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21.
Alejandro J Garcia Colton Tom Miriam Guemes Gloria Polanco Maria E Mayorga Korinna Wend Gustavo A Miranda‐Carboni Susan A Krum 《Journal of bone and mineral research》2013,28(2):283-290
The benefits of estrogens on bone health are well established; how estrogens signal to regulate bone formation and resorption is less well understood. We show here that 17β‐estradiol (E2)‐induced apoptosis of bone‐resorbing osteoclasts is mediated by cleavage and solubilization of osteoblast‐expressed Fas ligand (FasL). U2OS‐ERα osteoblast‐like cells expressing an EGFP‐tagged FasL at the C‐terminus showed decreased fluorescence after E2 treatment, indicative of a cleavage event. Treatment of U2OS‐ERα cultures with a specific MMP3 inhibitor in the presence of E2 blocked FasL cleavage and showed an increase in the number of EGFP‐FasL+ cells. siRNA experiments successfully knocked down MMP3 expression and restored full‐length FasL to basal levels. E2 treatment of both human and murine primary osteoblasts showed upregulation of MMP3 mRNA expression, and calvarial organ cultures showed increased expression of MMP3 protein and colocalization with the osteoblast‐specific RUNX2 after E2 treatment. In addition, osteoblast cell cultures derived from ERαKO mice showed decreased expression of MMP3 but not MMP7 and ADAM10, two known FasL proteases, demonstrating that ERα signaling regulates MMP3. Also, conditioned media of E2‐treated calvarial osteoblasts showed an approximate sixfold increase in the concentration of soluble FasL, indicating extensive cleavage, and soluble FasL concentrations were reduced in the presence of a specific MMP3 inhibitor. Finally, to show the role of soluble FasL in osteoclast apoptosis, human osteoclasts were cocultured with MC3T3 osteoblasts. Both a specific MMP3 inhibitor and an MMP inhibitor cocktail preserved osteoclast differentiation and survival in the presence of E2 and demonstrate the necessity of MMP3 for E2‐induced osteoclast apoptosis. These experiments further define the molecular mechanism of estrogen's bone‐protective effects by inducing osteoclast apoptosis through upregulation of MMP3 and FasL cleavage. © 2013 American Society for Bone and Mineral Research 相似文献
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Significant reduction in positive surgical margin rate after laparoscopic radical prostatectomy by application of the modified surgical margin recommendations of the 2009 International Society of Urological Pathology consensus
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24.
Veronika Pilz Kathrin Wolf Susanne Breitner Regina Rückerl Wolfgang Koenig Wolfgang Rathmann Josef Cyrys Annette Peters Alexandra Schneider 《International journal of hygiene and environmental health》2018,221(3):510-518
Background
Long-term exposure to ambient air pollution contributes to the global burden of disease by particularly affecting cardiovascular (CV) causes of death. We investigated the association between particle number concentration (PNC), a marker for ultrafine particles, and other air pollutants and high sensitivity C-reactive protein (hs-CRP) as a potential link between air pollution and CV disease.Methods
We cross-sectionally analysed data from the second follow up (2013 and 2014) of the German KORA baseline survey which was conducted in 1999–2001. Residential long-term exposure to PNC and various other size fractions of particulate matter (PM10 with size of <10?μm in aerodynamic diameter, PMcoarse 2.5–10?μm or PM2.5?<?2.5?μm, respectively), soot (PM2.5abs: absorbance of PM2.5), nitrogen oxides (nitrogen dioxide NO2 or oxides NOx, respectively) and ozone (O3) were estimated by land-use regression models. Associations between annual air pollution concentrations and hs-CRP were modeled in 2252 participants using linear regression models adjusted for several confounders. Potential effect-modifiers were examined by interaction terms and two-pollutant models were calculated for pollutants with Spearman inter-correlation <0.70.Results
Single pollutant models for PNC, PM10, PMcoarse, PM2.5abs, NO2 and NOx showed positive but non-significant associations with hs-CRP. For PNC, an interquartile range (2000 particles/cm3) increase was associated with a 3.6% (95% CI: ?0.9%, 8.3%) increase in hs-CRP. A null association was found for PM2.5. Effect estimates were higher for women, non‐obese participants, for participants without diabetes and without a history of cardiovascular disease whereas ex-smokers showed lower estimates compared to smokers or non-smokers. For O3, the dose-response function suggested a non-linear relationship. In two-pollutant models, adjustment for PM2.5 strengthened the effect estimates for PNC and PM10 (6.3% increase per 2000 particles/cm3 [95% CI: 0.4%; 12.5%] and 7.3% per 16.5?μg/m3 [95% CI: 0.4%; 14.8%], respectively).Conclusion
This study adds to a scarce but growing body of literature showing associations between long-term exposure to ultrafine particles and hs-CRP, one of the most intensely studied blood biomarkers for cardiovascular health. Our results highlight the role of ultrafine particles within the complex mixture of ambient air pollution and their inflammatory potential. 相似文献25.
