High Imminent Vertebral Fracture Risk in Subjects With COPD With a Prevalent or Incident Vertebral Fracture

Subjects with chronic obstructive pulmonary disease (COPD) have an increased risk of vertebral fractures (VFs); however, VF incidence is largely unknown. Therefore, the aim of our study was to determine the incidence of new and/or worsening VF in subjects with COPD. Smokers and subjects with COPD (GOLD II–IV) from the ECLIPSE study with complete set of chest CT scans (baseline and 1‐ and 3‐year follow‐up) to evaluate vertebrae T₁ down to L₁ were included. If a VF was diagnosed on the last scan, detailed VF assessment of the previous scans was performed. VFs were scored according to the method of Genant as mild, moderate, or severe. Main outcome measure was the cumulative incidence of new and/or worsening VF at subject level, within 1 and 3 years. Of 1239 subjects (mean age 61 years, 757 males [61%], 999 subjects with COPD), 253 (20.5%) had ≥1 prevalent VF. The cumulative incidence of VFs was 10.1% within 1 year and 24.0% within 3 years. After adjustment for age, sex, body mass index (BMI), pack‐years, and smoking status, prevalence and incidence were similar between smokers and COPD GOLD stages. Within 1 year, 29.2% of the subjects with a prevalent VF had an incident VF, compared with 5.1% in absence of prevalent VF (hazard ratio [HR] = 5.1; 95% confidence interval [CI] 3.6–7.4) and 58.5% versus 15.0% within 3 years (HR = 3.6; 95% CI 2.9–4.6). The incidence of VF was higher with increasing number and severity of prevalent VFs. Among subjects having an incident VF within the first year, 57.3% had a subsequent VF within the next 2 years. In this study, more than half of the smokers and subjects with COPD with a prevalent VF or an incident VF within the first year sustained a subsequent VF within 3 years. The 3‐year risk was even higher in the presence of multiple or severe prevalent VFs. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

The cell and molecular basis of leukocyte common antigen (CD45)- triggered, lymphocyte function-associated antigen-1-/intercellular adhesion molecule-1-dependent, leukocyte adhesion

We recently reported that cross-linking the leukocyte common antigen (CD45) can rapidly induce aggregation of human peripheral blood mononuclear cells via lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) interactions. Herein, we have examined both T-cell--monocyte cellular interactions and the molecular signaling that are involved in this phenomenon. Experiments using highly purified T lymphocytes showed that CD45-induced aggregation requires the presence of both T cells and monocytes. Cross- linking CD45 only on T lymphocytes, but not on monocytes, initiated cellular clustering after reconstituting to the respective untreated cell type. By several criteria, CD45-induced clustering of T cells to autologous monocytes was shown to be Fc-receptor--independent. When comparing intracellular signaling in leukocyte aggregation induced by CD45 cross-linking versus phorbol myristate-12-13-acetate (PMA) treatment, the former was found to be fivefold to 10-fold more sensitive to H-8, a reagent that effectively blocks cAMP- and cGMP- dependent protein kinases. On the other hand, reagents that increase intracellular cAMP levels (eg, dbcAMP, forskolin, and IBMX), protein kinase C (PKC) inhibitors (eg, staurosporine), and tyrosine kinase inhibitors (eg, herbimycin A and genistein) all readily inhibited PMA- induced, but not CD45 monoclonal antibody-induced, aggregation. We conclude that cross-linking the leukocyte common antigen on T cells induces LFA-1--/ICAM-1--dependent T-cell--monocyte aggregation through a unique signaling pathway independent of PKC, which involves instead cAMP-/cGMP-dependent protein kinases.     

Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells

It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell; however, demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here, we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser‐capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multi‐lineage differentiation within CCO‐deficient areas. Interestingly, we observed infrequent CCO deficiency that was restricted to luminal cells, suggesting that niche succession, and by inference stem cell location, is located within the luminal layer. CCO‐deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

他汀类药物：增加糖尿病发生风险

他汀类药物是否会增加糖尿病发病风险,一直备受争论。本研究根据已发表和未发表的文献资料,用Meta方法分析该类药物使用与糖尿病发生的相关性。     

Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte

The glomerular filtration barrier consists of podocytes, the glomerular basement membrane, and endothelial cells covered with a glycocalyx. Heparan sulphate (HS) in the glomerular filtration barrier is reduced in patients with proteinuria, which is associated with increased expression of the HS‐degrading enzyme heparanase. Previously, we showed that heparanase is essential for the development of proteinuria in experimental diabetic nephropathy. Vitamin D supplementation reduces podocyte loss and proteinuria in vitro and in vivo. Therefore, we hypothesize that vitamin D reduces proteinuria by reducing glomerular heparanase. Adriamycin‐exposed rats developed proteinuria and showed increased heparanase expression, which was reduced by 1,25‐dihydroxyvitamin D₃ (1,25‐D₃) treatment. In vitro, adriamycin increased heparanase mRNA in the podocyte, which could be corrected by 1,25‐D₃ treatment. In addition, 1,25‐D₃ treatment reduced transendothelial albumin passage after adriamycin stimulation. In line with these results, we showed direct binding of the vitamin D receptor to the heparanase promoter, and 1,25‐D₃ dose‐dependently reduced heparanase promoter activity. Finally, 1,25‐D₃‐deficient 25‐hydroxy‐1α‐hydroxylase knockout mice developed proteinuria and showed increased heparanase, which was normalized by 1,25‐D₃ treatment. Our data suggest that the protective effect of vitamin D on the development of proteinuria is mediated by inhibiting heparanase expression in the podocyte. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.