Exaggerated IDO1 expression and activity in Langerhans cells from patients with atopic dermatitis upon viral stimulation: a potential predictive biomarker for high risk of Eczema herpeticum.

BACKGROUND: Atopic dermatitis (AD) is a heterogenous and highly complex disease characterized by an increased microbial colonization. For unknown reasons, a subgroup of patients with AD develops Eczema herpeticum (EH), a severe viral complication due to spreading of herpes simplex virus (HSV). Indoleamine 2,3-dioxygenase (IDO1) is a tryptophan (Trp)-catabolizing enzyme which is assumed to be instrumental in the antibacterial and antiviral defence mechanisms. METHODS: Comparative investigation of the IDO1 expression and activity in freshly isolated monocytes, plasmacytoid DC (pDC) and in vitro-generated Langerhans cells (LC) obtained from AD patients with HSV infections and EH and nonatopic controls. RESULTS: We demonstrate an increase in Trp degradation in the serum of patients during acute EH episodes. Circulating pDC from patients with history of EH display an increased IDO1 expression. An increased Trp degradation is detected in the supernatants of circulating monocytes from AD patients with acute EH. Mature LC from AD patients with history of EH and with acute EH display an increased IDO1 expression and activity, respectively. In LC from patients with history of EH, viral signals induce an exaggerated IDO1 expression and activity. CONCLUSION: IDO1 expression and activity in LC seem to be involved in the pathophysiology of EH in AD and could represent a predictive biomarker for patients with risk to develop EH and other viral complications.

Phenotypic plasticity in sexual communication signal of a noctuid moth.

Variability within sex pheromone signalling systems is generally believed to be low because of strong stabilizing selection; yet the noctuid moth Heliothis subflexa (Hs) shows significant intraspecific variation. One possible explanation is that females may alter their sex pheromone blend depending on prevailing olfactory cues in the habitat, which we termed the 'experience hypothesis'. This could be adaptive if Hs females experiencing the pheromone of another species, Heliothis virescens (Hv), responded to reduce the frequency of heterospecific matings. We exposed Hs females to no pheromone, Hs pheromone or Hv pheromone in the first 3 days of their adult lives. Hs females in the latter treatment produced significantly more of the acetate Z11-16:OAc, which inhibits the attraction of Hv males. To our knowledge, this is the first study showing adaptive phenotypic plasticity in a moth sex pheromone and suggests that behavioural differentiation may precede genetic divergence in the sexual signals of moths.

Primary Solid and Cystic Tumours of the Exocrine Pancreas in Cats.

Tumours of the exocrine pancreas are rare in cats and few cases are described in the literature. Cystic tumours of the pancreas are not included in the World Health Organization (WHO) international histological classification of tumours of domestic animals. The aim of this study was to characterize the pathology of primary epithelial tumours of the feline exocrine pancreas, with emphasis on cystic tumours. We reviewed tumours of the exocrine pancreas in 70 cats, including complete tumours or the entire pancreas (n = 18) and excisional biopsy samples of pancreatic tumours (n = 52). Macroscopically, the tumours were grouped as solid (n = 45) or cystic (n = 25). Solid tumours were subdivided into adenomas (n = 5) and carcinomas (n = 40) and cystic neoplasms into adenomas (n = 15), carcinomas (n = 7) and cases with diverse growth patterns (n = 3). All five grossly solid adenomas had acinar morphology, while the macroscopically solid carcinomas showed acinar (n = 17), tubular (n = 14) or mixed (n = 9) growth microscopically. Cystic adenomas had acinar (n = 2), tubular (n = 12) or mixed (n = 1) growth, while cystic carcinomas had exclusively tubular growth (n = 7). Three cases with cystic lesions showed diverse histopathological growth patterns. The clinical outcome was available in 57 cases. The majority of cats with carcinomas died or were humanely destroyed during or shortly after surgery (n = 32). However, 2/7 animals with cystic carcinomas showed longer survival times. Cats with cystic adenomas had survival times of up to 5 years. The results of this study show that cystic pancreatic tumours should be considered a differential diagnosis in cats with cystic intra-abdominal masses, even though these are not yet described in the WHO classification. Based on the relatively long survival times of cats with cystic adenomas, complete resection with subsequent histopathological examination is recommended.

Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra-223 source for targeted alpha therapy.

PURPOSE: In targeted radionuclide therapy, regional tumors are targeted with radionuclides delivering therapeutic radiation doses. Targeted alpha therapy (TAT) is of particular interest due to its ability to deliver alpha particles of high linear energy transfer within the confines of the tumor. However, there is a lack of data related to alpha particle distribution in TAT. These data are required to more accurately estimate the absorbed dose on a cellular level. As a result, there is a need for a dosimeter that can estimate, or better yet determine the absorbed dose deposited by alpha particles in cells. In this study, as an initial step, the authors present a transmission dosimetry design for alpha particles using A549 lung carcinoma cells, an external alpha particle emitting source (radium 223; Ra-223) and a Timepix pixelated semiconductor detector. METHODS: The dose delivery to the A549 lung carcinoma cell line from a Ra-223 source, considered to be an attractive radionuclide for alpha therapy, was investigated in the current work. A549 cells were either unirradiated (control) or irradiated for 12, 1, 2, or 3 h with alpha particles emitted from a Ra-223 source positioned below a monolayer of A549 cells. The Timepix detector was used to determine the number of transmitted alpha particles passing through the A549 cells and DNA double strand breaks (DSBs) in the form of γ-H2AX foci were examined by fluorescence microscopy. The number of transmitted alpha particles was correlated with the observed DNA DSBs and the delivered radiation dose was estimated. Additionally, the dose deposited was calculated using Monte Carlo code SRIM. RESULTS: Approximately 20% of alpha particles were transmitted and detected by Timepix. The frequency and number of γ-H2AX foci increased significantly following alpha particle irradiation as compared to unirradiated controls. The equivalent dose delivered to A549 cells was estimated to be approximately 0.66, 1.32, 2.53, and 3.96 Gy after 12, 1, 2, and 3 h irradiation, respectively, considering a relative biological effectiveness of alpha particles of 5.5. CONCLUSIONS: The study confirmed that the Timepix detector can be used for transmission alpha particle dosimetry. If cross-calibrated using biological dosimetry, this method will give a good indication of the biological effects of alpha particles without the need for repeated biological dosimetry which is costly, time consuming, and not readily available.

Clinical pharmacology, pharmacodynamics and interactions with esmolol.

The clinical pharmacology and pharmacodynamic data from several clinical trials are summarized. The pharmacokinetic profile of esmolol alone and in the presence of digoxin, morphine and warfarin was studied. Conversely the effect of esmolol on these drugs was monitored. No clinically important effects were observed on vital signs, blood chemistry or hematology. The pharmacokinetic interactions associated with administration of these drug combinations were statistically significant in several cases, but they were not considered to be of clinical importance.

[Advances in the pathogenesis of atopic dermatitis]. / Neues in der Pathophysiologie der atopischen Dermatitis.

The incidence of atopic dermatitis (AD) is noticeably increasing in industrialized countries. New insights into the pathogenesis of this disease are mirrored by a changed terminology suggested by the World Allergy Organization: a distinction between a so-called atopic and non-atopic dermatitis. The pathogenesis of the AD, which this article concentrates on, is highly complex. Genetic and environmental factors play a pivotal role in triggering AD. The complex pattern of cytokines and chemokines, reflecting a deviated immune response in AD patients, is a focus of research, as are the involvement of various cells and the epidermal barrier. Research concerning T cells with regulatory features as well as IgE-mediated autoreactivity will soon give insight into the defective tolerance of atopic patients and might possibly lead to new concepts in the management of the disease.