1,721,008 research outputs found
Bone quality in Pycnodysostosis: micropetrosis, locally distorted osteocyte lacuno-canalicular network and heterogenous mineralization pattern in an adult female patient with multiple fractures
No full textAbstract Pycnodysostosis is a very rare skeletal dysplasia caused by biallelic loss-of-function mutations in cathepsin K, a proteolytic enzyme highly expressed by osteoclasts. Deficiency of cathepsin K impairs bone resorption, and bone remodeling and leads to progressive osteosclerosis and bone fragility. Moreover, cathepsin K is also expressed by mature osteocytes. Whether the density, size and viability of osteocytes and the osteocyte lacuno-canalicular network (OLCN) are also altered and thereby impact bone quality in pycnodysostosis has not been explored. We used light microscopy, quantitative backscattered electron imaging and confocal laser scanning microscopy to examine bone material obtained from a 57-year-old female patient obtained during surgical correction after femoral head fracture. The cortex consisted of a compact shell of multilayered collagen fibrils oriented in parallel to the periosteum reflecting vigorous primary bone apposition, multiple osteons with concentrically ordered lamellae and scattered patches of woven bone. The trabecular area was very dense with BV/TV, varying locally from 30.3% to 67.4%. The bone matrix was overmineralized (average calcium content: +7.5% versus reference values, with a fivefold increase of highly mineralized areas >27 weight % calcium). Numerous multinucleated osteoclasts and fringes of demineralized matrix were viewed on bone surfaces. The density (number/mm2: 193 to 223) and area (20 μm2) of the osteocyte lacunae and their canalicular length (0.05 μm/μm3 bone volume) were within normal range. However, numerous bone packets exhibited (hyper)mineralized osteocyte lacunas (micropetrosis) resulting in a locally disrupted OLCN. In summary, our data indicate that in pycnodysostosis not only osteoclast function is impaired but also osteocyte viability is decreased, leading to micropetrosis, distorted OLCN and heterogenous mineralization pattern. Thus, osteoclasts and osteocytes both contribute to reduce bone quality. However, the presence of a dense osteocyte network in large areas of the sample indicates that cathepsin K is not essential for the formation of the OLCN
Einfluss von MAPK-activated protein kinase-2 (MK2) auf den Knochenstoffwechsel - Ergebnisse aus dem murinen MK2-Knockout-Modell
Get PDFObjective:
To determine whether mitogen-activated protein kinase (MAPK) - activated protein kinase 2 (MK2) contributes to the regulation of bone structure, bone turnover and osteoclastogenesis. MK2 acts as an intracellular signal transduction molecule mediating inflammatory signals and is part of the p38 MAPK pathway. This pathway is most responsive to stress stimuli (e.g. cytokine stimulation) and features a number of phosphorylation steps until activation of MK2. Recent studies have shown the positive effect of p38 MAPK inhibition and mk2-gene deletion on bone in mice suffering from severe arthritis. This is the first study investigating the effect of a mk2-gene knockout on bone in healthy C57/BL6 mice.
Methods:
Mice on a C57/BL6 background which were deficient of the mk2-gene were killed and examined after 4, 11 or 26 weeks. Healthy C57/BL6 mice were used as wild-type controls. Right tibiae were decalcified and paraffin sections were stained for TRAP. Undecalcified, left tibiae were analyzed by µCT and then embedded in methacrylate. Sections were then subjected to Goldner’s staining. Sections stained for TRAP and Goldner were analyzed by histomorphometry to quantify bone volume, trabecular bone properties and osteoclast as well as osteoblast numbers. Calcein was injected intraperitoneally seven and two days before mice were killed and methacrylate sections were assessed to determine mineral apposition rate. Serum levels of OPG, osteocalcin, RANKL, RatLaps and TRAP 5b were measured by ELISA. Mechanical stability of mice femora was detected using a four-point-bending experiment.
