TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma

PURPOSE In leukemic cutaneous T-cell lymphoma (L-CTCL), malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased immunoglobulin E (IgE), and decreased T-helper (TH)-1 responses, and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, TH2 and TH17 cells. EXPERIMENTAL DESIGN We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells, and studied the immunomodulatory effects of treatment modalities in patients with L-CTCL. RESULTS Twelve out of 12 patients with L-CTCL overproduced TH2 cytokines. Remaining benign T cells were also strongly TH2 biased, suggesting a global TH2 skewing of the T-cell repertoire. Culture of benign T cells away from the malignant clone reduced TH2 and enhanced TH1 responses, but separate culture had no effect on malignant T cells. Coculture of healthy T cells with L-CTCL T cells reduced IFNγ production and neutralizing antibodies to interleukin (IL)-4 and IL-13 restored TH1 responses. In patients, enhanced TH1 responses were observed following a variety of treatment modalities that reduced malignant T-cell burden. CONCLUSIONS A global TH2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. TH2 cytokines from malignant cells strongly inhibited TH1 responses. Our results suggest that therapies that inhibit TH2 cytokine activity, by virtue of their ability to improve TH1 responses, may have the potential to enhance both anticancer and antipathogen responses.

Cutaneous lesions associated with dual infection caused by canine distemper virus and orthopoxvirus in a domestic cat.

BACKGROUND Within the context of an increased epidemiological pressure caused by canine distemper virus (CDV) in Switzerland together with a potential re-emergence of endemic pathogens such as orthopoxviruses (OPXV), dual infections are possible among susceptible species. OBJECTIVE To describe a case of concurrent CDV and OPXV infection in a cat. ANIMAL A 5-year-old, neutered male cat was presented with erythema, crusts and ulcerations around the left eye. High-grade pruritus and a severe conjunctivitis were also present. METHODS Formalin-fixed skin biopsy samples were obtained from lesional skin. Histopathology, CDV immunohistochemistry and CDV and OPXV RT-PCR were performed. RESULTS Histopathological examination showed severe epidermal necrosis extending to the follicular walls and a dermal infiltration, predominantly eosinophilic. Intranuclear and intracytoplasmic eosinophilic inclusion bodies were visible in the wall of affected hair follicles, with occasional formation of syncytia. The RT-PCR revealed the contextual presence of both CDV and OPXV. Scattered cells stained positive for CDV by immunohistochemistry. CONCLUSION AND DISCUSSION Dual infections with CDV and OPXV, although rare, may occur and represent additional differential diagnoses for ulcerative skin lesions in cats.

Cutaneous reactive angiomatosis with combined histological pattern mimicking a cellulitis

Cutaneous reactive angiomatoses (CRA) encompass a distinct group of rare benign reactive vascular proliferations that include reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. The etiology of these conditions, often associated with either localized or systemic diseases, is poorly understood. We report a 72-year-old woman who presented giant diffuse cellulitis-like plaques on the right lower limb and the pelvis and a reduction of her general condition with fever. Light microscopy studies revealed combined features of reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. A small arteriovenous fistula of the right lower leg was thought to act as trigger. Systemic corticosteroids resulted in the clinical remission of the skin lesions. Our observation provides strong evidence that reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis, previously regarded as distinct forms of CRA, may show overlapping histopathological features and most likely represent facets of the same disease.

