Efficacy and safety of intravenous meropenem and tobramycin versus ceftazidime and tobramycin in cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic bacterial broncho-pulmonary infection. Although intravenous (IV) antibiotic therapy is regarded as standard treatment in CF, only few randomised trials comparing different antibiotic compounds exist. METHODS: We report on a prospective multicenter interventional trial of IV meropenem (120 mg/kg/day) or IV ceftazidime (200-400 mg/kg/day), each administered together with IV tobramycin (9-12 mg/kg/day). Outcome measures were changes in lung function, microbiological sputum burden and blood inflammatory marker. Liver and renal function values were measured to assess safety. RESULTS: One hundred eighteen patients (59/59) were included into the study with the following indications: first infection of P. aeruginosa (n=6), acute pulmonary exacerbation (n=34) and suppression therapy of chronic P. aeruginosa colonization (n=78). Both treatments improved lung function measures, bacterial sputum burden and CRP levels with no differences between treatment groups observed. A significant higher elevation for alkaline phosphatase (p<0.0001) was observed for patients in the meropenem/tobramycin group. CONCLUSIONS: IV antibiotic therapy in CF patients with meropenem/tobramycin is as effective as with ceftazidime/tobramycin regarding lung function, microbiological sputum burden and systemic inflammatory status. Hepato-biliary function should be monitored carefully during IV treatment, possibly important in CF patients with pre-existing liver disease.

Increased invasive potential and up-regulation of MMP-2 in MDA-MB-231 breast cancer cells expressing the beta3 integrin subunit

Integrins are a family of transmembrane adhesion receptors that might transduce signals from the extracellular matrix into the inside of cells after ligand binding. In order to investigate whether beta3 integrins expressed in tumor cells might mediate such outside-in signaling, human MDA-MB-231 breast cancer cells that were stably transfected with either beta3 integrin or mock-transfected were investigated in a matrigel degradation assay and a grafting experiment was performed on the developing chicken chorioallantoic membrane (CAM). After cultivation on matrigel for time periods between one and five days, more matrigel was digested in the wells in which beta3 integrin expressing cells were incubated than in wells of mock-transfected cells. Furthermore, extracts of beta3 integrin expressing cells contained higher levels of MMP-2 protein as determined by immunoblotting and more MMP-2 associated gelatinase activity as detected by zymography than extracts of mock-transfected cells. Matrigel degradation and gelatinase activity as well as MMP-2 expression were elevated when beta3 integrin expressing cells were incubated in the presence of the RGD peptide (mimicking an integrin ligand). After grafting on 10 day-old embryonic chicken CAM for three to five days, beta3 integrin expressing cells assembled in spheroids showed higher rates of spreading on the CAM surface and CAM invasion as well as a significant MMP-2 up-regulation compared to mock-transfected cells. The results from the in vivo and in vitro experiments allow the conclusion that the presence of beta3 integrin in MDA-MB-231 breast cancer cells induced an increased MMP-2 expression and activity that might contribute to the enhanced invasive potential observed.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells

Infection with bacteria such as Chlamydia pneumonia, Helicobacter pylori or Porphyromonas gingivalis may be triggering the secretion of inflammatory cytokines that leads to atherogenesis. The mechanisms by which the innate immune recognition of these pathogens could lead to atherosclerosis remain unclear. In this study, using human vascular endothelial cells or HEK-293 cells engineered to express pattern-recognition receptors (PRRs), we set out to determine Toll-like receptors (TLRs) and functionally associated PRRs involved in the innate recognition of and response to lipopolysaccharide (LPS) from H. pylori or P. gingivalis. Using siRNA interference or recombinant expression of cooperating PRRs, we show that H. pylori and P. gingivalis LPS-induced cell activation is mediated through TLR2. Human vascular endothelial cell activation was found to be lipid raft-dependent and to require the formation of heterotypic receptor complexes comprising of TLR2, TLR1, CD36 and CD11b/CD18. In addition, we report that LPS from these bacterial strains are able to antagonize TLR4. This antagonistic activity of H. pylori or P. gingivalis LPS, as well as their TLR2 activation capability may be associated with their ability to contribute to atherosclerosis.

High-molecular weight adiponectin is independently associated with the extent of coronary artery disease in men

OBJECTIVE: Adiponectin has anti-atherogenic properties and low circulating adiponectin has been linked to coronary atherosclerosis. Yet, there is considerable evidence that the high-molecular weight (HMW) complex of adiponectin is the major active form of this adipokine. We therefore investigated whether HMW adiponectin is associated with the extent of coronary artery disease (CAD) in men. RESEARCH DESIGN AND METHODS: Associations among CAD, HMW adiponectin and the HMW/total-adiponectin ratio were assessed in 240 male patients undergoing elective coronary angiography. Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. RESULTS: We found significant inverse correlations between angiographic scores and HMW adiponectin [Extent Score (ES): r=-0.39; Gensini Score (GS): r=-0.35; and Severity Score (SS): r=-0.40, all P<0.001], and the HMW/total-adiponectin ratio (ES: r=-0.49; GS: r=-0.46; SS: r=-0.46; all P<0.001). Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both P<0.001). ROC analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (P<0.001, P=0.010, respectively). CONCLUSIONS: HMW adiponectin and the HMW/total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin.

