The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

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BackgroundChronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patients. Currently, it is not clear which factors determine progression to fibrosis. We investigated whether DNA\methylation profile as determined by pyrosequencing can distinguish patients with mild from those with advanced/severe fibrosis in non-alcoholic liver disease (NAFLD) and alcoholic liver disease (ALD). To this end, paraffin-embedded liver biopsies were collected from patients with biopsy-proven NAFLD or ALD, as well as paraffin-embedded normal liver resections, genomic DNA isolated, bisulfite converted and pyrosequencing assays used to quantify DNA methylation at specific CpGs within PPARα, PPARα, TGFβ1, Collagen 1A1 and PDGFα genes. Furthermore, we assessed the impact of age, gender and anatomical location within the liver on patterns of DNA methylation in the same panel of genes.ResultsDNA methylation at specific CpGs within genes known to affect fibrogenesis distinguishes between patients with mild from those with severe fibrosis in both NAFLD and ALD, although same CpGs are not equally represented in both etiologies. In normal liver, age, gender or anatomical location had no significant impact on DNA methylation patterns in the liver.ConclusionsDNA methylation status at specific CpGs may be useful as part of a wider set of patient data for predicting progression to liver fibrosis.

MR imaging of superficial cranial arteries is accurate in the initial diagnosis of GCA giant cell arteritis . Sensitivity probably decreases after more than 5 days of sCS systemic corticosteroid therapy; thus, imaging should not be delayed. Clinical trial registration no. DRKS00000594 .

SUMMARYBackground: Most ocular changes in pregnancy are harmless. For example, 14% of pregnant women need a new eyeglass prescription. Some changes, however, are serious, such as retinal effects of hypertension, which can be a sign of pre-eclampsia. Ocular changes may give rise to uncertainty about the administration of ophthalmological drugs or the optimal method of childbirth.

ABSTRACT.Purpose: Endogenous endophthalmitis is a severe and potentially blinding complication caused by haematogenous spreading of microorganisms. We evaluated the causative microorganisms, disposition to and prognosis of the disease. Methods: Thirty-one eyes of 28 patients were treated between 1996 and 2006 as the result of an endogenous endophthalmitis. Results: The microorganisms responsible for infection could be identified in 94% of all eyes investigated. Candida isolates were obtained in 15, gram-positive isolates in 11, gram-negative in one and Aspergillus in two of the 29 eyes studied. The majority of patients suffered from severe general disease (immunodeficiency, severe surgical procedures, diabetes mellitus) and one third were intravenous drug abusers. Only one patient was otherwise healthy. The prognosis depended on the causative microorganisms. Whereas none of the eyes with Candida infection became blind, all except two of the eyes with gram-positive bacteria, Nocardia or Aspergillus infection lost visual function or had to be enucleated. Conclusion: Compared to postoperative endophthalmitis, patients with endogenous endophthalmitis are more likely to have Candida isolates. Visual prognosis depends mainly on the underlying microorganisms, and is particularly poor in the case of infection with gram-positive bacteria or Aspergillus.

Giant cell arteritis, if untreated, progresses to involve the aorta and its collateral branches, leading to various complications. Late diagnosis and treatment can have serious consequences, including irreversible loss of visual function.

Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.