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tomekkorbak

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[ "More than 800 miles added to U.S. Bicycle Route System\n\nA network of signed bicycle routes designed to criss-cross the US has grown to 6,790 miles with the certification of new routes in Washington state, Massachusetts, Ohio, Illinois and the District of Columbia.", "\n\nAdventure Cycling Association is coordinating efforts in the 40 states willing to participate in the plan to create a nationwide bicycle route system. ", "In a joint announcement, AASHTO’s executive director Bud Wright said his organization seeks to provide “safe and reliable transportation system no matter how many wheels their vehicles use.”", "\n\nWashington — USBR 10\n\nWashington state’s certification was reported here earlier this month: “US Bike Route 10 is approved for Washington state.” ", "It describes how the scenic corridor across the North Cascades National Park uses the Northern Tier Bicycle Route between Anacortes and Newport on the Idaho border.", "\n\nAt 407 miles, it was the longest among those approved in the latest certification. ", "Adventure Cycling points out that it ends at an international ferry terminal in Anacortes.", "\n\nMassachusetts — USBR 1\n\nThe approval for USBR 1 in Massachusetts includes many historical sites along the coast route. ", "It uses the Paul Dudley White Bicycle Path along the Charles River through Boston, Cambridge, Watertown, and Newton, along with the Northern Strand Community Trail to the north of Boston. ", "It is 20 miles long.", "\n\nParts of USBR 50 are in Maryland and Washington DC, following the Chesapeake and Ohio Canal Towpath. ", "Long range plans call for a corridor stretching all the way to San Francisco.", "\n\nWashington DC — USBR 50\n\nThe 3.6 miles of USBR 50 certified for the District of Columbia connects the C&O Canal Towpath to Georgetown.", "\n\nIllinois — USBR 36 and 37\n\nThe two routes combine for 76 miles along the Lake Michigan coastline and connect the Wisconsin border in the west and the Indiana border in the east. ", "USBR 36 and 37 also pass through Chicago, Highland Park and Lake County on roads and trails." ]

{ "pile_set_name": "Pile-CC" }

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[ "# Contributor Covenant Code of Conduct\n\n## Our Pledge\n\nIn the interest of fostering an open and welcoming environment, we as\ncontributors and maintainers pledge to making participation in our project and\nour community a harassment-free experience for everyone, regardless of age, body\nsize, disability, ethnicity, gender identity and expression, level of experience,\nnationality, personal appearance, race, religion, or sexual identity and\norientation.", "\n\n## Our Standards\n\nExamples of behavior that contributes to creating a positive environment\ninclude:\n\n* Using welcoming and inclusive language\n* Being respectful of differing viewpoints and experiences\n* Gracefully accepting constructive criticism\n* Focusing on what is best for the community\n* Showing empathy towards other community members\n\nExamples of unacceptable behavior by participants include:\n\n* The use of sexualized language or imagery and unwelcome sexual attention or\nadvances\n* Trolling, insulting/derogatory comments, and personal or political attacks\n* Public or private harassment\n* Publishing others' private information, such as a physical or electronic\n address, without explicit permission\n* Other conduct which could reasonably be considered inappropriate in a\n professional setting\n\n## Our Responsibilities\n\nProject maintainers are responsible for clarifying the standards of acceptable\nbehavior and are expected to take appropriate and fair corrective action in\nresponse to any instances of unacceptable behavior.", "\n\nProject maintainers have the right and responsibility to remove, edit, or\nreject comments, commits, code, wiki edits, issues, and other contributions\nthat are not aligned to this Code of Conduct, or to ban temporarily or\npermanently any contributor for other behaviors that they deem inappropriate,\nthreatening, offensive, or harmful.", "\n\n## Scope\n\nThis Code of Conduct applies both within project spaces and in public spaces\nwhen an individual is representing the project or its community. ", "Examples of\nrepresenting a project or community include using an official project e-mail\naddress, posting via an official social media account, or acting as an appointed\nrepresentative at an online or offline event. ", "Representation of a project may be\nfurther defined and clarified by project maintainers.", "\n\n## Enforcement\n\nInstances of abusive, harassing, or otherwise unacceptable behavior may be\nreported by contacting the project team at [mvvmcross@gmail.com](mailto:mvvmcross@gmail). ", "All\ncomplaints will be reviewed and investigated and will result in a response that\nis deemed necessary and appropriate to the circumstances. ", "The project team is\nobligated to maintain confidentiality with regard to the reporter of an incident.", "\nFurther details of specific enforcement policies may be posted separately.", "\n\nProject maintainers who do not follow or enforce the Code of Conduct in good\nfaith may face temporary or permanent repercussions as determined by other\nmembers of the project's leadership.", "\n\n## Attribution\n\nThis Code of Conduct is adapted from the [Contributor Covenant][homepage], version 1.4,\navailable at [http://contributor-covenant.org/version/1/4][version]\n\n[homepage]: http://contributor-covenant.org\n[version]: http://contributor-covenant.org/version/1/4/\n" ]

{ "pile_set_name": "Github" }

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[ "Long-term outcome of simultaneous transurethral resection of bladder tumor and prostate in patients with nonmuscle invasive bladder tumor and bladder outlet obstruction.", "\nWe evaluated the long-term outcome of simultaneous transurethral bladder tumor and prostate resection in patients with nonmuscle invasive bladder tumor and bladder outlet obstruction. ", "Between April 1997 and April 2006, 213 patients with nonmuscle invasive bladder tumor who had a minimum followup of 24 months were included in the study, including group 1-107 with transurethral resection of bladder tumor only and group 2-106 with transurethral bladder tumor and prostate resection. ", "Simultaneous transurethral bladder tumor and prostate resection was performed at surgeon discretion. ", "The records were retrospectively analyzed for clinicopathological parameters, recurrence and progression rates, time to recurrence and postoperative uroflowmetry results in the 2 groups. ", "There were no significant differences in clinicopathological parameters between the 2 groups. ", "At a mean followup of 54.3 and 50.1 months in groups 1 and 2, respectively, group 2 patients with a tumor less than 3 cm or a single tumor had a significantly lower recurrence rate than group 1 patients. ", "None of the 31 patients with recurrence in group 2 had recurrence in the bladder neck or prostatic urethra where transurethral prostate resection had been done. ", "There was no significant difference in the progression rate between the 2 groups. ", "The 60-month recurrence-free probability in groups 1 and 2 was 43.4% and 52.0%, respectively. ", "Three months after surgery the postvoid residual urine volume had significantly decreased in group 2. ", "Simultaneous transurethral bladder tumor and prostate resection may help decrease bladder cancer recurrence and delay time to recurrence without the risk of cancer implantation when transurethral prostate resection is done, especially in patients with a papillary, solitary-appearing bladder lesion less than 3 cm." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Carcinoma embolization in coronary artery causing myocardial infarction: diagnosis from coronary thromboaspirate.", "\nA unique case of myocardial infarction due to coronary artery tumor embolism from colonic adenocarcinoma is described. ", "A 79-year-old man with a history of rectal carcinoma with lung metastases 15 years and 9 years before, respectively, was subjected to primary percutaneous coronary intervention for myocardial infarction with aspiration of a thrombus from the occluded artery. ", "The retrieved material contained fragments of adenocarcinoma tissue. ", "To the best of our knowledge, this is the first reported case of adenocarcinoma coronary embolism diagnosed during life from coronary artery aspirate." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "# coding=utf-8\n# --------------------------------------------------------------------------\n# Copyright (c) Microsoft Corporation. ", "All rights reserved.", "\n# Licensed under the MIT License. ", "See License.txt in the project root for\n# license information.", "\n#\n# Code generated by Microsoft (R) AutoRest Code Generator.", "\n# Changes may cause incorrect behavior and will be lost if the code is\n# regenerated.", "\n# --------------------------------------------------------------------------\n\nfrom msrest.serialization import Model\n\n\nclass ApplicationGatewayBackendHealth(Model):\n \"\"\"List of ApplicationGatewayBackendHealthPool resources.", "\n\n :param backend_address_pools:\n :type backend_address_pools:\n list[~azure.mgmt.network.v2018_08_01.models.", "ApplicationGatewayBackendHealthPool]\n \"\"\"\n\n _attribute_map = {\n 'backend_address_pools': {'key': 'backendAddressPools', 'type': '[ApplicationGatewayBackendHealthPool]'},\n }\n\n def __init__(self, *, backend_address_pools=None, **kwargs) -> None:\n super(ApplicationGatewayBackendHealth, self).__init__(**kwargs)\n self.backend_address_pools = backend_address_pools\n" ]

{ "pile_set_name": "Github" }

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[ "package com.github.dhaval2404.imagepicker.sample\n\nimport android.widget.", "ImageView\nimport androidx.annotation.", "DrawableRes\nimport com.bumptech.glide.", "Glide\nimport com.bumptech.glide.request.", "RequestOptions\nimport java.io.", "File\n\nfun ImageView.setDrawableImage(@DrawableRes resource: Int, applyCircle: Boolean = false) {\n val glide = Glide.with(this).load(resource)\n if (applyCircle) {\n glide.apply(RequestOptions.circleCropTransform()).into(this)\n } else {\n glide.into(this)\n }\n}\n\nfun ImageView.setLocalImage(file: File, applyCircle: Boolean = false) {\n val glide = Glide.with(this).load(file)\n if (applyCircle) {\n glide.apply(RequestOptions.circleCropTransform()).into(this)\n } else {\n glide.into(this)\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "INTRODUCTION {#s1}\n============\n\nMaraviroc (MVC) is a first-in-class selective chemokine coreceptor type-5 (CCR5) antagonist indicated for the treatment of CCR5-tropic (R5) HIV-1 infection in both treatment-naive and treatment-experienced patients in the United States,[@R1] and in treatment-experienced patients in the European Union.[@R2] MVC is primarily metabolized by hepatic cytochrome P450 (CYP) 3A enzymes, with negligible metabolic activity for other CYP enzymes and is also a substrate for the efflux transport P-glycoprotein (P-gp).[@R3] MVC exposures have been shown to increase significantly when coadministered with potent CYP3A/P-gp inhibitors.[@R3] As such, the recommended MVC dose in the presence of potent CYP3A/P-gp inhibitors is 150 mg twice daily (BID).[@R1]\n\nPatients with HIV-1 infection are disproportionately affected by viral hepatitis, specifically hepatitis C virus (HCV), which can lead to life-threatening complications.[@R4] Approximately 25% of HIV-infected patients in the United States and Europe are coinfected with HCV, accounting for \\>75% of liver-related deaths in HIV-infected patients.[@R5] Boceprevir (BOC) and telaprevir (TVR) are newly approved HCV protease inhibitors indicated (in combination with pegylated interferon alpha and ribavirin) for the treatment of genotype 1 chronic HCV in adult patients with compensated liver disease.[@R6] BOC is a potent inhibitor of CYP3A, and TVR is also a potent inhibitor of CYP3A and an inhibitor of P-gp[@R6]; however, some unexpected drug interactions with HIV protease inhibitors have led to recommendations against the coadministration of BOC with darunavir/ritonavir, atazanavir/ritonavir, lopinavir/ritonavir, and fosamprenavir/ritonavir, and against the coadministration of TVR with darunavir/ritonavir, lopinavir/ritonavir, and fosamprenavir/ritonavir.[@R6]\n\nGiven the limited treatment options for HIV-1 and HCV coinfected patients, it is therefore important to investigate potential drug interactions of BOC and TVR with MVC. ", "This study was conducted to estimate the effect of BOC 800 mg 3 times daily (TID) and TVR 750 mg TID on the pharmacokinetics (PK) of MVC, and to describe the PK of BOC and TVR when dosed in combination with MVC 150 mg BID. ", "The safety and tolerability of MVC in combination with BOC and TVR was also assessed.", "\n\nMETHODS {#s2}\n=======\n\nStudy Population {#s2-1}\n----------------\n\nEligible volunteers were healthy adults (aged 18--55 years) who had a body mass index of 17.5--30.5 kg/m^2^, and a body weight of more than 50 kg. ", "Volunteers who had used prescription or nonprescription drugs or dietary supplements within 7 days or 5 half-lives (whichever was longer) before the start of study treatment were not permitted to take part in the study. ", "Volunteers who had used herbal supplements or hormonal methods of contraception within 28 days (6 months for Depo-Provera) were also not permitted to take part in the study. ", "Volunteers with positive results for HIV-1, HIV-2, hepatitis B serology (hepatitis B surface antigen, hepatitis B core antibody), or anti-HCV serology (as determined by multi-antigen enzyme immunoassay), or who had a history of hypersensitivity to the study drugs, were excluded.", "\n\nStudy Design and Treatment {#s2-2}\n--------------------------\n\nThis was an open-label, fixed-sequence, phase I study (NCT01597895) conducted at a single site (Pfizer Clinical Research Unit, Brussels, Belgium). ", "After a screening visit within 28 days before the start of treatment, volunteers received MVC 150 mg BID (every 12 hours) for 5 days (treatment period 1), followed by MVC 150 mg BID plus BOC 800 mg TID (every 8 hours) for 10 days (treatment period 2), then MVC 150 mg BID plus TVR 750 mg TID (every 8 hours) for 10 days (treatment period 3), with a ≥10-day wash-out between periods 2 and 3 ([Fig. ", "1](#F1){ref-type=\"fig\"}).", "\n\n{#F1}\n\nStudy treatment was administered with 240 mL water at ambient temperature 30 minutes after a standard fat meal/snack (approximately 20 g fat and ≥500 calories). ", "On PK assessment days (day 5 of treatment period 1 and day 10 of treatment periods 2 and 3), volunteers ate a standardized breakfast containing approximately 20 g fat and 800--1000 calories and received only a single (morning) dose of MVC, as well as only the morning and afternoon doses of BOC and TVR. ", "Study personnel conducted mouth checks to ensure treatment compliance. ", "To standardize conditions on PK sampling days, all volunteers were required to refrain from lying down \\[except when required for vital signs and electrocardiogram (ECG) assessments\\] and eating and drinking beverages other than water during the first 4 hours after dosing.", "\n\nVolunteers could be discontinued from the study at any time at their own request, or on the grounds of safety concerns, behavioral reasons, or inability to comply with the study activity or procedures, at the investigators\\' discretion.", "\n\nThis study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonization. ", "The final