at the level of gene sequence, age, or expression, in contrast to some previous studies. The early conservation model was supported with gene duplication and birth that were the most rare for genes expressed in early development. Finally, for all gene properties, we observed the least conservation for genes expressed in late development or adult, consistent with both models. Overall, with the modular approach, we showed that different levels of molecular evolution follow different patterns of developmental constraints. Thus both models are valid, but with respect to different genomic features.

American Cancer Society guideline for the early detection of prostate cancer: update 2010.

In 2009, the American Cancer Society (ACS) Prostate Cancer Advisory Committee began the process of a complete update of recommendations for early prostate cancer detection. A series of systematic evidence reviews was conducted focusing on evidence related to the early detection of prostate cancer, test performance, harms of therapy for localized prostate cancer, and shared and informed decision making in prostate cancer screening. The results of the systematic reviews were evaluated by the ACS Prostate Cancer Advisory Committee, and deliberations about the evidence occurred at committee meetings and during conference calls. On the basis of the evidence and a consensus process, the Prostate Cancer Advisory Committee developed the guideline, and a writing committee drafted a guideline document that was circulated to the entire committee for review and revision. The document was then circulated to peer reviewers for feedback, and finally to the ACS Mission Outcomes Committee and the ACS Board of Directors for approval. The ACS recommends that asymptomatic men who have at least a 10-year life expectancy have an opportunity to make an informed decision with their health care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to make a decision whether to be tested.

Early antifungal intervention strategies in ICU patients.

PURPOSE OF REVIEW: Despite progress in the understanding of the pathophysiology of invasive candidiasis, and the development of new classes of well tolerated antifungals, invasive candidiasis remains a disease difficult to diagnose, and associated with significant morbidity and mortality. Early antifungal treatment may be useful in selected groups of patients who remain difficult to identify prospectively. The purpose of this review is to summarize the recent development of risk-identification strategies targeting early identification of ICU patients susceptible to benefit from preemptive or empirical antifungal treatment. RECENT FINDINGS: Combinations of different risk factors are useful in identifying high-risk patients. Among the many risk factors predisposing to invasive candidiasis, colonization has been identified as one of the most important. In contrast to prospective surveillance of the dynamics of colonization (colonization index), integration of clinical colonization status in risk scores models significantly improve their accuracy in identifying patients at risk of invasive candidiasis. SUMMARY: To date, despite limited prospective validation, clinical models targeted at early identification of patients at risk to develop invasive candidiasis represent a major advance in the management of patients at risk of invasive candidiasis. Moreover, large clinical studies using such risk scores or predictive rules are underway.

Early settlement and growth of Western Iowa; or, Reminiscences,1906.

Observations and experiences of the early growth in the mid to late 1800's of western Iowa of Rev. John Todd of Tabor, Iowa. It also includes his biography.

Early childhood network, 2005.

This brochure states the mission of the Early Childhood Network along with contact names and addresses of the specialists and consultants in the Iowa Department of Education and the Iowa Area Education Agencies for the years 2005/2006.

Islet-brain1/JNK-interacting protein-1 is required for early embryogenesis in mice.

Islet-brain1/JNK-interacting protein-1 (IB1/JIP-1) is a scaffold protein that organizes the JNK, MKK7, and MLK1 to allow signaling specificity. Targeted disruption of the gene MAPK8IP1 encoding IB1/JIP-1 in mice led to embryonic death prior to blastocyst implantation. In culture, no IB1/JIP-1(-/-) embryos were identified indicating that accelerated cell death occurred during the first cell cycles. IB1/JIP-1 expression was detected in unfertilized oocytes, in spermatozoa, and in different stages of embryo development. Thus, despite the maternal and paternal transmission of the IB1/JIP-1 protein, early transcription of the MAPK8IP1 gene is required for the survival of the fertilized oocytes.

Public health significance of bipolar disorder: implications for early intervention and prevention.

OBJECTIVES: Early intervention and preventive strategies have become major targets of research and service development in psychiatry over the last few years. Compared to schizophrenia, bipolar disorder (BD) has received limited attention in this regard. In this paper, we review the available literature in order to explore the public health significance of BD and the extent to which this may justify the development of early intervention strategies for this disorder. METHODS: The main computerized psychiatric literature databases were accessed. This included Medline and PsychInfo, using the following keywords: bipolar, early intervention, staging model, burden, caregiver, public health, and manic depression. RESULTS: BD is often recurrent and has an impact that goes well beyond symptomatic pathology. The burden it incurs is linked not only to its cardinal clinical features, but also to cognitive dysfunction, poor functional outcome, poor physical health, high rate of comorbidities, and suicide. At a societal level, BD induces enormous direct and indirect costs and has a major impact on caregivers. The available literature reveals a usually long delay between illness onset and the start of treatment, and the absence of specific guidelines for the treatment of the early phase of BD. CONCLUSIONS: Considering the major impact of BD on patients and society, there is an urgent need for the development of early intervention strategies aimed at earlier detection and more specific treatment of the early phase of the disorder.

Early production of IL-4 in susceptible mice infected with Leishmania major rapidly induces IL-12 unresponsiveness.

Previous results have documented a burst of IL-4 mRNA that peaks in draining lymph nodes of susceptible BALB/c mice 16 h after infection with Leishmania major. The importance of this early IL-4 response in subsequent Th2 cell maturation is supported by observations showing that 1) neutralization of IL-4 at the initiation of infection or 2) administration of IL-12, which results in an inhibition of the 16 h IL-4 mRNA burst, inhibits Th2 cell development. However, both treatments are effective in hampering Th2 cell development only if given at a time when IL-4 has been produced for &lt;48 h. At this time after infection, lymph node CD4+ T cells from BALB/c mice no longer respond to IL-12. This IL-12 unresponsiveness is prevented in mice treated with anti-IL-4 Abs at the initiation of infection. Finally, the inhibition of Th2 development in BALB/c mice treated with anti-IL-4 Abs at the onset of infection results from maintenance of IL-12 responsiveness, since it requires IL-12. Together, these results reveal a narrow window of time, between 16 h and &lt;48 h after infection, during which IL-4 produced rapidly in BALB/c mice renders T cells unresponsive to IL-12, allowing their differentiation toward the Th2 phenotype.

Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures.

Xenobiotic exposure is a risk factor in the etiology of neurodegenerative disease. It was recently hypothesized that restricted exposure during brain development could predispose for a neurodegenerative disease later in life. As neuroinflammation contributes to progressive neurodegeneration, it is suspected that neurodevelopmental xenobiotic exposure could elicit a neuroinflammatory process, which over time may assume a detrimental character. We investigated the neurotoxic effects of paraquat (PQ) in three-dimensional whole rat brain cell cultures, exposed during an early differentiation stage, comparing immediate effects-directly post exposure-with long-term effects, 20 days after interrupted PQ-administration. Adverse effects and neuroinflammatory responses were assessed by measuring changes in gene- and protein-expression as well as by determining cell morphology changes. Differentiating neural cultures were highly susceptible to PQ and showed neuronal damage and strong astrogliosis. After the 20-day washout period, neurons partially recovered, whereas astrogliosis persisted, and was accompanied by microglial activation of a neurodegenerative phenotype. Our data shows that immediate and long-term effects of subchronic PQ-exposure differ. Also, PQ-exposure during this window of extensive neuronal differentiation led to a delayed microglial activation, of a character that could promote further pro-inflammatory signals that enable prolonged inflammation, thereby fueling further neurodegeneration.