Orientation perception is a fundamental property of the visual system and an important basic processing stage for visual scene perception. Neurophysiological studies have found broader tuning curves and increased noise in orientation-selective neurons of senescent monkeys and cats, results that suggest an age-related decline in orientation perception. However, behavioral studies in humans have found no evidence for such decline, with performance being comparable for younger and older participants in orientation detection and discrimination tasks. Crucially, previous behavioral studies assessed performance for cardinal orientation only, and it is well known that the human visual system prefers cardinal over oblique orientations, a phenomenon called the oblique effect. We hypothesized that age-related changes depend on the orientation tested. In two experiments, we investigated orientation discrimination and reproduction for a large range of cardinal and oblique orientations in younger and older adults. We found substantial age-related decline for oblique but not for cardinal orientations, thus demonstrating that orientation perception selectively declines for oblique orientations. Taken together, our results serve as the missing link between previous neurophysiological and human behavioral studies on orientation perception in healthy aging. 相似文献
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Christiane Drechsler Benjamin Schmiedeke Markus Niemann Daniel Schmiedeke Johannes Krämer Irina Turkin Katja Blouin Andrea Emmert Stefan Pilz Barbara Obermayer-Pietsch Frank Weidemann Frank Breunig Christoph Wanner 《Journal of inherited metabolic disease》2014,37(2):289-295
Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40?±?13 years (42 % males), and a mean 25(OH)D of 23.5?±?11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D?≤?15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p?=?0.04). The mean LV mass was distinctively different with 170?±?75 g in deficient, 154?±?60 g in moderately deficient and 128?±?58 g in vitamin D sufficient patients (p?=?0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial. 相似文献
28.
Helmut Roth Lars G. Fritsche Christoph Meier Peter Pilz Martin Eigenthaler Philipp Meyer-Marcotty Angelika Stellzig-Eisenhauer Peter Proff Cláudia M. Kanno Bernhard HF Weber 《Clinical oral investigations》2014,18(2):377-384
Objectives
Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.Materials and methods
Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.Results
We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.Conclusions
Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.Clinical relevance
Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options. 相似文献29.
In the present paper we offer a detailed comparison of hospital costs between California and New York and two Canadian provinces (Ontario and British Columbia) in 1981 and 1985. We find that production technologies differ significantly between the two countries and between California and New York. Marginal costs and their distributions also differ across jurisdictions and across different size hospitals. Marginal cost levels were the lowest in Canadian hospitals for almost all outputs in both years and their distribution was also the tightest. Some very mild scale effects were also present in the acute care production. Hospitals in California experienced for the most part increasing marginal costs for acute care, whereas Canadian hospitals showed the reverse pattern. In New York we find a weak negative scale effect in acute care production. Density estimates conditional on hospital output reinforce these results. 相似文献
30.
Verena Theiler-Schwetz Christian Trummer Martin R. Grübler Martin H. Keppel Armin Zittermann Andreas Tomaschitz Spyridon N. Karras Winfried Mrz Stefan Pilz Stephanie Gngler 《Nutrients》2022,14(7)
Accumulating evidence suggests that potential cardiovascular benefits of vitamin D supplementation may be restricted to individuals with very low 25-hydroxyvitamin D (25(OH)D) concentrations; the effect of vitamin D on blood pressure (BP) remains unclear. We addressed this issue in a post hoc analysis of the double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011–2014) with 200 hypertensive patients with 25(OH)D levels <30 ng/mL. We evaluated whether 2800 IU of vitamin D3/day or placebo (1:1) for 8 weeks affects 24-hour systolic ambulatory BP in patients with 25(OH)D concentrations <20 ng/mL, <16 ng/mL, and <12 ng/mL and whether achieved 25(OH)D concentrations were associated with BP measures. Taking into account correction for multiple testing, p values < 0.0026 were considered significant. No significant treatment effects on 24-hour BP were observed when different baseline 25(OH)D thresholds were used (all p-values > 0.30). However, there was a marginally significant trend towards an inverse association between the achieved 25(OH)D level with 24-hour systolic BP (−0.196 per ng/mL 25(OH)D, 95% CI (−0.325 to −0.067); p = 0.003). In conclusion, we could not document the antihypertensive effects of vitamin D in vitamin D-deficient individuals, but the association between achieved 25(OH)D concentrations and BP warrants further investigations on cardiovascular benefits of vitamin D in severe vitamin D deficiency. 相似文献