protocol, amendments, and informed consent documentation were reviewed and approved by the study center institutional review board. ", "All volunteers provided written, informed consent before participating in any study procedures.", "\n\nPharmacokinetic Assessment {#s2-3}\n--------------------------\n\nBlood samples for MVC PK analysis were collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose on day 5 of treatment period 1 (MVC) and on day 10 of treatment periods 2 (MVC and BOC) and 3 (MVC and TVR). ", "Blood samples for BOC and TVR PK analysis were collected predose and at 0.5, 1, 2, 3, 4, 6, and 8 hours postdose on day 10 of treatment periods 2 and 3, respectively. ", "Samples of 4 mL were taken to provide a minimum volume of 1.5 mL plasma for PK analysis and were transferred into appropriately labeled tubes containing sodium heparin (MVC), dipotassium ethylenediaminetetra-acetic acid (K~2~EDTA) (BOC), or tripotassium ethylenediaminetetra-acetic acid (K~3~EDTA) (TVR). ", "All samples were centrifuged at approximately 1700 g for approximately 10 minutes at 4°C. ", "For MVC and BOC, plasma was extracted and stored in appropriately labeled screw-capped polypropylene tubes at approximately −20°C (MVC) or −70°C (BOC) within 1 hour of collection. ", "Plasma extraction for TVR followed the same process, although after centrifugation approximately 1 mL plasma was transferred to an appropriately labeled screw-capped polypropylene tube containing 0.05 mL of 10% formic acid, before mixing thoroughly and being stored at approximately −70°C. ", "Formic acid solution was added to plasma to allow for accurate quantification of TVR by preventing TVR epimerization.", "\n\nPlasma samples were analyzed for MVC (Tandem Labs, West Trenton, NJ),[@R10] and for BOC and TVR (Covance Bioanalytical Services, Shanghai, China), using a solid-phase extraction and a validated high-performance liquid chromatography/dual mass spectrometry assay.", "\n\nNoncompartmental analyses were performed using standard methods with eNCA version 2.2 (Pfizer, Inc, New York, NY). ", "Area under the plasma concentration--time curve (AUC) from predose (0 hours) to 12 hours (AUC~12~; MVC) or 8 hours postdose (AUC~8~; BOC and TVR) was determined by the linear/log trapezoidal method, whereas plasma concentration at 12 hours (C~12~; MVC) or 8 hours postdose (C~8~; BOC and TVR), maximum plasma concentration (C~max~), and time to C~max~ (T~max~) were determined by direct observation.", "\n\nSafety and Tolerability {#s2-4}\n-----------------------\n\nAll observed and volunteered adverse events (AEs) were recorded and assessed by the investigator for severity and relationship to study treatment. ", "Additional safety assessments included standard hematology, urinalysis, and chemistry laboratory assessments, physical examinations, vital signs (blood pressure and pulse) measurements, and ECGs. ", "Orthostatic hypotension, a concentration-dependent AE observed with MVC,[@R11] was defined as a decrease of ≥20 mm Hg for systolic blood pressure or ≥10 mm Hg for diastolic blood pressure 2 minutes after standing from a supine position, and may have been symptomatic or asymptomatic.", "\n\nSample Size {#s2-5}\n-----------\n\nA minimum sample size of 12 volunteers was required to provide 90% confidence intervals (CIs) for the difference between treatments on the natural logarithmic scale of ±0.1536 for MVC AUC~12~, ±0.2745 for MVC C~max~, and ±0.1493 for MVC C~12~, with 80% coverage probability. ", "To allow for any volunteers who might not complete the study, 14 volunteers were enrolled.", "\n\nConstruction of 90% CIs was chosen based on FDA Guidance \"Statistical Approaches to Establishing Bioequivalence.", "\"[@R12] Because of the nature of normal-theory construction of 90% CIs, this corresponds to performing 2 one-sided tests hypothesis at the 5% level of significance.", "\n\nStatistical Analysis {#s2-6}\n--------------------\n\nNatural log-transformed AUC~12~, C~max~, and C~12~ for MVC were analyzed using a mixed effect model with treatment as fixed effect and subject as a random effect. ", "MVC alone was the reference treatment, and MVC plus BOC and MVC plus TVR were the test treatments. ", "Estimates of the adjusted mean differences (Test--Reference) and corresponding 90% CIs were obtained from the model. ", "The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.", "\n\nBOC and TVR PK data were summarized descriptively and compared with mean historical minimum plasma concentrations (C~min~) data (102 ng/mL and 1802 ng/mL, respectively).[@R1] BOC and TVR data were determined to be comparable with the historical data if the mean C~8~ for both agents fell within the 50% range of their historical C~min~ values: 51--204 ng/mL for BOC and 901--3604 ng/mL for TVR, based on simulations. ", "Safety data were summarized descriptively.", "\n\nRESULTS {#s3}\n=======\n\nStudy Population {#s3-1}\n----------------\n\nA total of 14 volunteers were enrolled and treated. ", "All 14 completed treatment periods 1 and 2, but 1 volunteer withdrew during the wash-out period (between periods 2 and 3) because of an AE (severe asthmatic crisis) that was not considered to be related to treatment, and thus did not participate in treatment period 3.", "\n\nAll volunteers were men with a mean age (SD) of 33.3 years. ", "The majority (n = 12/14, 85.7%) were white with the remaining 2 volunteers (14.3%) being of other races (one of Hispanic ethnicity and one of Asian ancestry). ", "Volunteers had a mean (SD) weight of 79.3 (11.4) kg and body mass index of 24.4 (2.8) kg/m^2^.\n\nBioanalytical Summary {#s3-2}\n---------------------\n\nCalibration standard responses were linear over the range of 0.5--500 ng/mL for MVC, 25--2500 ng/mL for BOC, and 50--5000 ng/mL for TVR. ", "The between-day assay accuracy, expressed as percent relative error for quality-control concentrations in the low, medium, and high-diluted quality control samples ranged from 4.6%--7.3% for MVC, −5.2%--3.7% for BOC, and −0.6%--0.8% for TVR. ", "Assay precision, expressed as the between-day percent coefficient of variation (%CV) of the mean estimated concentrations of quality-control samples, was ≤7.4% for the low (1.5 ng/mL), medium (50 and 150 ng/mL), high (375 ng/mL), and diluted (375 ng/mL) concentrations of MVC. ", "Assay precision (%CV) for BOC was ≤5.6% for the low (75 ng/mL), medium (250 ng/mL), high (1800 ng/mL), and diluted (12,500 ng/mL) concentrations, and for TVR was ≤3.8% for the low (150 ng/mL), medium (500 ng/mL), high (3600 ng/mL), and diluted (25,000 ng/mL) concentrations.", "\n\nPlasma MVC PK {#s3-3}\n-------------\n\nMVC plasma exposure (based on AUC~12~ and C~max~) was increased by approximately 3-fold in the presence of BOC, and by approximately 8- to 9-fold in the presence of TVR ([Table 1](#T1){ref-type=\"table\"}; [Fig. ", "2](#F2){ref-type=\"fig\"}). ", "MVC C~12~ values were approximately 3-fold higher for MVC plus BOC (66.1 ng/mL), and approximately 10-fold higher for MVC plus TVR (235.5 ng/mL), when compared with MVC alone (23.8 ng/mL).", "\n\n###### \n\nGeometric Means and Adjusted Geometric Mean Ratios for MVC PK Parameters Alone and in the Presence of BOC and TVR\n\n![](", "qai-65-564-g002)\n\n{#F2}\n\nIntersubject variability for MVC, as measured by the geometric %CV for AUC~12~, C~max~, and C~12~ was 24%--36% when MVC was coadministered with either BOC or TVR ([Table 1](#T1){ref-type=\"table\"}).", "\n\nC~max~ was achieved within a median T~max~ of 2.0 (range, 1.0--6.0) hours when MVC was administered alone, 2.0 (range, 0.5--3.0) hours when MVC was administered with BOC, and 3.0 (range, 2.0--4.0) hours when MVC was given with TVR.", "\n\nPlasma BOC and TVR PK {#s3-4}\n---------------------\n\nWhen coadministered with MVC, BOC and TVR exposures were consistent with historical data ([Table 2](#T2){ref-type=\"table\"}), indicating