Herpes simplex virus type 1 (HSV-1) persists within the host in the presence of concomitant immunity by establishing a latent infection within sensory neurons. HSV-1 latency is widely viewed as a ...neuron-enforced quiescent state of the virus, in which a lack of viral protein synthesis prevents recognition of the infected neuron by the host immune system. On the basis of recent findings, however, we propose a more dynamic view of HSV-1 latency characterized by persistent or intermittent low-level viral gene expression in some latently infected neurons. We further propose that HSV-1-specific memory/effector CD8
+ T lymphocytes that are retained in the ganglion in close apposition to the neurons prevent full reactivation and virion formation through IFN-γ production and an additional undefined mechanism(s).
To examine the normal murine corneal stroma for the presence of bone marrow-derived leukocytes.
Wholemounts of paraformaldehyde-fixed corneal stroma from normal mice at 5 to 16 weeks of age were ...examined in single- and double-color immunomorphologic studies performed with confocal microscopy. The phenotype, morphology, distribution, and density of immunopositive cells were determined.
Numerous CD45(+) cells with pleomorphic and dendriform morphology were found within the pericentral and central region of the corneal stroma (200-300 cells/mm(2)). Dual-color immunostaining demonstrated that 100% of the CD45(+) cells coexpressed CD11b and 50% coexpressed F4/80. Approximately 30% of the total cells and 50% of the F4/80(+) cells coexpressed major histocompatibility complex (MHC) class II antigens. Very small to negligible numbers of cells expressed markers of dendritic cells (CD11c) or granulocytes (Ly6G). Markers for T-cells and NK cells were absent from the corneal stroma, indicating that all the cells identified in the stroma were of the myeloid lineage.
The normal murine corneal stroma contains a significant number of CD45(+) leukocytes. Most these cells express the CD11b marker, but not other dendrite, granulocyte, T-cell, or NK markers, placing them in the monocyte/macrophage lineage.
Many important aspects of cancer biology, such as cancer initiation, progression, and metastasis, have been studied in animal models, mostly mice. As long as cancer was considered primarily a genetic ...disease, the study of transplantable mouse tumors, or even human tumor xenografts in immunocompromised mice, appeared to suffice. Many important genetic events that lead to transformation and in vivo tumor growth were elucidated. However, many even more important factors that determine whether or not the genetic potential of a tumor cell will be realized, such as the host response to the tumor and the tumor microenvironment that influences this response over a long period of time of tumor development, remained untested and unappreciated. This is slowly changing with the advent of molecular techniques that have spurred efforts to engineer better mouse models of human tumors. In this review, we show results of our efforts to combine a genetic mouse model of spontaneous human adenocarcinomas based on a Kras mutation, with an important human molecule MUC1 that is abnormally expressed on human adenocarcinomas, promoting oncogenesis, proinflammatory tumor microenvironment, and immunosurveillance.
During early childhood, herpes simplex virus type 1 (HSV-1) can establish a latent infection in sensory neurons, which then serves as a reservoir of the virus during recurrent disease. Accordingly, ...recurrent herpetic disease appears to result primarily from the reactivation of latent virus and its transport down nerve axons to the periphery, rather than from exogenous re-infection. Eradicating latent HSV-1 from sensory neurons is not currently feasible but recent findings implicating host immunity in maintaining HSV-1 in a latent state provide promise for immunological intervention in recurrent herpetic disease. We propose, and provide supporting evidence, for the concept that CD8
+ T cells regulate
HSV-1 gene expression during latency.
Recent studies have demonstrated that projected climate change will likely enhance nitrogen (N) and phosphorus (P) loss from farms and farmland, with the potential to worsen freshwater ...eutrophication. Here, we investigate the relative importance of the climate and land use drivers of nutrient loss in nine study catchments in Europe and a neighboring country (Turkey), ranging in area from 50 to 12,000 km2. The aim was to quantify whether planned large-scale, land use change aimed at N and P loss reduction would be effective given projected climate change. To this end, catchment-scale biophysical models were applied within a common framework to quantify the integrated effects of projected changes in climate, land use (including wastewater inputs), N deposition, and water use on river and lake water quantity and quality for the mid-21st century. The proposed land use changes were derived from catchment stakeholder workshops, and the assessment quantified changes in mean annual N and P concentrations and loads. At most of the sites, the projected effects of climate change alone on nutrient concentrations and loads were small, whilst land use changes had a larger effect and were of sufficient magnitude that, overall, a move to more environmentally focused farming achieved a reduction in N and P concentrations and loads despite projected climate change. However, at Beyşehir lake in Turkey, increased temperatures and lower precipitation reduced water flows considerably, making climate change, rather than more intensive nutrient usage, the greatest threat to the freshwater ecosystem. Individual site responses did however vary and were dependent on the balance of diffuse and point source inputs. Simulated lake chlorophyll-a changes were not generally proportional to changes in nutrient loading. Further work is required to accurately simulate the flow and water quality extremes and determine how reductions in freshwater N and P translate into an aquatic ecosystem response.
Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest ...the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40(+) cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L(+) cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L(+) cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11c. Our findings demonstrate rapid infiltration of activated (OX40(+)) CD4(+) T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II(+) CD11c(+) DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.
To evaluate the role of CD4(+) T cells in the development of murine herpes stromal keratitis (HSK).
The corneas of wild-type (WT) BALB/c mice and three types of CD4-deficient BALB/c mice (CD4(-/-), ...CD4-depleted, CD4 and CD8 double-depleted) were infected with different doses of HSV-1 RE, and HSK incidence and severity were monitored. Corneal infiltrates were quantitatively and functionally assayed by flow cytometric analysis of individually digested diseased corneas and documented histologically.
At a relatively high infectious dose (1 x 10(5) pfu/cornea): (1) CD4-deficient and WT BALB/c mice had severe HSK with a similar incidence (80%-100%), whereas HSK did not develop in mice deficient in both CD4(+) and CD8(+) T cells; (2) neutrophils were the predominate leukocyte in the corneas of CD4-deficient and WT mice; (3) the corneas of WT mice had activated, HSV-1-specific CD4(+) T cells, but few if any CD8(+) T cells; (4) the corneas of CD4-deficient mice had activated, HSV-1-specific CD8(+) T cells; and (5) HSK in CD4-deficient mice was transient, showing loss of CD8(+) T cells at 2 to 3 weeks after infection (pi) followed by a loss of neutrophils. At a relatively low infectious dose of HSV-1 (10(3) pfu/cornea) severe HSK developed in 80% to 90% of WT mice, but in only 30% to 40% of CD4-deficient mice.
CD4(+) T cells preferentially mediate HSK, but, in their absence, a high infectious dose of HSV-1 can induce histologically similar but transient HSK that is mediated by CD8(+) T cells.
Approximately 7 days after HSV-1 corneal infection, BALB/c mice develop tissue-destructive inflammation in the cornea termed herpes stromal keratitis (HSK), as well as periocular skin lesions that ...are characterized by vesicles, edema, and fur loss. CD4(+) T cells and Th1 cytokines contribute to both the immunopathology in the cornea and the eradication of viral replication in the skin. We demonstrate that disruption of CD40/CD154 signaling does not impact the initial expansion of CD4(+) T cells in the draining lymph nodes, but dramatically reduces the persistence and Th1 polarization of these cells. Despite the reduced Th1 response, CD154(-/-) mice developed HSK and periocular skin disease with similar kinetics and severity (as assessed by clinical examination) as wild-type (WT) mice. However, when the composition of the inflammatory infiltrate was examined by flow cytometric analysis, CD154(-/-) mice exhibited significantly fewer CD4(+) and CD8(+) T cells and neutrophils than WT mice at the peak of HSK. Moreover, CD4(+) T cells from infected corneas of CD154(-/-) mice produced significantly less IFN-gamma than those of WT mice when stimulated with viral Ags in vitro. The IFN-gamma production of cells from infected corneas of WT mice was not affected by addition of anti-CD154 mAb to the stimulation cultures. This suggests that CD154 signaling is required at the inductive phase, but not at the effector phase, of the Th1 response within the infected cornea. We conclude that local disruption of CD40/CD154 signaling is not likely to be a useful therapy for HSK.
The semi-distributed, dynamic INCA-N model was used to simulate the behaviour of dissolved inorganic nitrogen (DIN) in two Finnish research catchments. Parameter sensitivity and model structural ...uncertainty were analysed using generalized sensitivity analysis. The Mustajoki catchment is a forested upstream catchment, while the Savijoki catchment represents intensively cultivated lowlands. In general, there were more influential parameters in Savijoki than Mustajoki. Model results were sensitive to N-transformation rates, vegetation dynamics, and soil and river hydrology. Values of the sensitive parameters were based on long-term measurements covering both warm and cold years. The highest measured DIN concentrations fell between minimum and maximum values estimated during the uncertainty analysis. The lowest measured concentrations fell outside these bounds, suggesting that some retention processes may be missing from the current model structure. The lowest concentrations occurred mainly during low flow periods; so effects on total loads were small.
The scientific data to guide the management of Peutz-Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to ...update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.
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