The impact of bisphosphonates on the osteoblast proliferation and Collagen gene expression in vitro

<p>Abstract</p> <p>Background</p> <p>Bisphosphonates are widely used in the clinical treatment of bone diseases with increased bone resorption. In terms of side effects, they are known to be associated with osteonecrosis of the jaw (BONJ).</p> <p>The objective of this study was to evaluate the effect of bisphosphonates on osteoblast proliferation by cell count and gene expression analysis of cyclin D1 <it>in vitro</it>. Furthermore, the gene expression of the extracellular matrix protein collagen type I was evaluated. Nitrogen-containing and non-nitrogen-containing bisphosphonates have been compared on gene expression levels.</p> <p>Methods</p> <p>Human osteoblast obtained from hip bone were stimulated with zoledronate, ibandronate and clodronate at concentrations of 5 × 10^-5M over the experimental periods of 1, 2, 5, 10 and 14 days. At each point in time, the cells were dissolved, the mRNA extracted, and the gene expression level of cyclin D1 and collagen type I were quantified by Real-Time RT-PCR. The gene expression was compared to an unstimulated osteoblast cell culture for control.</p> <p>Results</p> <p>The proliferation appeared to have been influenced only to a small degree by bisphosphonates. Zolendronate led to a lower cyclin D1 gene expression after 10 days. The collagen gene expression was enhanced by nitrogen containing bisphosphonates, decreased however after day 10. The non-nitrogen-containing bisphosphonate clodronate, however, did not significantly influence cyclin D1 and collagen gene expression.</p> <p>Conclusions</p> <p>The above data suggest a limited influence of bisphosphonates on osteoblast proliferation, except for zoledronate. The extracellular matrix production seems to be initially advanced and inhibited after 10 days. Interestingly, clodronate has little influence on osteoblast proliferation and extracellular matrix production in terms of cyclin D1 and collagen gene expression.</p

Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Lung fibrosis is a devastating pulmonary disorder characterized by alveolar epithelial injury, extracellular matrix deposition and scar tissue formation. Due to its potent collagenolytic activity, cathepsin K, a lysosomal cysteine protease is an interesting target molecule with therapeutic potential to attenuate bleomycin-induced pulmonary fibrosis in mice. We here tested the hypothesis that over-expression of cathepsin K in the lungs of mice is protective in bleomycin-induced pulmonary fibrosis.</p> <p>Methods</p> <p>Wild-type and cathepsin K overexpressing (cathepsin K transgenic; cath K tg) mice were challenged intratracheally with bleomycin and sacrificed at 1, 2, 3 and 4 weeks post-treatment followed by determination of lung fibrosis by estimating lung collagen content, lung histopathology, leukocytic infiltrates and lung function. In addition, changes in cathepsin K protein levels in the lung were determined by immunohistochemistry, real time RT-PCR and western blotting.</p> <p>Results</p> <p>Cathepsin K protein levels were strongly increased in alveolar macrophages and lung parenchymal tissue of mock-treated cathepsin K transgenic (cath K tg) mice relative to wild-type mice and further increased particularly in cath K tg but also wild-type mice in response to bleomycin. Moreover, cath K tg mice responded with a lower collagen deposition in their lungs, which was accompanied by a significantly lower lung resistance (R_L) compared to bleomycin-treated wild-type mice. In addition, cath K tg mice responded with a lower degree of lung fibrosis than wild-type mice, a process that was found to be independent of inflammatory leukocyte mobilization in response to bleomycin challenge.</p> <p>Conclusion</p> <p>Over-expression of cathepsin K reduced lung collagen deposition and improved lung function parameters in the lungs of transgenic mice, thereby providing at least partial protection against bleomycin-induced lung fibrosis.</p

Testing Evolutionary and Dispersion Scenarios for the Settlement of the New World

Background: Discussion surrounding the settlement of the New World has recently gained momentum with advances in molecular biology, archaeology and bioanthropology. Recent evidence from these diverse fields is found to support different colonization scenarios. The currently available genetic evidence suggests a ""single migration'' model, in which both early and later Native American groups derive from one expansion event into the continent. In contrast, the pronounced anatomical differences between early and late Native American populations have led others to propose more complex scenarios, involving separate colonization events of the New World and a distinct origin for these groups. Methodology/Principal Findings: Using large samples of Early American crania, we: 1) calculated the rate of morphological differentiation between Early and Late American samples under three different time divergence assumptions, and compared our findings to the predicted morphological differentiation under neutral conditions in each case; and 2) further tested three dispersal scenarios for the colonization of the New World by comparing the morphological distances among early and late Amerindians, East Asians, Australo-Melanesians and early modern humans from Asia to geographical distances associated with each dispersion model. Results indicate that the assumption of a last shared common ancestor outside the continent better explains the observed morphological differences between early and late American groups. This result is corroborated by our finding that a model comprising two Asian waves of migration coming through Bering into the Americas fits the cranial anatomical evidence best, especially when the effects of diversifying selection to climate are taken into account. Conclusions: We conclude that the morphological diversity documented through time in the New World is best accounted for by a model postulating two waves of human expansion into the continent originating in East Asia and entering through Beringia.Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)[11070091]Fundacao de Amparo a Ciencia do Estado de Sao Paulo (FAPESP)[04/01253-0]Conselho Nacional de Pesquisa (CNPq)[301126-04.6]Max Planck GesellschaftEVAN Marie Curie Research Training Network[MRTN-CT-019564

The role of open abdomen in non-trauma patient : WSES Consensus Paper

The open abdomen (OA) is defined as intentional decision to leave the fascial edges of the abdomen un-approximated after laparotomy (laparostomy). The abdominal contents are potentially exposed and therefore must be protected with a temporary coverage, which is referred to as temporal abdominal closure (TAC). OA use remains widely debated with many specific details deserving detailed assessment and clarification. To date, in patients with intra-abdominal emergencies, the OA has not been formally endorsed for routine utilization; although, utilization is seemingly increasing. Therefore, the World Society of Emergency Surgery (WSES), Abdominal Compartment Society (WSACS) and the Donegal Research Academy united a worldwide group of experts in an international consensus conference to review and thereafter propose the basis for evidence-directed utilization of OA management in non-trauma emergency surgery and critically ill patients. In addition to utilization recommendations, questions with insufficient evidence urgently requiring future study were identified.Peer reviewe