Results:
Loss of MK2-function led to a marked increase in bone mineral density caused by impaired osteoclastogenesis. TRAP-histomorphometry showed an increase in bone volume per total volume by up to 40% in 11 wk old MK2-/- mice with a higher number of trabecular bone and reduced trabecular separation. Same results were found for 26 wk old MK2-/- mice. The number of trabecular osteoclasts was strongly reduced in 11 and 26 wk old MK2-/- mice while osteoblast numbers were unchanged between the two groups. Connectivity-density and bone mineral density assessed by µCT were significantly increased in 11 wk old knockout mice. 11 wk old MK2-/- mice also showed a significantly higher mineral apposition rate than wild-type mice. Moreover, four-point-bending tests demonstrated a higher mechanical stability of mk2-deficient bones. Serum levels of OPG were markedly increased in mk2-deficient mice while serum levels of RatLaps and TRAP 5b activity were significantly lower in MK2-/- mice. There was no change in RANKL-levels between both groups while wild-type mice showed higher levels of osteocalcin at 11 weeks.
Conclusion:
MK2-/- mice have increased bone mineral density associated with impaired osteoclast differentiation. mk2-knockout causes ameliorated bone structure with a reduction in osteoclast numbers which leads to improved mechanical bone properties and changes in serum markers of bone metabolism. These results suggest the major importance of the p38 MAPK pathway and its downstream kinase MK2 in bone homeostasis and osteoclastogenesis. In osteoimmunology MK2 might have a key role in linking the effects of the immune system to the bone.Hintergrund und Ziele:
Diese Arbeit untersucht den Einfluss der Mitogen-activated protein kinase (MAPK) - activated protein kinase 2 (MK2) auf die Knochenstruktur, den Knochenstoffwechsel und die Osteoklastogenese. MK2 ist Bestandteil des p38 MAPK-Signalweges, der als intrazellulärer Signalweg eine Rolle bei der Antwort der Zelle auf extrazelluläre Signale spielt. Dieser Signalweg wird v.a. durch Faktoren, die Zellstress symbolisieren(z.B. Zytokine), stimuliert und setzt sich aus einer Reihe von Phosphorylierungs-schritten bis schließlich hin zur Aktivierung von MK2 zusammen. In den letzten Jahren zeigten Studien den positiven Effekt einer p38 MAPK-Inhibition bzw. einer mk2-Gendeletion auf den Knochen von Mäusen mit einer schweren Arthritis. Diese Studie untersucht nun erstmals die Auswirkung eines mk2-Knockouts auf den Knochen gesunder C57/BL6-Mäuse.
Methoden:
C57/BL6-Mäuse mit einem mk2-Gen-Knockout wurden im Alter von 4, 11 bzw. 26 Wochen getötet und anschließend untersucht. Gesunde C57/BL6-Mäuse dienten als Wildtyp-Kontrollgruppe. Nach der Präparation wurden die rechten Tibiae decalcifiziert und TRAP-gefärbte Paraffinschnitte angefertigt. Die nicht-decalcifizierten, linken Tibiae wurden im µCT untersucht und anschließend in Methacrylat eingebettet. Danach erfolgte an den Schnitten eine Goldner-Färbung. Die TRAP- und Goldner-gefärbten Schnitte wurden schließlich histomorphometrisch untersucht, um das Knochenvolumen, die Eigenschaften des trabekulären Knochens sowie die Osteoklasten- und Osteoblastenzahl zu bestimmen. Den Mäusen wurde sieben und zwei Tage vor dem Tod intraperitoneal Calcein injiziert, um an Methacrylatschnitten die Knochenanbaurate (Mineral Apposition Rate) messen zu können. Mittels ELISA wurden die Konzentrationen an OPG, Osteocalcin, RANKL, RatLaps und TRAP 5b im Serum bestimmt. Die mechanische Stabilität der Mäusefemora wurde mittels eines Four-Point-Bending Experiments festgestellt.