Association of lipopolysaccharide-binding protein and coronary artery disease in men

OBJECTIVES: In this study we tested the hypothesis that lipopolysaccharide-binding protein (LBP) might be able to be used as a biomarker for coronary artery disease (CAD). BACKGROUND: The mechanisms by which the innate immune recognition of pathogens could lead to atherosclerosis remain unclear. Lipopolysaccharide-binding protein is the first protein to encounter lipopolysaccharide and to deliver it to its cellular targets, toll-like receptors; therefore, its presence might be a reliable biomarker that indicates activation of innate immune responses. METHODS: A total of 247 men undergoing elective coronary angiography were studied, and the extent of coronary atherosclerosis was assessed by 2 established scores: "extent score" and "severity score." Levels of LBP, markers of inflammation, and traditional risk factors for CAD were assessed. RESULTS: Serum LBP concentration was significantly increased in 172 patients with angiographically confirmed CAD compared with 75 individuals without coronary atherosclerosis (20.6 +/- 8.7 pg/ml vs. 17.1 +/- 6.0 pg/ml, respectively; p = 0.002). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of prevalent CAD (p < 0.05 in all models). CONCLUSIONS: Lipopolysaccharide-binding protein might serve as a novel marker for CAD in men. The present results underlie the potential importance of innate immune mechanisms for CAD. Further studies are warranted to bolster the data and to identify pathogenetic links between innate immune system activation and atherosclerosis.

Cervical soft tissue imaging using a mobile CBCT scanner with a flat panel detector in comparison with corresponding CT and MRI data sets

OBJECTIVE: The aim of this study was to evaluate soft tissue image quality of a mobile cone-beam computed tomography (CBCT) scanner with an integrated flat-panel detector. STUDY DESIGN: Eight fresh human cadavers were used in this study. For evaluation of soft tissue visualization, CBCT data sets and corresponding computed tomography (CT) and magnetic resonance imaging (MRI) data sets were acquired. Evaluation was performed with the help of 10 defined cervical anatomical structures. RESULTS: The statistical analysis of the scoring results of 3 examiners revealed the CBCT images to be of inferior quality regarding the visualization of most of the predefined structures. Visualization without a significant difference was found regarding the demarcation of the vertebral bodies and the pyramidal cartilages, the arteriosclerosis of the carotids (compared with CT), and the laryngeal skeleton (compared with MRI). Regarding arteriosclerosis of the carotids compared with MRI, CBCT proved to be superior. CONCLUSIONS: The integration of a flat-panel detector improves soft tissue visualization using a mobile CBCT scanner.

3D C-arm as an alternative modality to CT in postmortem imaging: technical feasibility

OBJECT: The aim of our study was to demonstrate the image quality of the new device using human cadavers, extending the horizon of available imaging modalities in forensic medicine. MATERIALS AND METHODS: Six human cadavers were examined, revealing C-arm data sets of the head, neck thorax, abdomen and pelvis. High-resolution mode was performed with 500 fluoroscopy shots during a 190 degrees orbital movement with a constant tube voltage of 100 kV and a current of 4.6 mA. Based on these data sets subsequent three-dimensional reconstructions were generated. RESULTS: Reconstructed data sets revealed high-resolution images of all skeletal structures in a near-CT quality. The same image quality was available in all reconstruction planes. Artefacts caused by restorative dental materials are less accentuated in CBCT data sets. The system configuration was not powerful enough to generate sufficient images of intracranial structures. CONCLUSION: After the here-demonstrated encouraging preliminary results, the forensic indications that would be suitable for imaging with a 3D C-arm have to be defined. Promising seems the visualization local limited region of interest as the cervical spine or the facial skeleton.

Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.

Femoral head injuries: Which treatment strategy can be recommended?

Despite different operative and non-operative treatment regimens, the outcome after femoral head fractures has changed little over the past decades. The initial trauma itself as well as secondary changes such as posttraumatic osteoarthritis, avascular necrosis or heterotopic ossification is often responsible for severe loss of function of the afflicted hip joint. Anatomic reduction of all fracture fragments seems to be a major influencing factor in determining the outcome quality. Eight years ago we inaugurated a new surgical approach for better access and visualisation for the treatment of femoral head fractures, using the "trochanteric flip" (digastric) osteotomy. Thus inspection of the entire hip joint and accurate fragment reduction under direct visual control are possible. After good initial experiences with this operative procedure we changed our standard treatment regimen to this approach in an attempt to achieve the most accurate anatomic reduction of the femoral head in every affected patient. Between 1998 and 2006 we operated on 12 patients with femoral head fractures associated with posterior hip dislocation, using the new surgical approach. Patients were followed for 2-96 months and outcome was documented with the Merle d'Aubigne and Postel score as well as the Thompson and Epstein score. The posttraumatic formation of heterotopic bone was documented with the Brooker score. Retrospective analysis of these 12 patients showed good or excellent results in 10 patients (83.3%). The two patients with poor outcome developed an avascular necrosis of the femoral head and underwent total hip arthroplasty. Periarticular heterotopic ossification was seen in five patients. In four patients this caused a significantly reduced range of motion and was therefore considered as a posttraumatic complication. The two patients with the most severe heterotopic bone formation (Brooker III and IV) had initially sustained multiple injuries including brain injury. Comparing our results with earlier published series including our own before changing the treatment protocol, the data suggest a favorable outcome in patients with trochanteric flip (digastric) osteotomy for the treatment of femoral head fractures.