that MVC had no notable impact on the PK profile of BOC and TVR.", "\n\n###### \n\nSummary of Plasma BOC and TVR Pharmacokinetic Parameters in the Presence and Absence (Historical Studies) of MVC\n\n![](", "qai-65-564-g004)\n\nSafety and Tolerability {#s3-5}\n-----------------------\n\nAE incidence was higher during treatment with MVC plus BOC (100%) and MVC plus TVR (92%) compared with MVC alone (43%), and the majority of AEs were considered to be treatment-related ([Table 3](#T3){ref-type=\"table\"}). ", "The most common treatment-related AEs occurring during treatment with MVC alone, MVC plus BOC, and MVC plus TVR, respectively, were headache, dysgeusia, and fatigue, as summarized in [Table 3](#T3){ref-type=\"table\"}. ", "No events of postural hypotension or dizziness were reported in this study.", "\n\n###### \n\nSummary of Safety\n\n![](", "qai-65-564-g005)\n\nAll AEs were mild to moderate in severity, with the exception of a severe event of asthmatic crisis following the completion of treatment period 2 (MVC plus BOC), which led to the discontinuation of 1 volunteer. ", "This AE was not considered to be related to treatment but related to a pre-existing and undisclosed history of asthma. ", "The event lasted 8 hours and resolved with treatment given.", "\n\nThere were no deaths, serious AEs, temporary discontinuations, or dose reductions because of AEs in this study. ", "No clinically significant changes in laboratory parameters, vital signs, or ECGs were reported.", "\n\nDISCUSSION {#s4}\n==========\n\nA significant proportion of HIV-infected individuals are coinfected with HCV and consequently are at increased risk for severe liver disease.[@R5] As liver fibrogenesis may be caused by stimulation of CCR5 receptors, MVC, a CCR5 antagonist, may have a beneficial effect on liver fibrosis. ", "There is, therefore, increasing interest in using MVC as part of treatment regimens for HIV/HCV coinfected patients. ", "Preliminary data from investigators from the University of Brescia (Italy) demonstrated a significant improvement in liver stiffness in 54 patients over 24 weeks when MVC 150 mg BID was added to antiretroviral regimens compared with existing regimens alone (*P* = 0.03).[@R17] Furthermore, an ongoing study (NCT01327547) is primarily evaluating the safety of MVC in 120 HIV/HCV coinfected patients, as well as assessing the potential antifibrotic activity of MVC as a secondary objective.", "\n\nBOC and TVR are newly approved HCV protease inhibitors that have been shown to cause significant drug interactions. ", "As such, many HIV protease inhibitors are not recommended to be coadministered with either BOC or TVR, thus limiting treatment options in HIV/HCV coinfected patients.[@R6] The study reported in this article was designed to investigate the effect of coadministration of BOC 800 mg BID and TVR 750 mg TID on the PK of MVC 150 mg BID, and to describe the PK of BOC and TVR when dosed in combination with MVC. ", "Our results confirm that, when coadministered with either BOC or TVR, overall MVC exposure is increased significantly.", "\n\nTVR seemed to have a greater impact on MVC plasma exposure than BOC, as indicated by an 8- to 9-fold increase in both mean MVC AUC~12~ and C~max~ values after coadministration compared with a 3-fold increase with BOC. ", "The greater increase in MVC exposures observed with TVR was expected, as TVR has been shown to increase the AUC of midazolam (a probe substrate for CYP3A) by 796% as compared with 430% with BOC after oral coadministration of midazolam and an increase in the AUC of digoxin (a probe for P-gp) by 85% as compared with 19% with BOC.[@R6] Furthermore, a potential mechanism for the magnitude of this interaction observed with TVR may be interplay between inhibition of CYP3A/P-gp and organic ion transporter 1B1 (OATP1B1) by TVR,[@R8] as MVC has been shown to be a substrate for OATP1B1.[@R18] In vitro data suggest that TVR is a more potent inhibitor of OATP1B1 with an IC~50~ of 2.2 μM compared with an IC~50~ of 18 μM for BOC.[@R20] Additionally, inhibition of OATP1B1 is more likely to occur in vivo with TVR given that the unbound C~max~/OATP1B1 IC~50~ ratio for TVR is 0.95, whereas the ratio for BOC is only 0.04.[@R20] The combination of CYP3A/OATP1B1 inhibition by TVR was most likely also observed in a study where TVR was coadministered with atorvastatin, a substrate for both CYP3A and OATP1B1.[@R8] In this study, TVR increased the AUC of atorvastatin 7.88-fold whereas in a similar study, BOC only increased the exposure of atorvastatin 2.30-fold.[@R6]\n\nThe magnitude of the MVC interaction with TVR is also consistent with that observed in a previous drug interaction study where MVC was dosed in combination with saquinavir/ritonavir (SQV/r), where MVC exposures were increased 9.77-fold.[@R1] To date, TVR and SQV/r are the only 2 agents shown to increase the geometric mean MVC AUC greater than 5-fold. ", "Similarly to TVR, SQV/r is a potent inhibitor of CYP3A (increases midazolam AUC 11.4-fold), an inhibitor of P-gp (increases digoxin AUC by 49%) and an inhibitor of OATP1B1 (IC~50~ = 2.1 μM).[@R22]\n\nIn the present study, MVC average concentrations (C~avg~), when dosed at 150 mg BID in the presence of TVR and BOC, were 474 ng/mL and 151 ng/mL, respectively. ", "The exposures seen in this study are within the exposure range observed in phase III clinical studies evaluating the efficacy and safety of MVC in patients with CCR5-topic HIV-1[@R24] and are at or above the C~avg~ exposure at which near maximal virologic efficacy is achieved with MVC (≥75--100 ng/mL).[@R25] These findings suggest that MVC should be dosed at 150 mg BID when coadministered with either BOC or TVR, consistent with current dose recommendations for MVC when dosed in combination with other potent CYP3A inhibitors.[@R1] However, as regulatory discussions are pending, we would suggest that prescribers should refer to your local prescribing information for MVC dosing recommendations with BOC and TVR in their region.", "\n\nAs with most drug--drug interaction studies, healthy volunteers, rather than patients, were enrolled in this study. ", "MVC is primarily metabolized by the liver and therefore exposures have the potential to be higher in HIV/HCV coinfected patients with hepatic impairment, as hepatic damage and disease may affect CYP enzyme activity.[@R27] A study conducted in HIV-negative subjects with hepatic impairment demonstrated that MVC exposures in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment had a geometric mean 25% (mild) and 46% (moderate) greater AUC~last~ and a 11% (mild) and 32% (moderate) greater C~max~ relative to subjects with normal hepatic function[@R33] after a single dose of MVC 300 mg. ", "As such, patients with moderate hepatic impairment receiving MVC with potent CYP3A inhibitors, such as BOC, should be monitored closely.[@R1] Currently, TVR is not recommended to be dosed in patients with moderate and severe hepatic impairment.[@R8] No exposure data are available for MVC in severe hepatic impairment, thus no recommendation in this population can be given at this time.", "\n\nIn this study, MVC did not seem to cause clinically significant changes in concentrations of either BOC or TVR as the mean PK exposures of BOC (AUC~8~ 5404 ng·h/mL; C~8~ 80.7 ng/mL) and TVR (AUC~8~ 21980 ng·h/mL; C~8~ 1943 ng/mL) after MVC coadministration were consistent with those previously reported when BOC (AUC~8~ 4601--7070 ng·h/mL; C~8~ 88.5--111 ng/mL) and TVR (AUC~8~ 18157--22300 ng·h/mL; C~8~ 1505--2030 ng/mL) were dosed alone.