Nucleophilic cross-linked, dextran coated iron oxide nanoparticles as basis for molecular imaging: synthesis, characterization, visualization and comparison with previous product.

We present a new synthesis protocol for a multivalent, multimodality, nucleophilic nanoparticle ideal for in vivo imaging. Stability requirements necessitated covalent cross-linking of the carbohydrate cage, easy functionalization the introduction of sterically accessible amine groups. The new protocol aimed at more uniform particle size, less clustering and superior magnetic properties compared with commercial nanoparticles. Particles were precipitated from Fe(2+) and Fe(3+) in the presence of 10 kDa dextran monodispersed from the aerosol phase. Cross-linking was achieved with epichlorhydrin, nuclophilication with NH3, purification with ultrafiltration and dialysis. Particles and a commercial product (Rienso®, Takeda Pharma) underwent physicochemical characterizations. Biocompatibility was assessed by Resazurin on LLC-PK1 cells; the internalization rate was measured for three cell lines (HAEC, HASMC, HT29). Core size was 5.61 ± 1.25 nm; hydrodynamic size was 49.56 ± 11.73 nm. The number of sterically accessible amine groups averaged 9.9. The cores showed cubic magnetite structure. Values of r1 and r2 were 10.9 and 148.17 mM(-1) s(-1). Cellular viability was unchanged after incubation. Introduction of aerosol phase dextran resulted in a reduction of the overall hydrodynamic diameter and a narrower size distribution of the synthesized particles. Electron tomography visualized for the first time the postulated 'hairy layer' of the dextran coating and enabled the measurement of the overall diameter of 100.2 ± 7.92 nm. The resulting nanoparticle is biocompatible, functionalizable and detectable at nanomolar concentrations with MRI and optical imaging. It can potentially serve as a platform for multimodal molecular imaging and targeted therapy approaches.

Prospective evaluation of high-resolution MRI using gadofosveset for stent-graft planning: comparison with CT angiography in 30 patients.

OBJECTIVE: The purpose of our study was to compare high-resolution gadofosveset-enhanced MR angiography (MRA) with the reference standard CT angiography (CTA) in planning endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms. SUBJECTS AND METHODS: Thirty consecutive patients were included in this prospective study. CTA was performed routinely before EVAR for stent-graft implantation planning and selection. In addition, first-pass and, after a delay of 10 minutes, steady-state MRA were performed using the blood pool contrast agent gadofosveset for study purposes. Standard diameter and length parameters for stent-graft evaluation rendered from CTA and MRA were compared. According to the results of MRA measurements, stent-grafts were selected for each patient and compared with the device actually implanted. Image quality was assessed using subjective image quality parameters. RESULTS: Diameter and length measurements showed small but significant differences (p < 0.001) between MRA and CTA. Stent-graft selection according to these measurements showed 100% concordance between both modalities. Subjective imaging parameters showed significantly better results for CTA compared with MRA (p < 0.001). CONCLUSION: In this study, MRA using a blood pool contrast agent has shown the ability to provide reliable and exact measurements before EVAR, allowing noninvasive planning of the intervention despite lower image-quality and without the disadvantages of ionizing radiation and nephrotoxicity.

Efficacy and safety of current drug therapies for invasive aspergillosis.

Invasive aspergillosis (IA) is a potentially lethal infection that affects mostly immunocompromised patients. The therapeutic goals are to restore leucocyte function and to reduce the fungal burden by effective antifungal agents and, contingently, by surgery. Several drugs for the treatment of IA are currently licensed. The longest known among them is amphotericin B (AmB). In well-performed clinical trials, approximately 30-50% of participants treated with AmB showed complete or partial response. However, this drug is associated with considerable acute and chronic toxicity which was somewhat mitigated by the development of lipid-based formulations. In contrast, voriconazole (VRC) is better tolerated, penetrates well into the central nervous system and may be given intravenously and orally in a sequential manner. The overall rates of favourable response to VRC were similar to that for AmB. Most notably, double-digit rates of complete remission were observed in studies including extraordinarily high proportions of patients with proven IA and specific risk factors. Disadvantages of VRC include the genetically determined interindividual variability of pharmacokinetics and the potential for drug-drug interactions that may require therapeutic drug monitoring. The recently introduced caspofungin (CPF) offers an excellent safety profile, but underperformed in terms of efficacy against mold infections. Other antifungals such as itraconazole and posaconazole are presently recommended as second-line option for the therapy or prophylaxis of (non-)IA. The value of micafungin and anidulafungin remains to be investigated in randomized clinical trials. In guidelines released by relevant medical societies, VRC is recommended as the first choice in the treatment of IA. AmB, preferably given as a liposomal preparation, or combinatory antifungal regimens combining VRC or liposomal AmB with CPF are stated as alternative options.

