Purpose Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Patients and Methods Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Results Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). Conclusion To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

Poor human-to-human transmission of influenza A H5N1 virus has been attributed to the paucity of putative sialic acid alpha2-3 virus receptors in the epithelium of the human upper respiratory tract, and thus to the presumed inability of the virus to replicate efficiently at this site. We now demonstrate that ex vivo cultures of human nasopharyngeal, adenoid and tonsillar tissues can be infected with H5N1 viruses in spite of an apparent lack of these receptors.

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Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment.

In spite of continuing large inputs from anthropogenic sources, average concentrations of many trace metals in the Great Lakes remain quite low: 2.8-4.5 ng L -1 for Cd, 3.2-11 ng L -1 for Pb, and 87-277 ng L -1 for Zn. These metals are rapidly scavenged by the seston (suspended particulates) and have a rapid turnover rate in the water column. Factors that affect the distribution of dissolved trace metals include water depth, seston abundance, and biological processes. Higher concentrations are generally found in nearshore stations and especially near the urban centers and polluted river mouths. In summer, there is a marked depletion of Zn (and other bioactive metals) in the epilimnion of the offshore waters. The patchiness in the concentrations of the metals is attributed to spatial differences in the biological processes. With the exception of Cr, there is no systematic increase in concentration down the drainage basin from Lake Superior to Lake Ontario. Most of the Pb, Cd, and Zn loadings into the lakes are retained in the basin, but there is a significant export of dissolved Cu, Ni, and Cr via the St. Lawrence River.

Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here we report that CTCL patients show increased interleukin-15 (IL-15) in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 in T-cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6, and transcriptional induction of the onco-miR-21. Interruption of IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

[1] Measurements of gaseous elemental mercury (GEM) were made in three locations in Canada at altitudes from 0.1 to 7 km. In the summer in southeastern Canada, northwesterly winds bring air with a constant mixing ratio of GEM at altitudes up to 7 km, with a concentration near 1.5 nanograms per standard cubic meter of air (ng sm À3 ). In the winter in southern and central Ontario the mixing ratio is still approximately constant with altitude, but the concentration is 1.7 ng sm À3 . In the spring in the Arctic the concentration of gaseous elemental mercury at altitudes above 1 km is near 1.7 ng sm À3 ; however, there is evidence of episodic depletion of elemental mercury near the surface with mixing of depleted air to altitudes of 1 km. Measurements of GEM in cloud interstitial air and of mercury in cloud water indicate that the influence of a single cycling of air through cloud has little effect on the concentration of GEM. The GEM in air masses transported over the relatively unpopulated terrain of northern Canada during the summer indicates a lower limit of 5000 ng m À2 for an atmospheric column from the surface to 5 km. This gives a global burden of at least 2500 t for that altitude range. These data demonstrate the existence of a vast pool of mercury aloft, provide evidence for a long atmospheric lifetime, and illustrate the potential for long-range atmospheric transport of this metal at altitudes up to at least 7 km.