[@R1] These findings suggest that no dose adjustment for BOC or TVR is warranted when coadministered with MVC.", "\n\nFinally, MVC coadministered with BOC or TVR was generally well tolerated among the small population of healthy volunteers in this study. ", "Although AE incidence was higher during combination treatment, the majority of AEs were mild or moderate in severity, and there were no serious AEs, discontinuations because of treatment-related AEs, or deaths during the study. ", "The most frequently experienced AEs were dysgeusia and pruritus for the MVC plus BOC combination, and headache and fatigue for the MVC plus TVR combination. ", "Fatigue, dysgeusia, and pruritus seemed to be unique to the coadministration of MVC plus BOC or MVC plus TPV and were consistent with previous findings for BOC or TPV alone.[@R6] No postural hypotension or dizziness was reported in this study despite the significant increases in MVC exposures when coadministered with BOC or TVR.", "\n\nCONCLUSIONS {#s5}\n===========\n\nIn summary, MVC exposure was increased in the presence of BOC or TVR. ", "These findings are consistent with evidence that both BOC and TVR are potent inhibitors of CYP3A, and support dosing of MVC at 150 mg BID when coadministered with either BOC or TVR. ", "When coadministered with MVC, BOC and TVR exposures were consistent with historical BOC and TVR monotherapy data; therefore, no dose adjustment for BOC or TVR is warranted with MVC. ", "MVC coadministered with BOC or TVR was generally well tolerated with no unexpected safety findings.", "\n\nEditorial support was provided by Lynsey Stevenson of Complete Medical Communications.", "\n\nSupported by ViiV Healthcare and managed by Pfizer Inc.\n\nPresented at the 14th International Workshop on Clinical Pharmacology of HIV, April 23, 2013, Amsterdam, the Netherlands.", "\n\nM.V., A.P., C.K., A.F., and J.H. are employees of Pfizer, Inc and hold stock/stock options in Pfizer, Inc.\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Prevention of chronic lung disease in preterm infants by early postnatal dexamethasone therapy.", "\nRecent studies suggest that early dexamethasone therapy may lessen the pulmonary inflammation in preterm infants with respiratory distress syndrome (RDS). ", "To investigate whether early (<12 hr) postnatal dexamethasone therapy would reduce the incidence of chronic lung disease (CLD), a randomized, double-blind, controlled trial was conducted in 40 infants (birth weights from 500 to 1,999 gm) who had severe RDS and required mechanical ventilation within 6 hr of birth. ", "All infants received one dose of Survanta before they were randomly assigned to control (saline placebo) or dexamethasone-treated groups (0.5 mg/kg/d for 1 week, then tapered over 3 weeks). ", "Sequential analysis was performed with the end point of assessment being the presence or absence of CLD on postnatal Day 28. ", "Statistical significance favoring dexamethasone was reached when 12 consecutive pairs in which one infant had CLD and the other did not have CLD showed that ten pairs favored dexamethasone and two pairs favored control treatment. ", "Among the survivors, 12/15 were extubated in the dexamethasone group and 9/16 in the control group at the end of study. ", "Infants in the treated group had transient hyperglycemia and hypertension. ", "There was no difference between the groups in mortality and in incidence of sepsis or intraventricular hemorrhage. ", "We conclude that early postnatal dexamethasone therapy is potentially effective in the lessening of CLD in preterm infants. ", "To substantiate our result, large randomized controlled trials are needed and warranted." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "/* crypto/engine/eng_openssl.c */\n/*\n * Written by Geoff Thorpe (geoff@geoffthorpe.net) for the OpenSSL project\n * 2000.", "\n */\n/* ====================================================================\n * Copyright (c) 1999-2001 The OpenSSL Project. ", " All rights reserved.", "\n *\n * Redistribution and use in source and binary forms, with or without\n * modification, are permitted provided that the following conditions\n * are met:\n *\n * 1. ", "Redistributions of source code must retain the above copyright\n * notice, this list of conditions and the following disclaimer.", "\n *\n * 2. ", "Redistributions in binary form must reproduce the above copyright\n * notice, this list of conditions and the following disclaimer in\n * the documentation and/or other materials provided with the\n * distribution.", "\n *\n * 3. ", "All advertising materials mentioning features or use of this\n * software must display the following acknowledgment:\n * \"This product includes software developed by the OpenSSL Project\n * for use in the OpenSSL Toolkit. (", "http://www.OpenSSL.org/)\"\n *\n * 4. ", "The names \"OpenSSL Toolkit\" and \"OpenSSL Project\" must not be used to\n * endorse or promote products derived from this software without\n * prior written permission. ", "For written permission, please contact\n * licensing@OpenSSL.org.", "\n *\n * 5. ", "Products derived from this software may not be called \"OpenSSL\"\n * nor may \"OpenSSL\" appear in their names without prior written\n * permission of the OpenSSL Project.", "\n *\n * 6. ", "Redistributions of any form whatsoever must retain the following\n * acknowledgment:\n * \"This product includes software developed by the OpenSSL Project\n * for use in the OpenSSL Toolkit (http://www.OpenSSL.org/)\"\n *\n * THIS SOFTWARE IS PROVIDED BY THE OpenSSL PROJECT ``AS IS'' AND ANY\n * EXPRESSED OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE\n * IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR\n * PURPOSE ARE DISCLAIMED. ", " IN NO EVENT SHALL THE OpenSSL PROJECT OR\n * ITS CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL,\n * SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT\n * NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES;\n * LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION)\n * HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT,\n * STRICT LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE)\n * ARISING IN ANY WAY OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED\n * OF THE POSSIBILITY OF SUCH DAMAGE.", "\n * ====================================================================\n *\n * This product includes cryptographic software written by Eric Young\n * (eay@cryptsoft.com). ", " This product includes software written by Tim\n * Hudson (tjh@cryptsoft.com).", "\n *\n */\n/* ====================================================================\n * Copyright 2002 Sun Microsystems, Inc. ALL RIGHTS RESERVED.", "\n * ECDH support in OpenSSL originally developed by\n * SUN MICROSYSTEMS, INC., ", "and contributed to the OpenSSL project.", "\n */\n\n#include <stdio.h>\n#include <openssl/crypto.h>\n#include \"cryptlib.h\"\n#include <openssl/engine.h>\n#include <openssl/dso.h>\n#include <openssl/pem.h>\n#include <openssl/evp.h>\n#include <openssl/rand.h>\n#ifndef OPENSSL_NO_RSA\n# include <openssl/rsa.h>\n#endif\n#ifndef OPENSSL_NO_DSA\n# include <openssl/dsa.h>\n#endif\n#ifndef OPENSSL_NO_DH\n# include <openssl/dh.h>\n#endif\n\n/*\n * This testing gunk is implemented (and explained) lower down. ", "It also\n * assumes the application explicitly calls \"ENGINE_load_openssl()\" because\n * this is no longer automatic in ENGINE_load_builtin_engines().", "\n */\n#define TEST_ENG_OPENSSL_RC4\n#define TEST_ENG_OPENSSL_PKEY\n/* #define TEST_ENG_OPENSSL_RC4_OTHERS */\n#define TEST_ENG_OPENSSL_RC4_P_INIT\n/* #define TEST_ENG_OPENSSL_RC4_P_CIPHER */\n#define TEST_ENG_OPENSSL_SHA\n/* #define TEST_ENG_OPENSSL_SHA_OTHERS */\n/* #define TEST_ENG_OPENSSL_SHA_P_INIT */\n/* #define TEST_ENG_OPENSSL_SHA_P_UPDATE */\n/* #define TEST_ENG_OPENSSL_SHA_P_FINAL */\n\n/* Now check what of those algorithms are actually enabled */\n#ifdef OPENSSL_NO_RC4\n# undef TEST_ENG_OPENSSL_RC4\n# undef TEST_ENG_OPENSSL_RC4_OTHERS\n# undef TEST_ENG_OPENSSL_RC4_P_INIT\n# undef TEST_ENG_OPENSSL_RC4_P_CIPHER\n#endif\n#if defined(OPENSSL_NO_SHA) || defined(OPENSSL_NO_SHA0) || defined(OPENSSL_NO_SHA1)\n# undef