A reappraisal of current dosing strategies for intravenous fosfomycin in children and neonates.

The rising incidence of multi-drug resistant bacterial pathogens has renewed interest in the long-known antibacterial fosfomycin. Not least because of its low toxicological potential, there is good clinical experience with intravenous fosfomycin for various Gram-positive and Gram-negative infections in the treatment of children and neonates. However, the current dosing recommendations for intravenous fosfomycin vary widely in paediatric patients. In the present review, we summarized available plasma pharmacokinetic data derived from neonates or children following intravenous administration of fosfomycin. Subsequently, we used this information for recalculation of different dosing strategies and simulated a variety of clinically applied dosing regimens. The percentage of time above the minimal inhibitory concentration (T>MIC) was calculated for each dosing strategy, as this pharmacokinetic-pharmacodynamic parameter was shown to be most predictive of antimicrobial and clinical success of fosfomycin treatment. Our data corroborate the current practice of selecting the dosage of intravenous fosfomycin primarily on the basis of bodyweight and age in paediatric patients. As with other 'time-dependent' antibacterials, a dosing interval of 6-8 hours should be preferred over 12 hours except for immature neonates. Given a T>MIC target of 40-70%, currently recommended dosing strategies appear to be insufficient in children aged 1-12 years, if pathogens with MICs of ≥32 mg/L are suspected and subjects are presenting with normal renal function. Likewise, the lowest recommended daily dose for neonates and infants (aged up to 12 months) of 100 mg/kg bodyweight of fosfomycin should be considered only for pre-term neonates with a postmenstrual age below 40 weeks.

Uterine artery embolization for the treatment of adenomyosis: a review.

During the past 10 years, uterine artery embolization (UAE) has been investigated as a possible therapy for adenomyosis. All publications available from 1999 through 2010 are included in this report. Levels of evidence and trial classifications were evaluated according to the guidelines developed by the United States Preventive Services Task Force. Long-term data are available from 511 affected women from 15 studies. Improvements were reported by 387 patients (75.7%). The median follow-up was 26.9 months. UAE as treatment for adenomyosis shows significant clinical and symptomatic improvements on a short- and long-term basis.

Rapid and sensitive determination of the antibiotic linezolid in low plasma volumes by high-performance liquid chromatography.

A rapid and sensitive method for the determination of linezolid by high-performance liquid chromatography (HPLC) with UV detection (251 nm) is presented. Linezolid is an important antibiotic against severe infections caused by multi-resistant bacterial pathogens. Scientific efforts continue investigating its effectiveness in different conditions and patient populations including children and newborns. Because plasma samples in a pediatric setting or from animal models are usually collected in low volumes, there is a necessity for a reliable and precise analytical method that is reliable and precise even at sample volumes below 50 microL. The presented method is suitable for plasma sample volumes of 20 microL and can be performed with basic HPLC equipment. Linezolid is extracted from plasma with 10% methanol-90% dichloromethane at neutral conditions and separated isocratically on a microbore ODS column using ammonium acetate buffer (pH 4.4, 0.5%, w/v) and acetonitrile (84:16, v/v) as the eluent. The method exerts linearity from 0.05-40 mg/L and meets commonly accepted specifications regarding accuracy and precision.

Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections.

