The impact of colony‐stimulating factor‐1 on fracture healing: An experimental study

The role of colony stimulating factor‐1 (CSF‐1) in the regulation of osteoclasts and bone remodeling suggests that CSF‐1 may also be involved in regulation of bone healing. The ability of CSF‐1 to promote healing of bone defects was tested in a rabbit model. Twenty‐four New Zeeland rabbits were included in the study. Animals were assigned to two groups: the control group (n = 12) was treated by plate fixation. The animals in the second group (n = 12) were also stabilized by conventional plating and received additionally CSF‐1 for 2 weeks systemically. Histologic, histomorphometric, and radiologic examinations were performed to evaluate the healing process at 4, 8, and 12 weeks following surgery. Animals that were treated by CSF‐1 produced a significantly higher amount of mineralized bone over the first 8 weeks after fracture compared to the control animals. Furthermore, a higher number of osteoclasts was found in CSF‐1‐treated animals within the first 8 weeks, compared to the controls. The present data emphasize for the first time the importance of CSF‐1 in the bone healing. The use of CSF‐1 in addition to conventional fixation might be a novel approach for the treatment of bone defects. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:36–41, 2009     

Co-expression of endothelin-1 and vascular endothelial growth factor mediates increased vascular permeability in lung grafts before reperfusion.

Endothelin-1 (ET-1) protein levels increase in lung transplant recipients, although the source of ET-1 remains uncertain. Evidence is accumulating that ET-1 coregulates the expression of vascular endothelial growth/permeability factor (VEGF-A). By using real-time polymerase chain reaction and Western blotting, we describe upregulated ET-1 mRNA and VEGF-A protein levels as well as increased fluid content in donor lung-tissue biopsies before reperfusion. Hypoxia and ET-1 co-upregulate VEGF-A overexpression, therefore temporary VEGF-A antagonism during graft preservation might be of benefit in lung transplantation.     

Fleece bound sealing prevents pleural adhesions

This study assessed the value of haemostatic fleece (HF) in prevention of pleural adhesions in an experimental animal model. Forty rats were randomly assigned to four equal groups and underwent bilateral thoracotomy. In Group 1 standardized defects of 5 mm were generated in the visceral and the opposite parietal pleura without further coverage. In Group 2 a 5-mm piece of HF (TachoSil) was applied onto the intact pleura. In Group 3 a standardized pleural defect was completely covered by HF. The same kind of defect was only partially covered by HF in group 4 animals. Autopsy at 6 weeks (n=5, each group) revealed the fleece widely unchanged and covered by a smooth serous membrane. After 12 weeks (n=5, each group) the fleece had been completely resorbed. Histological studies revealed the area of the defect covered by regular mesothelium. In all animals pleural adhesions were detected only in the area without fleece coverage. In this experimental model HF prevented the development of pleural adhesions. This property may have clinical impact in patients with some probability of re-thoracotomy enabling to reduce the risk of pleural adhesions significantly.     

Error estimation of geometrical data obtained by histomorphometry of oblique vessel sections: a computer model study

The errors of radius and wall thickness of a single vessel due to oblique sectioning in histomorphometry are expressed as a function of the circular shape factor (CSF) of the section's lumen, assuming cylindrical geometry and the absence of tissue deformation. Using computer model trees generated by constrained constructive optimization, mean errors are estimated for an ensemble of vessel segments. A geometrical exclusion criterion for segments cut too obliquely is defined on the basis of a CSF-cutoff value. It is shown that CSF-values ranging from 0.95 to 0.9 are reasonable choices for a cutoff and lead to mean errors of the same order of magnitude (9.6% [9.3%] to 15.4% [14.8%] for the radius [wall thickness]) as errors due to histological tissue processing.     