TEST_ENG_OPENSSL_SHA\n# undef TEST_ENG_OPENSSL_SHA_OTHERS\n# undef TEST_ENG_OPENSSL_SHA_P_INIT\n# undef TEST_ENG_OPENSSL_SHA_P_UPDATE\n# undef TEST_ENG_OPENSSL_SHA_P_FINAL\n#endif\n\n#ifdef TEST_ENG_OPENSSL_RC4\nstatic int openssl_ciphers(ENGINE *e, const EVP_CIPHER **cipher,\n const int **nids, int nid);\n#endif\n#ifdef TEST_ENG_OPENSSL_SHA\nstatic int openssl_digests(ENGINE *e, const EVP_MD **digest,\n const int **nids, int nid);\n#endif\n\n#ifdef TEST_ENG_OPENSSL_PKEY\nstatic EVP_PKEY *openssl_load_privkey(ENGINE *eng, const char *key_id,\n UI_METHOD *ui_method,\n void *callback_data);\n#endif\n\n/* The constants used when creating the ENGINE */\nstatic const char *engine_openssl_id = \"openssl\";\nstatic const char *engine_openssl_name = \"Software engine support\";\n\n/*\n * This internal function is used by ENGINE_openssl() and possibly by the\n * \"dynamic\" ENGINE support too\n */\nstatic int bind_helper(ENGINE *e)\n{\n if (!", "ENGINE_set_id(e, engine_openssl_id)\n || !", "ENGINE_set_name(e, engine_openssl_name)\n#ifndef TEST_ENG_OPENSSL_NO_ALGORITHMS\n# ifndef OPENSSL_NO_RSA\n || !", "ENGINE_set_RSA(e, RSA_get_default_method())\n# endif\n# ifndef OPENSSL_NO_DSA\n || !", "ENGINE_set_DSA(e, DSA_get_default_method())\n# endif\n# ifndef OPENSSL_NO_ECDH\n || !", "ENGINE_set_ECDH(e, ECDH_OpenSSL())\n# endif\n# ifndef OPENSSL_NO_ECDSA\n || !", "ENGINE_set_ECDSA(e, ECDSA_OpenSSL())\n# endif\n# ifndef OPENSSL_NO_DH\n || !", "ENGINE_set_DH(e, DH_get_default_method())\n# endif\n || !", "ENGINE_set_RAND(e, RAND_SSLeay())\n# ifdef TEST_ENG_OPENSSL_RC4\n || !", "ENGINE_set_ciphers(e, openssl_ciphers)\n# endif\n# ifdef TEST_ENG_OPENSSL_SHA\n || !", "ENGINE_set_digests(e, openssl_digests)\n# endif\n#endif\n#ifdef TEST_ENG_OPENSSL_PKEY\n || !", "ENGINE_set_load_privkey_function(e, openssl_load_privkey)\n#endif\n )\n return 0;\n /*\n * If we add errors to this ENGINE, ensure the error handling is setup\n * here\n */\n /* openssl_load_error_strings(); */\n return 1;\n}\n\nstatic ENGINE *engine_openssl(void)\n{\n ENGINE *ret = ENGINE_new();\n if (!", "ret)\n return NULL;\n if (!", "bind_helper(ret)) {\n ENGINE_free(ret);\n return NULL;\n }\n return ret;\n}\n\nvoid ENGINE_load_openssl(void)\n{\n ENGINE *toadd = engine_openssl();\n if (!", "toadd)\n return;\n ENGINE_add(toadd);\n /*\n * If the \"add\" worked, it gets a structural reference. ", "So either way, we\n * release our just-created reference.", "\n */\n ENGINE_free(toadd);\n ERR_clear_error();\n}\n\n/*\n * This stuff is needed if this ENGINE is being compiled into a\n * self-contained shared-library.", "\n */\n#ifdef ENGINE_DYNAMIC_SUPPORT\nstatic int bind_fn(ENGINE *e, const char *id)\n{\n if (id && (strcmp(id, engine_openssl_id) !", "= 0))\n return 0;\n if (!", "bind_helper(e))\n return 0;\n return 1;\n}\n\nIMPLEMENT_DYNAMIC_CHECK_FN()\n IMPLEMENT_DYNAMIC_BIND_FN(bind_fn)\n#endif /* ENGINE_DYNAMIC_SUPPORT */\n#ifdef TEST_ENG_OPENSSL_RC4\n/*-\n * This section of code compiles an \"alternative implementation\" of two modes of\n * RC4 into this ENGINE. ", "The result is that EVP_CIPHER operation for \"rc4\"\n * should under normal circumstances go via this support rather than the default\n * EVP support. ", "There are other symbols to tweak the testing;\n * TEST_ENC_OPENSSL_RC4_OTHERS - print a one line message to stderr each time\n * we're asked for a cipher we don't support (should not happen).", "\n * TEST_ENG_OPENSSL_RC4_P_INIT - print a one line message to stderr each time\n * the \"init_key\" handler is called.", "\n * TEST_ENG_OPENSSL_RC4_P_CIPHER - ditto for the \"cipher\" handler.", "\n */\n# include <openssl/rc4.h>\n# define TEST_RC4_KEY_SIZE 16\nstatic int test_cipher_nids[] = { NID_rc4, NID_rc4_40 };\n\nstatic int test_cipher_nids_number = 2;\ntypedef struct {\n unsigned char key[TEST_RC4_KEY_SIZE];\n RC4_KEY ks;\n} TEST_RC4_KEY;\n# define test(ctx) ((TEST_RC4_KEY *)(ctx)->cipher_data)\nstatic int test_rc4_init_key(EVP_CIPHER_CTX *ctx, const unsigned char *key,\n const unsigned char *iv, int enc)\n{\n# ifdef TEST_ENG_OPENSSL_RC4_P_INIT\n fprintf(stderr, \"(TEST_ENG_OPENSSL_RC4) test_init_key() called\\n\");\n# endif\n memcpy(&test(ctx)->key[0], key, EVP_CIPHER_CTX_key_length(ctx));\n RC4_set_key(&test(ctx)->ks, EVP_CIPHER_CTX_key_length(ctx),\n test(ctx)->key);\n return 1;\n}\n\nstatic int test_rc4_cipher(EVP_CIPHER_CTX *ctx, unsigned char *out,\n const unsigned char *in, size_t inl)\n{\n# ifdef TEST_ENG_OPENSSL_RC4_P_CIPHER\n fprintf(stderr, \"(TEST_ENG_OPENSSL_RC4) test_cipher() called\\n\");\n# endif\n RC4(&test(ctx)->ks, inl, in, out);\n return 1;\n}\n\nstatic const EVP_CIPHER test_r4_cipher = {\n NID_rc4,\n 1, TEST_RC4_KEY_SIZE, 0,\n EVP_CIPH_VARIABLE_LENGTH,\n test_rc4_init_key,\n test_rc4_cipher,\n NULL,\n sizeof(TEST_RC4_KEY),\n NULL,\n NULL,\n NULL,\n NULL\n};\n\nstatic const EVP_CIPHER test_r4_40_cipher = {\n NID_rc4_40,\n 1, 5 /* 40 bit */ , 0,\n EVP_CIPH_VARIABLE_LENGTH,\n test_rc4_init_key,\n test_rc4_cipher,\n NULL,\n sizeof(TEST_RC4_KEY),\n NULL,\n NULL,\n NULL,\n NULL\n};\n\nstatic int openssl_ciphers(ENGINE *e, const EVP_CIPHER **cipher,\n const int **nids, int nid)\n{\n if (!", "cipher) {\n /* We are returning a list of supported nids */\n *nids = test_cipher_nids;\n return test_cipher_nids_number;\n }\n /* We are being asked for a specific cipher */\n if (nid == NID_rc4)\n *cipher = &test_r4_cipher;\n else if (nid == NID_rc4_40)\n *cipher = &test_r4_40_cipher;\n else {\n# ifdef TEST_ENG_OPENSSL_RC4_OTHERS\n fprintf(stderr, \"(TEST_ENG_OPENSSL_RC4) returning NULL for \"\n \"nid %d\\n\", nid);\n# endif\n *cipher = NULL;\n return 0;\n }\n return 1;\n}\n#endif\n\n#ifdef TEST_ENG_OPENSSL_SHA\n/* Much the same sort of comment as for TEST_ENG_OPENSSL_RC4 */\n# include <openssl/sha.h>\nstatic int test_digest_nids[] = { NID_sha1 };\n\nstatic int test_digest_nids_number = 1;\nstatic int test_sha1_init(EVP_MD_CTX *ctx)\n{\n# ifdef TEST_ENG_OPENSSL_SHA_P_INIT\n fprintf(stderr, \"(TEST_ENG_OPENSSL_SHA) test_sha1_init() called\\n\");\n# endif\n return SHA1_Init(ctx->md_data);\n}\n\nstatic int test_sha1_update(EVP_MD_CTX *ctx, const void *data, size_t count)\n{\n# ifdef TEST_ENG_OPENSSL_SHA_P_UPDATE\n fprintf(stderr, \"(TEST_ENG_OPENSSL_SHA) test_sha1_update() called\\n\");\n# endif\n return SHA1_Update(ctx->md_data, data, count);\n}\n\nstatic int test_sha1_final(EVP_MD_CTX *ctx, unsigned char *md)\n{\n# ifdef TEST_ENG_OPENSSL_SHA_P_FINAL\n fprintf(stderr, \"(TEST_ENG_OPENSSL_SHA) test_sha1_final() called\\n\");\n# endif\n return SHA1_Final(md, ctx->md_data);\n}\n\nstatic const EVP_MD test_sha_md = {\n NID_sha1,\n NID_sha1WithRSAEncryption,\n SHA_DIGEST_LENGTH,\n 0,\n test_sha1_init,\n test_sha1_update,\n test_sha1_final,\n NULL,\n NULL,\n EVP_PKEY_RSA_method,\n SHA_CBLOCK,\n sizeof(EVP_MD *) + sizeof(SHA_CTX),\n};\n\nstatic int openssl_digests(ENGINE *e, const EVP_MD **digest,\n const int **nids, int nid)\n{\n if (!", "digest) {\n /* We are returning a list of supported nids */\n *nids = test_digest_nids;\n return test_digest_nids_number;\n }\n /* We are being asked for a specific digest */\n if (nid == NID_sha1)\n *digest = &test_sha_md;\n else {\n# ifdef TEST_ENG_OPENSSL_SHA_OTHERS\n fprintf(stderr, \"(TEST_ENG_OPENSSL_SHA) returning NULL for \"\n \"nid %d\\n\", nid);\n# endif\n *digest = NULL;\n return 0;\n }\n return 1;\n}\n#endif\n\n#ifdef TEST_ENG_OPENSSL_PKEY\nstatic EVP_PKEY *openssl_load_privkey(ENGINE *eng, const char *key_id,\n UI_METHOD *ui_method,\n void *callback_data)\n{\n BIO *in;\n EVP_PKEY *key;\n fprintf(stderr, \"(TEST_ENG_OPENSSL_PKEY)Loading Private key %s\\n\",\n key_id);\n in = BIO_new_file(key_id, \"r\");\n if (!", "in)\n return NULL;\n key = PEM_read_bio_PrivateKey(in, NULL, 0, NULL);\n BIO_free(in);\n return key;\n}\n#endif\n" ]

{ "pile_set_name": "Github" }