Holocene flood frequency across the Central Alps – solar forcing and evidence for variations in North Atlantic atmospheric circulation

The frequency of large-scale heavy precipitation events in the European Alps is expected to undergo substantial changes with current climate change. Hence, knowledge about the past natural variability of floods caused by heavy precipitation constitutes important input for climate projections. We present a comprehensive Holocene (10,000 years) reconstruction of the flood frequency in the Central European Alps combining 15 lacustrine sediment records. These records provide an extensive catalog of flood deposits, which were generated by flood-induced underflows delivering terrestrial material to the lake floors. The multi-archive approach allows suppressing local weather patterns, such as thunderstorms, from the obtained climate signal. We reconstructed mainly late spring to fall events since ice cover and precipitation in form of snow in winter at high-altitude study sites do inhibit the generation of flood layers. We found that flood frequency was higher during cool periods, coinciding with lows in solar activity. In addition, flood occurrence shows periodicities that are also observed in reconstructions of solar activity from C-14 and Be-10 records (2500-3000, 900-1200, as well as of about 710, 500, 350, 208 (Suess cycle), 150, 104 and 87 (Gleissberg cycle) years). As atmospheric mechanism, we propose an expansion/shrinking of the Hadley cell with increasing/decreasing air temperature, causing dry/wet conditions in Central Europe during phases of high/low solar activity. Furthermore, differences between the flood patterns from the Northern Alps and the Southern Alps indicate changes in North Atlantic circulation. Enhanced flood occurrence in the South compared to the North suggests a pronounced southward position of the Westerlies and/or blocking over the northern North Atlantic, hence resembling a negative NAO state (most distinct from 4.2 to 2.4 kyr BP and during the Little Ice Age). South-Alpine flood activity therefore provides a qualitative record of variations in a paleo-NAO pattern during the Holocene. Additionally, increased South Alpine flood activity contrasts to low precipitation in tropical Central America (Cariaco Basin) on the Holocene and centennial time scale. This observation is consistent with a Holocene southward migration of the Atlantic circulation system, and hence of the ITCZ, driven by decreasing summer insolation in the Northern hemisphere, as well as with shorter-term fluctuations probably driven by solar activity. (C) 2013 Elsevier Ltd. All rights reserved.

Glacier response to the change in atmospheric circulation in the eastern Mediterranean during the Last Glacial Maximum

In this study, we document glacial deposits and reconstruct the glacial history in the Karagöl valley system in the eastern Uludağ in northwestern Turkey based on 42 cosmogenic 10Be exposure ages from boulders and bedrock. Our results suggest the Last Glacial Maximum (LGM) advance prior to 20.4 ± 1.2 ka and at least three re-advances until 18.6 ± 1.2 ka during the global LGM within Marine Isotope Stage-2. In addition, two older advances of unknown age are geomorphologically well constrained, but not dated due to the absence of suitable boulders. Glaciers advanced again two times during the Lateglacial. The older is exposure dated to not later than 15.9 ± 1.1 ka and the younger is attributed to the Younger Dryas (YD) based on field evidence. The timing of the glaciations in the Karagöl valley correlates well with documented archives in the Anatolian and Mediterranean mountains and the Alps. These glacier fluctuations may be explained by the change in the atmospheric circulation pattern during the different phases of North Atlantic Oscillation (NAO) winter indices.

Changing correlation structures of the Northern Hemisphere atmospheric circulation from 1000 to 2100 AD

Atmospheric circulation modes are important concepts in understanding the variability of atmospheric dynamics. Assuming their spatial patterns to be fixed, such modes are often described by simple indices from rather short observational data sets. The increasing length of reanalysis products allows these concepts and assumptions to be scrutinised. Here we investigate the stability of spatial patterns of Northern Hemisphere teleconnections by using the Twentieth Century Reanalysis as well as several control and transient millennium-scale simulations with coupled models. The observed and simulated centre of action of the two major teleconnection patterns, the North Atlantic Oscillation (NAO) and to some extent the Pacific North American (PNA), are not stable in time. The currently observed dipole pattern of the NAO, its centre of action over Iceland and the Azores, split into a north–south dipole pattern in the western Atlantic with a wave train pattern in the eastern part, connecting the British Isles with West Greenland and the eastern Mediterranean during the period 1940–1969 AD. The PNA centres of action over Canada are shifted southwards and over Florida into the Gulf of Mexico during the period 1915–1944 AD. The analysis further shows that shifts in the centres of action of either teleconnection pattern are not related to changes in the external forcing applied in transient simulations of the last millennium. Such shifts in their centres of action are accompanied by changes in the relation of local precipitation and temperature with the overlying atmospheric mode. These findings further undermine the assumption of stationarity between local climate/proxy variability and large-scale dynamics inherent when using proxy-based reconstructions of atmospheric modes, and call for a more robust understanding of atmospheric variability on decadal timescales.

