Acute exposure to simulated nocturnal traffic noise and cardiovascular complications and sleep disturbance-results from a pooled analysis of human field studies.

OBJECTIVES: A series of human field studies demonstrated that acute exposure to simulated nocturnal traffic noise is associated with cardiovascular complications and sleep disturbance, including endothelial dysfunction, increased blood pressure, and impaired sleep quality. A pooled analysis of these results remains to be established and is of tremendous interest to consolidate scientific knowledge. METHODS: We analyzed data from four randomized crossover studies (published between 2013 to 2021 and conducted at the University Medical Center Mainz, Germany). A total of 275 subjects (40.4% women, mean age 43.03 years) were each exposed to one control scenario (regular background noise) and at least to one traffic noise scenario (60 aircraft or train noise events) in their homes during nighttime. After each night, the subjects visited the study center for comprehensive cardiovascular function assessment, including the measurement of endothelial function and hemodynamic and biochemical parameters, as well as sleep-related variables. RESULTS: The pooled analysis revealed a significantly impaired endothelial function when comparing the two different noise sequences (0-60 vs. 60-0 simulated noise events, mean difference in flow-mediated dilation -2.00%, 95% CI -2.32; -1.68, p < 0.0001). In concordance, mean arterial pressure was significantly increased after traffic noise exposure (mean difference 2.50 mmHg, 95% CI 0.54; 4.45, p = 0.013). Self-reported sleep quality, the restfulness of sleep, and feeling in the morning were significantly impaired after traffic noise exposure (all p < 0.0001). DISCUSSION: Acute exposure to simulated nocturnal traffic noise is associated with endothelial dysfunction, increased mean arterial pressure, and sleep disturbance.

Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial.

INTRODUCTION: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). METHODS: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. RESULTS: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. DISCUSSION/CONCLUSION: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy: A case report.

BACKGROUND: Cancer of unknown primary (CUP) is a histological proven malignant tumor whose origin cannot be detected despite careful examination. Most cervical lymph node metastases in CUP (80%) will originate from head and neck sites, and 15% show infiltration of squamous carcinoma cells. The survival rates of CUP are poor: The 5-year-survival rate ranges from 10% to 15%. First-line treatment recommendation for advanced, inoperable squamous cell carcinoma of head/neck (HNSCC) was cetuximab plus platinum-fluorouracil chemotherapy until recently, when checkpoint inhibitors proved clinically beneficial therapies. CASE SUMMARY: Here, we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck (squamous cell carcinoma, human papillomavirus positive). The cancer was diagnosed during pregnancy 10 years ago, and after giving birth, the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission (CR). CR lasted 26 mo when new metastases (abdominal lymph node, lumbar vertebral body) emerged. Both manifestations were irradiated. From then on, the patient has not received any further treatment, and her disease has remained controlled. Ten years after the initial cancer diagnosis, the patient is still alive and in good health, representing an exceptional case of HNSCC. CONCLUSION: This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard "Avatar" model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine. METHODS: This study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. RESULTS: Engraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients' tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection. CONCLUSION: Including biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers.

A Prospective Real-World Multi-Center Study to Evaluate Progression-Free and Overall Survival of Radiotherapy with Cetuximab and Platinum-Based Chemotherapy with Cetuximab in Locally Recurrent Head and Neck Cancer.

Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27-0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33-0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma-backbone or add-on in immune-oncology?

Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. METHODS: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score. RESULTS: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009). CONCLUSION: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.

Genetic Mutations in a Patient with Chronic Myeloid Leukemia Showing Blast Crisis 10 Years After Presentation.

Since the introduction of tyrosine kinase inhibitors (TKI), the prospects for patients with chronic myeloid leukemia (CML) have improved significantly. Herein we present the case of a patient with CML who experienced blast crisis and development of acute myeloid leukemia (AML) 10 years after presentation. The CML was characterized by the gene fusion of breakpoint cluster region BCR and tyrosine-protein kinase ABL1. During treatment different therapeutic protocols including imatinib, nilotinib, dasatinib and ponatinib were applied due to development of resistance or non-response. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to describe cytogenetic and molecular aberrations elucidating the development into AML: A loss of chromosome 7, as well as an arising frequency of variants in the gene met proto-oncogene MET (p.T110I) and tyrosine-protein phosphatase non-receptor type 11 PTPN11 (p.Q510L) was observed. This report describes the comprehensive characterization of a clinical case showing multiple therapeutic resistances correlated with genetic aberrations.