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[ "Yan Vichnyi\n\nYan Vichnyi (; born 27 February 1997 in Zaporizhya, Ukraine) is a professional Ukrainian football goalkeeper.", "\n\nCareer\nVichnyi is a product of FC Metalurh Zaporizhia and UFK Kharkiv youth sportive systems.", "\n\nHe spent his career in the Ukrainian Premier League Reserves club FC Vorskla Poltava. ", "And in summer 2015 Vichnyi was promoted to the main-squad team of the FC Vorskla in the Ukrainian Premier League. ", "He made his debut for Vorskla Poltava in the Ukrainian Premier League in a match against FC Dynamo Kyiv on 4 October 2015.", "\n\nReferences\n\nExternal links \n Profile on FFU site \n \n\nCategory:1997 births\nCategory:Living people\nCategory:People from Zaporizhia\nCategory:Ukrainian footballers\nCategory:Association football goalkeepers\nCategory:Ukrainian Premier League players\nCategory:FC Vorskla Poltava players" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Dicerca tuberculata\n\nDicerca tuberculata is a species of metallic wood-boring beetle in the family Buprestidae. ", "It is found in North America.", "\n\nReferences\n\nFurther reading\n\n \n \n \n\nCategory:Buprestidae\nCategory:Articles created by Qbugbot\nCategory:Beetles described in 1837" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Wadō-Kuroya Station\n\nis a railway station on the Chichibu Main Line in Chichibu, Saitama, Japan, operated by the private railway operator Chichibu Railway.", "\n\nLines\nWadō-Kuroya Station is served by the Chichibu Main Line from to , and is located from Hanyū.", "\n\nStation layout\nThe station is staffed and consists of a single island platform serving two tracks. ", "An additional bidirectional loop runs alongside track 2 for use by freight services.", "\n\nPlatforms\n\nAdjacent stations\n\nHistory\n\nThe station opened as Kuroya Station on October 27, 1914. ", "The station name was changed to Wadō-Kuroya Station from April 1, 2008.", "\n\nPassenger statistics\nIn fiscal 2000, the station was used by an average of 462 passengers daily.", "\n\nSurrounding area\n Arakawa River\n National Route 140\n Hijiri Shrine\n\nSee also\n List of railway stations in Japan\n\nReferences\n\nExternal links\n\n Wado-Kuroya Station information (Saitama Prefectural Government) \n Wado-Kuroya Station information \n\nCategory:Railway stations in Saitama Prefecture\nCategory:Railway stations opened in 1914\nCategory:1914 establishments in Japan" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "by Daniel Loxton\n\nSkull Island, Canadaa still from the film King Kong.", "A sketch made from Kemp’s description many months after his sighting. ", "© 1933 RKO Pictures Inc., © 2005 Warner Bros. Entertainment Inc.The 1933 and 2005 versions of King Kong share many rich details, and a moral. ", "There are those who suggest that moral must be something about the power of love, but I suggest the moral is this:“Never, ever go to Skull Island.", "”Skull Island, the setting for the second act of King Kong, is an utterly nightmarish place. ", "A steaming jungle packed with prehistoric beasts and crawling with unlikely monsters, it is a place where even the insects can drag you away for dinner.", "It’s not surprising that this exotic, terrifying place awed Depression-era movie audiences. ", "When Kong opened in 1933, no one had ever seen anything like it. ", "The revolutionary special effects, the scope of imagination, the depth of immersion in another world — all these created a blockbuster experience that still echoes in the popular imagination today.", "My story begins on another, sleepier island: Vancouver Island, off the western coast of British Columbia, Canada.", "At the southern tip lies the provincial capital city of Victoria, a bustling tourist destination with a busy cruise ship port. ", "Today it bills itself as “the City of Gardens,” but in 1933 it enjoyed worldwide fame for something altogether more mysterious — nothing less than an 80-foot sea monster, called Cadborosaurus.", "According to legend, an awesome, primeval monster — a huge serpent with flippers, a mane, and a head something like that of a camel or horse — slides undetected through the frigid waters off British Columbia and Washington State. ", "Could a living dinosaur, a monster out of time, lurk here beneath the waves?That question hinges on a moment in history.", "Imagine yourself in 1933 for a moment. ", "The Great Depression was causing tremendous hardship at home, while daily newspaper headlines carried ever more bad news about Adolph Hitler. ", "As tensions continued to mount between the new Nazi government of Germany and the rest of Europe, war seemed increasingly likely.", "The news featured one bummer story after another, and people needed a pick-me-up. ", "In Victoria, that came in the form of headlines proclaiming, “Yachtsmen Tell Of Huge Serpent Seen Off Victoria.", "”Two civil servants, named Langley and Kemp, told the Victoria Daily Times that they’d each independently seen huge sea monsters. ", "According to Langley, he and his wife were out sailing when they heard “a grunt and a snort accompanied by a huge hiss,” and then “saw a huge object about 90 to 100 feet off,” of which “[t]he only part of it that we saw was a huge dome of what was apparently a portion of its back.” ", "It was, he said, only visible for a few seconds before diving.", "What strikes me about Langley’s monster — and contemporary critics were quick to point this out — is that it swam like a whale, it sounded like a whale, and it looked a whale. ", "Now, whales definitely live in the area: Humpbacks, grey whales, sperm whales, and others. ", "Even today, boatloads of whale-watching tourists leave Victoria’s downtown Inner Harbour every few minutes. ", "Given that we have no data here except a momentary, unsubstantiated, undeniably whale-like anecdote, the Langley sighting seems to me to be a completely trivial case.", "But the Kemp case was more interesting. ", "It was his sustained daylight sighting that fueled a Cadborosaurus media frenzy in Victoria and across the continent, inspiring a rash of copycat sightings — and launching an enduring legend.", "According to Kemp’s 1933 story, he and his family were picnicking one afternoon in the previous year, on a group of tiny islands just off Victoria, when they saw something extraordinary. ", "A huge creature swam up the channel between Chatham and Strongtide Islands leaving an impressive wake. ", "Kemp recalled, “The channel at this point is about 500 yards wide. ", "Swimming to the steep rocks of the island opposite, the creature shot its head out of the water on to the rock, and moving its head from side to side, appeared to be taking its bearings. ", "Then fold after fold of its body came to the surface. ", "Towards the tale it appeared serrated, like the cutting edge of a saw, with something moving flail-like at the extreme end. ", "The movements were like those of a crocodile. ", "Around the head appeared a sort of mane, which drifted round the body like kelp.", "”Kemp estimated the animal was over 60 feet long. ", "Although it was indistinct with distance — it was at least 1200 feet away, maybe 1500 — this was no fleeting sighting. ", "According to Kemp, they watched the monster for several minutes before it slid off the rocks swam away.", "What was it? ", "It sounds to me like a group of sea lions among the distant kelp, viewed at too great a distance and remembered with too great a dollop of imagination. ", "But the interesting question is, “Whose imagination?”Kemp’s description gives a clue. ", "Despite copycat sightings describing literal “sea serpents,” and despite the serpentine image of Cadborosaurus now popular among cryptozoologists, it’s striking that neither of the original eyewitness reports described serpents at all!Langley described something like a whale; Kemp described something like a dinosaur. ", "His monster, he