Estimated strength of the Atlantic overturning circulation during the last deglaciation

The Atlantic meridional overturning circulation affects the latitudinal distribution of heat, and is a key component of the climate system. Proxy reconstructions, based on sedimentary Pa-231/Th-230 ratios and the difference between surface-and deep-water radiocarbon ages, indicate that during the last glacial period, the overturning circulation was reduced during millennial-scale periods of cooling(1-5). However, much debate exists over the robustness of these proxies(6-8). Here e combine proxy reconstructions of sea surface and air temperatures and a global climate model to quantitatively estimate changes in the strength of the Atlantic meridional overturning circulation during the last glacial period. We find that, relative to the Last Glacial Maximum, the overturning circulation was reduced by approximately 14 Sv during the cold Heinrich event 1. During the Younger Dryas cold event, the overturning circulation was reduced by approximately 12 Sv, relative to the preceding warm interval. These changes are consistent with qualitative estimates of the overturning circulation from sedimentary Pa-231/Th-230 ratios. In addition, we find that the strength of the overturning circulation during the Last Glacial Maximum and the Holocene epoch are indistinguishable within the uncertainty of the reconstruction.

Greenland accumulation and its connection to the large-scale atmospheric circulation in ERA-Interim and paleoclimate simulations

Changes in Greenland accumulation and the stability in the relationship between accumulation variability and large-scale circulation are assessed by performing time-slice simulations for the present day, the preindustrial era, the early Holocene, and the Last Glacial Maximum (LGM) with a comprehensive climate model. The stability issue is an important prerequisite for reconstructions of Northern Hemisphere atmospheric circulation variability based on accumulation or precipitation proxy records from Greenland ice cores. The analysis reveals that the relationship between accumulation variability and large-scale circulation undergoes a significant seasonal cycle. As the contributions of the individual seasons to the annual signal change, annual mean accumulation variability is not necessarily related to the same atmospheric circulation patterns during the different climate states. Interestingly, within a season, local Greenland accumulation variability is indeed linked to a consistent circulation pattern, which is observed for all studied climate periods, even for the LGM. Hence, it would be possible to deduce a reliable reconstruction of seasonal atmospheric variability (e.g., for North Atlantic winters) if an accumulation or precipitation proxy were available that resolves single seasons. We further show that the simulated impacts of orbital forcing and changes in the ice sheet topography on Greenland accumulation exhibit strong spatial differences, emphasizing that accumulation records from different ice core sites regarding both interannual and long-term (centennial to millennial) variability cannot be expected to look alike since they include a distinct local signature. The only uniform signal to external forcing is the strong decrease in Greenland accumulation during glacial (LGM) conditions and an increase associated with the recent rise in greenhouse gas concentrations.

Outcome of standard and high-risk patients with acute anterior circulation stroke after stent retriever thrombectomy.