The present study aimed at assessing unbound extracellular concentrations of linezolid in inflamed soft tissue and bone of diabetic patients suffering from severe bacterial foot infections. Linezolid was administered intravenously twice daily at a dosage of 600 mg. At steady-state conditions, the microdialysis technique was utilised to sample serially interstitial space fluid from inflamed subcutaneous adipose tissue and metatarsal bone from 0-8h post dose in three representative patients. Mean peak concentrations of free linezolid in plasma, healthy subcutis, inflamed subcutis and cancellous bone were 16.6+/-3.0, 15.5+/-2.5, 15.8+/-2.8 and 15.1+/-4.1mg/L, respectively. The degree of tissue penetration as expressed by the ratio of the area under the concentration-time curve of free linezolid from 0-12h (fAUC(0-12)) in tissue to the fAUC(0-12) in plasma was 1.32+/-0.09, 1.12+/-0.22 and 1.09+/-0.11 for healthy subcutis, inflamed subcutis and bone, respectively. Based on currently available pharmacokinetic/pharmacodynamic targets, we conclude that linezolid administered at 600 mg twice daily may be considered an effective treatment in diabetic patients suffering from bacterial foot infection complicated by osteomyelitis.

Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections.

OBJECTIVES: In the attempt to overcome increasing glycopeptide- and methicillin-resistant soft tissue infections, daptomycin is presently considered as an attractive alternative to the class of glycopeptides. However, daptomycin dosing and its ability to penetrate into inflamed target tissues are still a matter of controversy. Thus, in the present investigation, we set out to evaluate daptomycin's ability to penetrate into inflamed subcutaneous adipose tissue and bone in diabetic patients presenting with severe bacterial foot infection. PATIENTS AND METHODS: The microdialysis technique was utilized to collect interstitial space fluid from inflamed subcutaneous adipose tissue and metatarsal bone. Plasma and unaffected subcutaneous adipose tissue served as reference compartments. Serial sampling of specimens at steady-state was performed from 0 to 8 h post-dose in five patients (Group A) and from 8 to 16 h after study drug administration in another group of four patients (Group B). In all subjects, daptomycin was administered intravenously once daily at a dosage of 6 mg/kg body weight for 4 consecutive days at minimum. RESULTS: Equilibrium between free tissue and plasma concentrations was achieved approximately 2 h post-infusion. Under steady-state conditions, the degree of tissue penetration was assessed by the calculation of the ratio of free (f) AUC of daptomycin in plasma to the fAUC in tissues. The mean ratios of the fAUC0-16 tissue to the fAUC0-16 plasma were 1.44, 0.98 and 1.08 for healthy tissue, inflamed subcutaneous adipose tissue and bone, respectively. The corresponding ratios of the fAUCs from 0 to 24 h were 1.54, 1.06 and 1.17, respectively. CONCLUSIONS: With the reservation that pharmacokinetic-pharmacodynamic targets for daptomycin in tissues are currently not established, we conclude that daptomycin given at intravenous doses of 6 mg/kg body weight once daily may be considered an effective treatment regimen in diabetic patients suffering from bacterial foot infection and osteomyelitis.

The effects of endurance and recreational exercise on subclinical evidence of atherosclerosis in young adults.

BACKGROUND: This study set out to identify the effects of recreational and endurance exercise on subclinical evidence of atherosclerosis in young adults. METHODS: Cardiovascular disease risk factors and intima-media thickness determination by B-mode ultrasonography of 150 subjects were correlated to endurance exercise, recreational exercise, and sedentary lifestyle. The subjects comprised 20- to 40-year-old men and women without cardiovascular disease. This cross-sectional, case-control study analyzed data on the laboratory parameters and information collected from a risk factor questionnaire. RESULTS: The athletes, both endurance and recreational groups, have significantly superior values with respect to physiognomy, lipid profile, and inflammatory markers in relation to the nonexercising study population (all P < 0.05). Detailed analysis showed markedly reduced values for relative body fat (relative reduction 14.3%), low-density lipoprotein (10.6%), and triglycerides (13.5%) and a 50% reduction of hs-C-reactive protein. In the univariate and multivariate comparison of athletic (n = 100) and nonathletic (n = 50) groups, exercise did not show to exert a significant influence on vascular wall parameters (for all, P > 0.05). CONCLUSION: Exercise, in recreational and endurance form, between the ages of 20 and 40 years exerts a preventive influence on cardiovascular risk factors but seems to fail to affect early, atherosclerotic vascular wall changes.

