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Background: Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation., Methods: We utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo., Findings: We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001)., Interpretation: Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis., Funding: Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB)., Competing Interests: Declaration of Interest Dr. Mehta has received funding from the National Institutes of Health Intramural Research Program (Z01 HL-06193); and has received research grants from Abbvie, Janssen, Novartis Corp, and Celgene. Dr. Gelfand reports personal fees from BMS, Boehringer Ingelheim, GSK, Lilly, Janssen Biologics, Novartis Corp., UCB (DSMB), Neuroder (DSMB), Dr. Reddy's Labs, Pfizer Inc., and Sun Pharma as well as grants from Abbvie, Boehringer Ingelheim, Janssen, Novartis Corp., Celgene, Ortho Dermatologics, and Pfizer, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier B.V.)

The development of ectodermal organs, such as teeth, requires epithelial-mesenchymal interactions. Basic helix-loop-helix (bHLH) transcription factors regulate various aspects of tissue development, and we have previously identified a bHLH transcription factor, AmeloD, from a tooth germ cDNA library. Here, we provide both in vitro and in vivo evidence that AmeloD is important in tooth development. We created AmeloD -knockout (KO) mice to identify the in vivo functions of AmeloD that are critical for tooth morphogenesis. We found that AmeloD -KO mice developed enamel hypoplasia and small teeth because of increased expression of E-cadherin in inner enamel epithelial (IEE) cells, and it may cause inhibition of the cell migration. We used the CLDE dental epithelial cell line to conduct further mechanistic analyses to determine whether AmeloD overexpression in CLDE cells suppresses E-cadherin expression and promotes cell migration. Knockout of epiprofin (Epfn), another transcription factor required for tooth morphogenesis and development, and analysis of AmeloD expression and deletion revealed that AmeloD also contributed to multiple tooth formation in Epfn -KO mice by promoting the invasion of dental epithelial cells into the mesenchymal region. Thus, AmeloD appears to play an important role in tooth morphogenesis by modulating E-cadherin and dental epithelial-mesenchymal interactions. These findings provide detailed insights into the mechanism of ectodermal organ development.

Psoriasis is an inflammatory skin disease associated with increased cardiovascular risk and serves as a reliable model to study inflammatory atherogenesis. Because neutrophils are implicated in atherosclerosis development, this study reports that the interaction among low-density granulocytes, a subset of neutrophils, and platelets is associated with a noncalcified coronary plaque burden assessed by coronary computed tomography angiography. Because early atherosclerotic noncalcified burden can lead to fatal myocardial infarction, the low-density granulocyte-platelet interaction may play a crucial target for clinical intervention.

Objective: Cells use various mechanisms to maintain cellular cholesterol homeostasis including efflux of cholesterol from the cellular plasma membrane to cholesterol acceptors such as HDLs (high-density lipoproteins). Little is known about the transfer of cholesterol from cells into the extracellular matrix. Using a unique monoclonal antibody that detects ordered cholesterol arrays (ie, cholesterol micro[or nano]-domains), we previously identified that particles containing these cholesterol domains accumulate in the extracellular matrix during cholesterol enrichment of human monocyte-derived macrophages and are found in atherosclerotic lesions. In this study, we further investigate these deposited particles containing cholesterol microdomains and discover their unexpected morphology., Approach and Results: Although appearing spherical at the resolution of the conventional fluorescence microscope, super-resolution immunofluorescence and atomic force microscopy of in situ cholesterol microdomains, and immunoelectron microscopy of isolated cholesterol microdomains revealed that the microdomains are not vesicles or 3-dimensional crystals but rather appear as branching irregularly shaped deposits of varying size. These cholesterol microdomain-containing deposits are shed from the plasma membrane into the extracellular matrix., Conclusions: To date, research on cellular excretion of excess cholesterol has demonstrated cellular cholesterol efflux in the form of membranous vesicles and discoidal HDL particles released into the fluid-phase medium. Shedding of plasma membrane cholesterol microdomains provides an additional mechanism for cells such as macrophages to maintain plasma membrane cholesterol homeostasis. Furthermore, recognition that macrophages shed cholesterol microdomains into the extracellular matrix is important to our understanding of extracellular buildup of cholesterol in atherosclerosis., (© 2018 American Heart Association, Inc.)

Fifty-three patients with inoperable non-small cell bronchial carcinoma were treated at four-weekly intervals with two cytostatic drugs, doxorubicin (50 mg/m2 on day 1) and ifosfamide (2000 mg/m2 on days 1-3). To avoid urotoxicity of ifosfamide, mesna, a uroprotective drug, was additionally given intravenously at a dose of three times 400 mg/m2 on days 1-3. All diagnoses had been histologically and/or cytologically confirmed. Adenocarcinoma was present in 22, large-cell undifferentiated carcinoma in 18, and squamous-cell carcinoma in 13. Distant metastases were present in 46, seven had a regionally localized tumour growth. There were one complete and 20 partial remissions (response rate 40%). Among a further 19 patients temporary growth arrest was registered. The remissions occurred in seven with adenocarcinoma, nine with large-cell carcinoma and five with squamous-cell carcinoma. Median remission was 8.3 months, mean survival time 10.5 months. Patients without response survived a mean of 5.5 months, patients with tumour progression for 1.3 months (Kaplan-Meier method). Most prominent among side-effects were cardiotoxicity and infection during the leukopenic phase. Urotoxicity was minor, due to treatment with mesna. The results suggest that doxorubicin and ifosfamide in combination can be considered an effective means, with acceptable toxicity, of treating advanced non-small cell bronchial carcinoma.

A 37-year-old woman who had developed diabetes insipidus after an abortion, requiring nasal substitution treatment with desmopressin (Minirin), began to suffer from fatigue, nocturnal sweating, cough and dyspnoea on exertion. Exogenous-allergic alveolitis was demonstrated by chest x-ray, lung function tests, blood gas analysis, broncho-alveolar lavage and transbronchial lung biopsy. After changing the treatment to an intramuscularly administered preparation and starting steroid therapy the clinical, radiological and lung function findings rapidly improved.