Epicardial shock‐wave therapy improves ventricular function in a porcine model of ischaemic heart disease

Previously we have shown that epicardial shock‐wave therapy improves left ventricular ejection fraction (LVEF) in a rat model of myocardial infarction. In the present experiments we aimed to address the safety and efficacy of epicardial shock‐wave therapy in a preclinical large animal model and to further evaluate mechanisms of action of this novel therapy. Four weeks after left anterior descending (LAD) artery ligation in pigs, the animals underwent re‐thoracotomy with (shock‐wave group, n = 6) or without (control group, n = 5) epicardial shock waves (300 impulses at 0.38 mJ/mm²) applied to the infarcted anterior wall. Efficacy endpoints were improvement of LVEF and induction of angiogenesis 6 weeks after shock‐wave therapy. Safety endpoints were haemodynamic stability during treatment and myocardial damage. Four weeks after LAD ligation, LVEF decreased in both the shock‐wave (43 ± 3%, p < 0.001) and control (41 ± 4%, p = 0.012) groups. LVEF markedly improved in shock‐wave animals 6 weeks after treatment (62 ± 9%, p = 0.006); no improvement was observed in controls (41 ± 4%, p = 0.36), yielding a significant difference. Quantitative histology revealed significant angiogenesis 6 weeks after treatment (controls 2 ± 0.4 arterioles/high‐power field vs treatment group 9 ± 3; p = 0.004). No acute or chronic adverse effects were observed. As a potential mechanism of action in vitro experiments showed stimulation of VEGF receptors after shock‐wave treatment in human coronary artery endothelial cells. Epicardial shock‐wave treatment in a large animal model of ischaemic heart failure exerted a positive effect on LVEF improvement and did not show any adverse effects. Angiogenesis was induced by stimulation of VEGF receptors. Copyright © 2014 John Wiley & Sons, Ltd.     

Effect of tranexamic acid on gross hematuria: A pilot randomized clinical trial study

Objective

Local forms of the tranexamic acid have been effective in treating many haemorrhagic cases. So that the aim of the current study is to assess the effectiveness of local tranexamic acid in controlling painless hematuria in patients referred to the emergency department.

Inflammation and postinfarct remodeling: overexpression of IkappaB prevents ventricular dilation via increasing TIMP levels

OBJECTIVE: Nuclear factor-kappa B (NF-kappaB) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IkappaB, the natural inhibitor of NF-kappaB, on ECM remodeling in a rat model of MI. METHODS: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IkappaB (n = 26) or LacZ reporter genes (n = 26). Sham-operated animals (n = 14) served as controls. RESULTS: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure-volume relationships in the IkappaB group compared to LacZ. NF-kappaB p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ (p<0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI (p<0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ (p<0.01 and p<0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated (p<0.05). CONCLUSION: Reducing NF-kappaB activity via IkappaB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IkappaB overexpression prevents ventricular dilation and consequently preserves cardiac function.     

Elevated levels of macrophage colony‐stimulating factor in human fracture healing

Macrophage colony‐stimulating factor (M‐CSF) plays a unique role in bone remodeling. However, to our knowledge, no data on the role of M‐CSF in fracture healing in humans have been published so far. This study addressed this issue. One hundred and thirteen patients with long‐bone fractures were included in the study and divided into two groups, according to their course of fracture healing. The first group contained 103 patients with normal fracture healing. Ten patients with impaired fracture healing formed the second group of the study. Volunteers donated blood samples as control. Serum samples were collected over a period of 6 months, following a standardized time schedule. In addition, M‐CSF levels were measured in fracture hematoma and serum of 11 patients with bone fractures. M‐CSF concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). Fracture hematoma contained significantly higher M‐CSF concentrations compared to M‐CSF concentrations in patient's serum. M‐CSF levels in fracture hematoma and in patient's serum were both significantly higher than M‐CSF concentrations measured in serum of healthy controls. Highly elevated M‐CSF serum concentrations were found in patients with physiological fracture healing over the entire observation period. Significant differences in the M‐CSF serum concentration between patients with normal fracture healing and patients with impaired fracture healing were not observed. This study indicates, for the first time, to our knowledge, a possible local and systemic involvement of M‐CSF in humans during fracture healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:671–676, 2010