Quality of life in patients with idiopathic subclavian vein thrombosis.

INTRODUCTION: Idiopathic subclavian vein thrombosis (SVT) is a rare disease but these otherwise healthy patients often suffer from prolonged clinical manifestations. The aim of this retrospective study was to assess the range and severity of thrombosis-related disability of the upper extremity in patients after an episode of documented idiopathic SVT in the long-term follow-up. MATERIALS AND METHODS: The quality of life (QoL) of 37 patients with documented idiopathic SVT was assessed by two standardized questionnaires (DASH and SF 36). The DASH and SF-36 questionnaire each use a 100 point scale. 0 stands for uncompromised functioning, 100 for maximum limitation in the DASH, while in the SF-36 0 marks the lowest rating of QoL and 100 indicates the best imaginable quality of life. RESULTS: Mean follow-up time was 120+/-80.1 months (range: 14 to 286 months). The mean DASH score was 10.7+/-12 and the mean scores for the SF-36 dimensions Physical Component Summary (PCS) and Mental Component System (MCS) were 52+/-9.3 and 46.3+/-9.5, respectively. CONCLUSIONS: Patients suffering from idiopathic SVT report good overall QoL judged by the mean DASH and satisfactory QoL by the SF-36 score in the long-term follow-up. These patients deal well with their physical limitations.

Multidetector CTA in the quantification of internal carotid artery stenosis: value of different reformation techniques and axial source images compared with selective carotid arteriography.

PURPOSE: To evaluate the role of 4 different reformation techniques and axial images from multidetector computed tomographic angiography (MDCTA) versus selective carotid arteriography (SCA) in patients with internal carotid artery (ICA) stenosis. METHODS: Imaging studies from 50 patients (43 men; mean age 70.3+/-8.0 years, range 51-85) with known cerebrovascular disease who underwent MDCTA and SCA in a single university hospital were retrospectively analyzed. Axial images, multiplanar reformation (MPR), curved planar reformation (CPR), volume rendering threshold (VRT), and virtual angioscopy (VA) images were reviewed by 2 independent observers who were blinded to the results of SCA, which served as the gold standard. The degree of stenosis was categorized as 0%-49%, 50%-69%, or 70%-99%; a stenosis >70% was considered as hemodynamically significant. RESULTS: Thirty-four hemodynamically significant stenoses were identified on SCA. The agreement with SCA images was good for both observers using axial CT images (kappa = 0.89 for observer 1 and 0.88 for observer 2); corresponding results for MPR and CPR were kappa = 0.91 and 0.92 for observer 1 and 0.88 and 0.91 for observer 2, respectively. VRT (kappa = 0.72 for observer 1 and 0.66 for observer 2) and VA (kappa = 0.74 for observer 1 and 0.70 for observer 2) showed a slightly inferior correlation with SCA images. Sensitivities for reformations and axial CT images were 100% each; corresponding specificities ranged from 85% to 95%. CONCLUSION: Axial images as well as all 4 reformation techniques agreed well with SCA in the grading of ICA stenosis.

High fosfomycin concentrations in bone and peripheral soft tissue in diabetic patients presenting with bacterial foot infection.