Antimicrobial Effect of Biocompatible Silicon Nanoparticles Activated Using Therapeutic Ultrasound.

In this study, we report a method for the suppression of Escherichia coli (E. coli) vitality by means of therapeutic ultrasound irradiation (USI) using biocompatible silicon nanoparticles as cavitation sensitizers. Silicon nanoparticles without (SiNPs) and with polysaccharide (dextran) coating (DSiNPs) were used. Both types of nanoparticles were nontoxic to Hep 2 cells up to a concentration of 2 mg/mL. The treatment of bacteria with nanoparticles and application of 1 W/cm2 USI resulted in the reduction of their viabilities up to 35 and 72% for SiNPs and DSiNPs, respectively. The higher bacterial viability reduction for DSiNPs as compared with SiNPs can be explained by the fact that the biopolymer shell of the polysaccharide provides a stronger adhesion of nanoparticles to the bacterial surface. Transmission electron microscopy (TEM) studies showed that the bacterial lipid shell was partially perforated after the combined treatment of DSiNPs and USI, which can be explained by the lysis of bacterial membrane due to the cavitation sensitized by the SiNPs. Furthermore, we have shown that 100% inhibition of E. coli bacterial colony growth is possible by coupling the treatments of DSiNPs and USI with an increased intensity of up to 3 W/cm2. The observed results reveal the application of SiNPs as promising antimicrobial agents.

A Novel Mouse Model of Staphylococcus aureus Vascular Graft Infection: Noninvasive Imaging of Biofilm Development in Vivo.

Staphylococcus aureus causes very serious infections of vascular grafts. Knowledge of the molecular mechanisms of this disease is largely lacking because of the absence of representable models. Therefore, the aim of this study was to set up a mouse model of vascular graft infections that closely mimics the human situation. A catheter was inserted into the right carotid artery of mice, which acted as a vascular graft. Mice were infected i.v. using 8 different S. aureus strains, and development of the infection was followed up. Although all strains had varying abilities to form biofilm in vitro and different levels of virulence in mice, they all caused biofilm formation on the grafts. This graft infection was monitored using magnetic resonance imaging (MRI) and 18F-fluordeoxyglucose positron emission tomography (FDG-PET). MRI allowed the quantification of blood flow through the arteries, which was decreased in the catheter after infection. FDG-PET revealed high inflammation levels at the site of the catheter after infection. This model closely resembles the situation in patients, which is characterized by a tight interplay between pathogen and host, and can therefore be used for the testing of novel treatment, diagnosis, and prevention strategies. In addition, combining MRI and PET with microscopic techniques provides an appropriate way to characterize the course of these infections and to precisely analyze biofilm development.

Characterization and prediction of the mechanism of action of antibiotics through NMR metabolomics.

BACKGROUND: The emergence of antibiotic resistant pathogenic bacteria has reduced our ability to combat infectious diseases. At the same time the numbers of new antibiotics reaching the market have decreased. This situation has created an urgent need to discover novel antibiotic scaffolds. Recently, the application of pattern recognition techniques to identify molecular fingerprints in 'omics' studies, has emerged as an important tool in biomedical research and laboratory medicine to identify pathogens, to monitor therapeutic treatments or to develop drugs with improved metabolic stability, toxicological profile and efficacy. Here, we hypothesize that a combination of metabolic intracellular fingerprints and extracellular footprints would provide a more comprehensive picture about the mechanism of action of novel antibiotics in drug discovery programs. RESULTS: In an attempt to integrate the metabolomics approach as a classification tool in the drug discovery processes, we have used quantitative (1)H NMR spectroscopy to study the metabolic response of Escherichia coli cultures to different antibiotics. Within the frame of our study the effects of five different and well-known antibiotic classes on the bacterial metabolome were investigated both by intracellular fingerprint and extracellular footprint analysis. The metabolic fingerprints and footprints of bacterial cultures were affected in a distinct manner and provided complementary information regarding intracellular and extracellular targets such as protein synthesis, DNA and cell wall. While cell cultures affected by antibiotics that act on intracellular targets showed class-specific fingerprints, the metabolic footprints differed significantly only when antibiotics that target the cell wall were applied. In addition, using a training set of E. coli fingerprints extracted after treatment with different antibiotic classes, the mode of action of streptomycin, tetracycline and carbenicillin could be correctly predicted. CONCLUSION: The metabolic profiles of E. coli treated with antibiotics with intracellular and extracellular targets could be separated in fingerprint and footprint analysis, respectively and provided complementary information. Based on the specific fingerprints obtained for different classes of antibiotics, the mode of action of several antibiotics could be predicted. The same classification approach should be applicable to studies of other pathogenic bacteria.