BACKGROUND AND PURPOSE Stent retrievers have become an important tool for the treatment of acute ischemic stroke. The aim of this study was to analyze outcome and complications in a large cohort of patients with stroke treated with the Solitaire stent retriever. The study also included patients who did not meet standard inclusion criteria for endovascular treatment: low or high baseline National Institutes of Health Stroke Scale score, ≥80 years of age, extensive ischemic signs in middle cerebral artery territory, and time from symptom onset to endovascular intervention>8 hours. METHODS Consecutive patients with acute anterior circulation stroke treated with the Solitaire FR were analyzed. Data on characteristics of endovascular interventions, complications, and clinical outcome were collected prospectively. Patients who met standard inclusion criteria were compared with those who did not. RESULTS A total of 227 patients were included. Mean age was 68.2±14.7 years, and median National Institutes of Health Stroke Scale score on admission was 16 (range, 2-36). Reperfusion was successful (thrombolysis in cerebral infarction, 2b-3) in 70.9%. Outcome was favorable (modified Rankin Scale, 0-2) in 57.7% of patients who met standard inclusion criteria and 30.3% of those who did not. The rates for symptomatic intracranial hemorrhage were 3.7% and 13.1%, for death 11.4% and 33.8%, and for symptomatic intraprocedural complications 2.5% and 4.8%, respectively. CONCLUSIONS Patients<80 years of age, without extensive pretreatment ischemic signs, and baseline National Institutes of Health Stroke Scale score≤30 had high rates of favorable outcome and low periprocedural complication rates after Solitaire thrombectomy. Successful reperfusion was also common in patients not fulfilling standard inclusion criteria, but worse clinical outcomes warrant further research with a special focus on optimal patient selection.

Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials.

BACKGROUND: High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26-1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54-0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56-1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. CONCLUSIONS/SIGNIFICANCE: Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.

Association Between Atmospheric Circulation Patterns and Firn-Ice Core Records from the Inilchek Glacierized Area, Central Tien Shan, Asia

Glacioclimatological research in the central Tien Shan was performed in the summers of 1998 and 1999 on the South Inilchek Glacier at 5100 - 5460 m. A 14.36 m firn-ice core and snow samples were collected and used for stratigraphic, isotopic, and chemical analyses. The firn-ice core and snow records were related to snow pit measurements at an event scale and to meteorological data and synoptic indices of atmospheric circulation at annual and seasonal scales. Linear relationships between the seasonal air temperature and seasonal isotopic composition in accumulated precipitation were established. Changes in the delta(18)O air temperature relationship, in major ion concentration and in the ratios between chemical species, were used to identify different sources of moisture and investigate changes in atmospheric circulation patterns. Precipitation over the central Tien Shan is characterized by the lowest ionic content among the Tien Shan glaciers and indicates its mainly marine origin. In seasons of minimum precipitation, autumn and winter, water vapor was derived from the arid and semiarid regions in central Eurasia and contributed annual maximal solute content to snow accumulation in Tien Shan. The lowest content of major ions was observed in spring and summer layers, which represent maximum seasonal accumulation when moisture originates over the Atlantic Ocean and Mediterranean and Black Seas.

Monsoonal Circulation of the McMurdo Dry Valleys, Ross Sea Region, Antarctica: Signal from the Snow Chemistry

McMurdo Dry Valleys (MDV, Ross Sea region, Antarctica) precipitation exhibits extreme seasonality in ion concentration, 3-5 orders of magnitude between summer and winter precipitation. To identify aerosol sources and investigate causes for the observed amplitude in concentration variability, four snow pits were sampled along a coast-Polar Plateau transect across the MDV. The elevation of the sites ranges from 50 to 2400 m and the distance from the coast from 8 to 93 km. Average chemistry gradients along the transect indicate that most species have either a predominant marine or terrestrial source in the MDV. Empirical orthogonal function analysis on the snow-chemistry time series shows that at least 57% of aerosol deposition occurs concurrently. A conceptual climate model, based on meteorological observations, is used to explain the strong seasonality in the MDV. Our results suggest that radiative forcing of the ice-free valleys creates a surface low-pressure cell during summer which promotes air-mass flow from the Ross Sea. The associated precipitating air mass is relatively warm, humid and contains a high concentration of aerosols. During winter, the MDV are dominated by air masses draining off the East Antarctic ice sheet, that are characterized by cold, dry and low concentrations of aerosols. The strong differences between these two air-mass sources create in the MDV a polar version of the monsoonal flow, with humid, warm summers and dry, cold winters.