OBJECTIVES: Appropriate antimicrobial therapy and surgical intervention may be required in diabetic patients presenting with severe bacterial foot infection. Methicillin-resistant Staphylococcus aureus (MRSA) agents such as fosfomycin are increasingly in demand because of recent concern regarding vancomycin and daptomycin efficacy and constant use. Intravenous fosfomycin is approved for the therapy of severe soft tissue infections and is highly active against methicillin-susceptible S. aureus and MRSA. in the present study we investigated fosfomycin's ability to penetrate bone tissue in diabetic patients suffering from severe bacterial foot infection. PATIENTS AND METHODS: The well established microdialysis technique was utilized to determine fosfomycin concentrations in metatarsal bone in nine patients scheduled for partial bone resection due to bacterial foot infection and osteomyelitis. Plasma and unaffected subcutaneous adipose tissue served as reference compartments. RESULTS: After a single intravenous dose of approximately 100 mg of fosfomycin per kg of body weight, the mean C(max), T(max) and AUC(0-6) for bone were 96.4 mg/L, 3.9 h and 330.0 mg x h/L, respectively. The degree of tissue penetration as determined by the ratios of the AUC(0-6) for bone to plasma and for subcutaneous adipose tissue to plasma were 0.43 +/- 0.04 and 0.76 +/- 0.05, respectively. CONCLUSIONS: On the basis of relevant pharmacokinetic-pharmacodynamic indices, it seems that fosfomycin is an effective antibiotic for the treatment of deep-seated diabetic foot infections with osseous matrix involvement.

Long-term quality of life assessment among patients undergoing uterine fibroid embolization.

OBJECTIVE: The purpose of this study was assessment of the long-term outcome of fibroid-associated quality of life among patients treated with uterine fibroid embolization. MATERIALS AND METHODS: A retrospective follow-up cohort study included all patients described in a 2006 publication. Analysis was performed with a questionnaire consisting of 49 questions about six topics. Assessment was focused on comparing symptoms and quality of life in long-term follow-up. RESULTS: The analysis was based on questionnaires completed by 39 patients. The median follow-up period was 7 years (interquartile range, 1.5 years). Uterine fibroid embolization led to a reduction of bleeding symptoms in 89.7% of the patients, pain in 78.9%, bulk-related symptoms in 89.5%, fatigue in 76.9%, limitations of social life in 92.9%, and depression in 78.6%. The median impairment scores for bleeding and pain decreased significantly from 7 to 0 and from 5 to 0 (both p < 0.001). The general quality-of-life index increased significantly from 4.5 to 9 (p < 0.001). In the long term, there was no significant difference in parameters assessed compared with the midterm follow-up findings. Six patients (15.4%) underwent hysterectomy an average of 32.1 months after intervention. Thirty-two patients (82.1%) continued to be satisfied with the intervention, and 30 patients (76.9%) answered that they would recommend uterine fibroid embolization to other patients. CONCLUSION: Uterine fibroid embolization seems to lead to notable long-term relief of fibroid-associated symptoms. In comparison with the midterm results, long-term outcome shows a clear continuance of improvement in general quality of life.

Daptomycin does not exert immunomodulatory effects in an experimental endotoxin model of human whole blood.

BACKGROUND: Recent studies have shown that distinct classes of antimicrobial agents might exert immunomodulatory effects in experimental settings. Daptomycin is the first member of the class of cyclic lipopeptide antibiotics, which exert their antimicrobial activity via a unique mode of action on the bacterial cytoplasmic membrane. Thus, we tested its ability to influence pro-inflammatory cytokines by use of an established experimental model of human endotoxemia. METHODS: A controlled experimental study design with 4 parallel groups was used. Whole blood from 10 healthy male volunteers was incubated either with saline (negative control), daptomycin (40 microg/ml, control), lipopolysaccharide (LPS; 50 pg/ml, positive control), or the combination of daptomycin plus LPS for 4 h. Real-time polymerase chain reaction was utilized for the measurement of selected pro-inflammatory cytokines, namely IL-1 beta, IL-6 (high sensitivity) and TNF-alpha on the mRNA level. Protein concentrations of these respective cytokines were measured in the supernatant using a commercially available ELISA. RESULTS: Incubation of whole blood with LPS significantly increased protein and mRNA levels of cytokines compared to baseline (p < 0.05). However, the combination of daptomycin plus LPS did not exert any significant effect on mRNA and protein levels of IL-1 beta, IL-6 (high sensitivity) and TNF-alpha after 2 and 4 h of incubation compared to LPS incubation alone. CONCLUSION: Daptomycin does not affect pro-inflammatory cytokines in the early phase of endotoxemia. This is most likely due to the unique mode of action of daptomycin, its low potential to penetrate into human cells and its high affinity to bacterial cytoplasmic membranes.