Label-free imaging and spectroscopic analysis of intracellular bacterial infections.

Staphylococcus aureus is one of the most frequent human pathogens that can also act as a facultative intracellular pathogen causing infections that are extremely difficult to treat. Only little is known about the pathogen's intracellular adaptation strategies to escape the host's response. Here, we present an advanced Raman-based imaging approach providing high quality false-color images to specifically identify intracellular S. aureus and to localize them exactly in three dimensions within endothelial cells. At the same time unprecedented insights into the metabolic characteristics of the pathogen are provided in a label-free and nondestructive manner. The spectral information reveals that the intracellular bacteria are in the exponential growth phase with a reduced replication rate and biochemically different from extracellular bacteria proving their adaptation to the host's conditions. This powerful biophotonic analysis tool paves the way for further mechanistic studies of difficult-to-investigate infection processes.

Making a big thing of a small cell--recent advances in single cell analysis.

Single cell analysis is an emerging field requiring a high level interdisciplinary collaboration to provide detailed insights into the complex organisation, function and heterogeneity of life. This review is addressed to life science researchers as well as researchers developing novel technologies. It covers all aspects of the characterisation of single cells (with a special focus on mammalian cells) from morphology to genetics and different omics-techniques to physiological, mechanical and electrical methods. In recent years, tremendous advances have been achieved in all fields of single cell analysis: (1) improved spatial and temporal resolution of imaging techniques to enable the tracking of single molecule dynamics within single cells; (2) increased throughput to reveal unexpected heterogeneity between different individual cells raising the question what characterizes a cell type and what is just natural biological variation; and (3) emerging multimodal approaches trying to bring together information from complementary techniques paving the way for a deeper understanding of the complexity of biological processes. This review also covers the first successful translations of single cell analysis methods to diagnostic applications in the field of tumour research (especially circulating tumour cells), regenerative medicine, drug discovery and immunology.

Chlamydia trachomatis-infected epithelial cells and fibroblasts retain the ability to express surface-presented major histocompatibility complex class I molecules.

The obligate intracellular bacterial pathogen Chlamydia trachomatis is the causative agent of a variety of infectious diseases such as trachoma and sexually transmitted diseases. In infected target cells, C. trachomatis replicates within parasitophorous vacuoles and expresses the protease-like activity factor CPAF. Previous studies have suggested that CPAF degrades the host transcription factors RFX5 and NF-κB p65, which are involved in the regulation of constitutive and inducible expression of major histocompatibility complex class I (MHC I). It was speculated that Chlamydia suppresses the surface presentation of MHC I in order to evade an effective immune response. Nevertheless, a recent study suggested that RFX5 and NF-κB p65 may not serve as target substrates for CPAF-mediated degradation, raising concerns about the proposed MHC I subversion by Chlamydia. Hence, we investigated the direct influence of Chlamydia on MHC I expression and surface presentation in infected host cells. By using nine different human cells and cell lines infected with C. trachomatis (serovar D or LGV2), we demonstrate that chlamydial infection does not interfere with expression, maturation, transport, and surface presentation of MHC I, suggesting functional antigen processing in bacterium-infected cells. Our findings provide novel insights into the interaction of chlamydiae with their host cells and should be taken into consideration for the design of future therapies and vaccines.

Persistent Chlamydia trachomatis infection of HeLa cells mediates apoptosis resistance through a Chlamydia protease-like activity factor-independent mechanism and induces high mobility group box 1 release.

Intracellular persistence of Chlamydia trachomatis has been implicated in the development of chronic infection that can result in pelvic inflammatory disease and tubal sterility. By inhibition of host cell apoptosis, chlamydiae have evolved a strategy to maintain the intracellular environment for replication and persistence. Both antiapoptotic host cell-derived factors and the chlamydial protease-like activity factor (CPAF) are involved in Chlamydia-mediated apoptosis resistance. Here, we show that in HeLa cells infected with gamma interferon (IFN-γ)-induced persistent C. trachomatis serovar D, the expression of CPAF is downregulated, and proapoptotic protease substrates are not cleaved. Persistent infection protected HeLa cells from apoptosis when they were exposed to staurosporine. Small-interfering RNA-mediated inhibition of myeloid cell leukemia 1 (Mcl-1) protein upregulation sensitized persistently infected cells for apoptosis. The inhibitor of apoptosis protein 2 (IAP-2) seems not to be relevant in this context because IAP-2 protein was not induced in response to IFN-γ treatment. Although apoptosis was inhibited, persistent infection caused cell membrane disintegration, as measured by the increased release of cytokeratin 18 from HeLa cells. Moreover, persistently infected cells released significantly increased amounts of high mobility group box 1 (HMGB1) protein which represents a proinflammatory damage-associated pattern molecule. The data of this study suggest that cells infected with persistent C. trachomatis are protected from apoptosis independently of CPAF but may promote chronic inflammation through HMGB1 release.