Ergebnisse:
Der Verlust der MK2-Aktivität äußerte sich in einer deutlich verbesserten Knochendichte bei einer eingeschränkten Osteoklastogenese. In der TRAP-Histomorphometrie zeigten die 11 Wochen alten MK2-/--Mäuse eine Zunahme der Knochenmasse um bis zu 40% und eine größere Zahl an Knochentrabekeln sowie einen reduzierten Abstand der Trabekel untereinander. Ähnliche Ergebnisse waren bei den 26 Wochen alten MK2-/--Mäusen festzustellen. Die Anzahl an Osteoklasten im trabekulären Knochen war bei den 11 und 26 Wochen alten Knockout-Mäusen stark reduziert. Die Anzahl an Osteoblasten war dagegen in beiden Gruppen etwa gleich. Die µCT-Messungen ergaben einen signifikanten Anstieg der Connectivity-Density und der Knochendichte bei den 11 Wochen alten MK2-/--Mäusen. Auch die Mineral Apposition Rate war bei den 11 Wochen alten MK2-/--Mäusen signifikant erhöht. Weiterhin wiesen die Knochen der Knockout-Mäuse im Four-Point-Bending Test eine verbesserte mechanische Stabilität auf. Die Serumkonzentration an OPG war bei den MK2-/--Mäusen signifikant erhöht, während die Konzentration an RatLaps und die TRAP 5b-Aktivität bei MK2-/--Mäusen signifikant niedriger waren. Knockout- und Wildtyp-Mäuse zeigten eine ähnliche Konzentration an RANKL, wohingegen die Osteocalcin-Konzentration bei den 11 Wochen alten Wildtyp-Mäusen erhöht war
Schlussfolgerungen:
MK2-/--Mäuse besitzen eine größere Knochendichte als Wildtyp-Mäuse in Verbindung mit einer beeinträchtigten Osteoklastendifferenzierung. Ein mk2-Knockout führt zu einer verbesserten Knochenstruktur und einer Abnahme der Osteoklastenzahl. Dies resultiert in einer höheren mechanischen Stabilität und in Veränderungen der Serummarker des Knochenstoffwechsels. Diese Ergebnisse machen die Bedeutung des p38 MAPK-Signalweges und dessen downstream Kinase MK2 im Rahmen der Knochenhomöostase und der Osteoklastogenese deutlich. Auf dem Gebiet der Osteoimmunologie spielt MK2 somit eine Schlüsselrolle in der Verknüpfung der Effekte des Immunsystems auf den Knochen
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Does subclinical inflammation contribute to impairment of function of knee joints in aged individuals? High prevalence of ultrasound inflammatory findings
Get PDFObjectives. To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (≥60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters.
Methods. Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis.
Results. A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively].
Conclusion. The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints
No full textObjective. Osteoarthritis (OA) is a leading cause of pain and physical disability in middle-aged and older individuals. We undertook this study to determine predictors of the development of severe OA, apart from age and overweight.Methods. Joint replacement surgery due to severe hip or knee OA was recorded over a 15-year period in the prospective Bruneck cohort study. Demographic characteristics and lifestyle and biochemical variables, including the level of soluble vascular cell adhesion molecule 1 (VCAM-1), were assessed at the 1990 baseline visit and tested as predictors of joint replacement surgery.Results. Between 1990 and 2005, hip or knee joint replacement due to OA was performed in 60 subjects. VCAM-1 level emerged as a highly significant predictor of the risk of joint replacement surgery. Intervention rates were 1.9, 4.2, and 10.1 per 1,000 person-years in the first, second, and third tertiles, of the VCAM-1 level, respectively. In multivariable logistic regression analysis, the adjusted relative risk of joint replacement surgery in the highest versus the lowest tertile group of VCAM-I level was 3.9 (95% confidence interval 1.7-8.7) (P < 0.001). Findings were robust in various sensitivity analyses and were consistent in subgroups. Addition of the VCAM-1. level to a risk model already including age, sex, and body mass index resulted in significant gains in model discrimination (C statistic) and calibration and in more accurate risk classification of individual participants.Conclusion. The level of soluble VCAM-1 emerged as a strong and independent predictor of the risk of hip and knee joint replacement due to severe OA. If our findings can be reproduced in other epidemiologic cohorts, they will assist in routine risk classification and will contribute to a better understanding of the etiology of OA
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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