Altered cerebrovenous drainage in patients with migraine as assessed by phase-contrast magnetic resonance imaging.

OBJECTIVE: We aimed to assess whether migraine is associated with changes in the distribution of the venous drainage through primary and secondary pathways by using phase-contrast magnetic resonance imaging (MRI). METHODS: We examined 26 patients (37.3 ± 13.9 years) with recurring migraine headaches and 26 age- and gender-matched controls with no neurologic disease (37.3 ± 13.7 years) on a 3 Tesla MR scanner. A 2D time-of-flight MR-venography of the upper neck region was performed to visualize the venous vasculature. Cine-phase contrast scans with high-velocity encoding were employed to quantify arterial inflow and flow in the primary venous channels (right and left jugular veins), whereas scans with low-velocity encoding were employed to quantify flow in the secondary venous channels (epidural, vertebral, and deep cervical veins). RESULTS: Patients with migraine showed (i) a higher prevalence of dense secondary extracranial venous networks (15 vs. 2, P = 0.00002) and (ii) a significantly larger percentage of venous outflow through secondary channels (10.5% vs. 5.5%; of total cerebral blood flow, P = 0.02). This mainly included drainage through epidural, vertebral, and deep cervical veins. CONCLUSION: Migraine patients showed a significantly larger percentage of venous outflow through secondary channels. The mechanism of this alteration remains to be elucidated. Potential mechanisms include repeated release of vasoactive substances or growth factors.

Protein kinase A regulates growth, sporulation, and pigment formation in Aspergillus fumigatus.

Aspergillus fumigatus is an opportunistic human pathogenic fungus causing severe infections in immunocompromised patients. Cyclic AMP (cAMP) signal transduction plays an important role in virulence. A central component of this signaling cascade is protein kinase A (PKA), which regulates cellular processes by phosphorylation of specific target proteins. Here we describe the generation and analysis of A. fumigatus mutants expressing the gene encoding the catalytic subunit of PKA, pkaC1, under control of an inducible promoter. Strains overexpressing pkaC1 showed high PKA activity, reduced growth, sporulation deficiency, and formation of a dark pigment in the mycelium. These data indicate that cAMP-PKA signaling is involved in the regulation of important processes, such as growth, asexual reproduction, and biosynthesis of secondary metabolites. Furthermore, elevated PKA activity led to increased expression of the pksP gene. The polyketide synthase PksP is an essential enzyme for production of dihydroxynaphthalene-melanin in A. fumigatus and contributes to virulence. Our results suggest that increased pksP expression is responsible for pigment formation in the mycelium. Comparative proteome analysis of the pkaC1-overexpressing strain and the wild-type strain led to the identification of proteins regulated by the cAMP-PKA signal transduction pathway. We showed that elevated PKA activity resulted in activation of stress-associated proteins and of enzymes involved in protein biosynthesis and glucose catabolism. In contrast, proteins which were involved in nucleotide and amino acid biosynthesis were downregulated, as were enzymes involved in catabolism of carbon sources other than glucose.

High-spatial-resolution multistation MR angiography with parallel imaging and blood pool contrast agent: initial experience.

The purpose of this study was to prospectively evaluate the diagnostic accuracy of reader detection of 75% or greater stenosis at high-spatial-resolution multistation magnetic resonance (MR) angiography performed with matrix coils and a blood pool contrast agent. Ten healthy volunteers and 10 patients were examined. All participants provided informed consent to participate in this institutional review board-approved study. For contrast agent-enhanced multistation MR angiography, an albumin-binding gadolinium chelate, gadofosveset trisodium, was used. Imaging was performed during the first-pass and steady-state phases of the contrast agent. Vessel conspicuity on the first-pass MR angiograms obtained in both volunteers and patients was rated as excellent for 93% of vessels. At steady-state imaging, vessel conspicuity was rated as excellent or good for 89% of vessels. Gadofosveset trisodium-enhanced MR angiography yielded sensitivities of 100% and 97% and specificities of 96% and 97% for detection of significant disease in the carotid and lower extremity arteries, respectively.