said, “gave the impression that it was much more like a reptile than a serpent….”Responding to the Kemp sighting, one letter to the editor offered an opinion that Caddy might be a sauropod dinosaur called diplodocus. ", "This writer noted Caddy’s long neck and long tail, and called it “probable that it has legs with webbed feet with which it propels itself.", "”Kemp seized on this dinosaur idea with enthusiasm, and produced an eyewitness sketch consistent with a sauropod. ", "He agreed, “Diplodocus describes better what we saw than anything else. ", "My first feelings on viewing the creature were of being transferred to a prehistoric period when all sorts of hideous creatures abounded.” ", "He said the creature’s movements “were not fishlike, but rather more like the movement of a huge lizard.", "”This combination of elements — a swimming sauropod dinosaur, and the notion of being transported to a prehistoric world full of terrible monsters — sounded very familiar to me. ", "I was reminded of another sauropod, filmed swimming in a primal environment teaming with hideous creatures: Skull Island, as depicted in the blockbuster film King Kong! ", "Comparing Kemp’s description and sketch with stills from the film, the parallels are striking.", "The most famous Loch Ness monster hoax photo () compared with a still from the film King Kong. ", "Both images feature small models. ", "© 1933 RKO Pictures Inc., © 2005 Warner Bros. Entertainment Inc.Could the film have inspired Kemp’s story? ", "The timeline certainly works: Kong, it happens, opened in Victoria just six months before Kemp and Langley created the legend of Cadborosaurus. ", "It blew movie-goers away, scared the socks off of people, and stuck in the memories of all who saw it. (", "Not coincidentally, the legend of the Loch Ness Monster was likewise created immediately after the release of King Kong, and the several key Nessie sightings seem almost lifted from the film. ", "It’s especially notable that the infamous fake “Surgeon’s Photo” looks virtually identical to a shot from the movie.)Is this similarity between Cadborosaurus and Kong suspicious? ", "You bet.", "Kemp’s original sighting was extremely uncertain, as he admitted, because of the tremendous distance involved (well over a thousand feet). ", "He couldn’t make out the key details. ", "For example, the creature’s head was just a blob. ", "It’s likely he saw a distant group of marine mammals swimming and climbing the rocks (as is entirely typical in the area), but was unable to make out what they were at that distance. ", "Perhaps he puzzled about it for a few months before King Kong planted a seed….When he finally met Langley, heard his sea monster story, and compared notes, Kemp’s memories were a year old, and very probably contaminated by Hollywood.", "That’s a recipe for a legend — but as scientific data, it’s a disaster.", "Where does this leave Cadborosaurus? ", "As so often in the paranormal world, it seems that the entire legendary edifice, all the sightings that followed, the books and TV programs and place in pop culture, all rests on a foundation of smoke.", "Smoke, and the flickering screen of a cinema._______________________________________________________________________________________________I found this interesting little article while poking around the web for Kong material... It's mostly about the Cadbororsaurus/Canadian sightings, of course, but it did mention that the Loch Ness Monster burst into public consciousness only after 1934, which was only a year after Kong's release. ", "Nessie has been sighted now and then for centuries before, but only after that photo popped up did it capture the world's attention... was it because of the ever-growing access to cameras, and thus more tangible proof, or were people's imaginations influenced by a Skull Island beast?Found here: http://www.skeptic.com/reading_room/sku ... nd-canada/" ]

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[ "Liquid Rhythms\n\nSaturdays from 1 am - 4 am\n\nLiquid Rhythms mixshow started on KRCL 90.9 FM back in Feb. 1997, and is now widely listened too one of the longest running mixshows of its kind, nationally and internationally. ", "DJ Kenn Burrola brings you a variety of Dance Music every week live in the mix. ", "From House Music, Electro House, Progressive House, EDM, etc. – ", "and also includes a RewindMix and an Old School mix." ]

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[ "Introduction: origin of chloroplasts {#Sec1}\n====================================\n\nOrganelles known as chloroplasts are characteristic for plant cells and eukaryotic algae (Leister [@CR49]). ", "Their main purpose is housing numerous metabolic reactions necessary for the life of the cell, such as photosynthesis---production of nutrients from water and carbon dioxide with use of absorbed sunlight. ", "They are believed to have originated from cyanobacteria, which have either invaded or been engulfed by a heterotrophic host cell approximately 1.5 billion years ago (Chan et al. [", "@CR10]). ", "In the process of primary endosymbiogenesis, the vast majority of cyanobacterial genes has either been lost or transferred to nucleus of host cell. ", "In parallel to these changes, some host genes acquired leading sequences, which made the transport of their products into the organelle possible (Green [@CR34]). ", "These changes eventually led to establishment of organelle known as primary plastid (Fig.", " [1](#Fig1){ref-type=\"fig\"}). ", "However, endosymbiosis has not ended there. ", "Majority of species belonging to Plantae has acquired secondary chloroplasts by establishing an endosymbiotic connection with chloroplast-containing algae. ", "The process begins with engulfment (or invasion by) a plastid-containing algal cell, which eventually either loses its nuclear genes or transfers them to the nucleus of a host cell (Fig.", " [1](#Fig1){ref-type=\"fig\"}) (Green [@CR34]; Turmel et al. [", "@CR83]). ", "It is worth noting that organelle-to-host nucleus gene transfer continues to this day (Kleine et al. [", "@CR45]). ", "This review will focus on analysis of the current knowledge about structure of chloroplast genomes and potential practical applications of plastome sequencing and engineering. ", "The terms 'plastid' and 'chloroplast' will be used throughout the text interchangeably. ", "The former term regards plastids that are not capable of photosynthesis due to the lack of chlorophyll.", "Fig.", " 1Structure of a typical chloroplast genome on example of *Arabidopsis thaliana*. *", "SSCR* small single copy region, *LSCR* large single copy region, and *IR-A and IR-B* inverted repeats. ", "Length of plastome and its parts in kbp\n\nStructure of chloroplast genome {#Sec2}\n===============================\n\nEach plastid has its own independent genome. ", "The vast majority of analyzed plastid DNA molecules (cpDNA) is inherited maternally and was found to be double-stranded and have a circular structure. ", "However, it is worth noting that branched and linear cpDNA molecules may also exist in some plants, such as maize seedlings and *Medicago truncatula* (Shaver et al. [", "@CR70], Oldenburg and Bendich [@CR64]). ", "cpDNA molecules are a part of protein-DNA complex known as nucleoid. ", "A single nucleoid contains 10--20 cpDNA copies and may be (1) surrounded by thylakoids in the center of chloroplast (red algae), (2) found in circular form in girdle lamellae (brown algae), or (3) found in matrix, between thylakoids (Kuroiwa [@CR48], Kobayashi et al. [", "@CR46]). ", "cpDNA usually exists in form of a monomer, but it is also capable of creating multimers (dimers, trimers, and the least common tetramers) (Lu et al. [", "@CR54]). ", "Unlike nuclear genome, plastome does not create complexes with histones. ", "However, the presence of plastome-encoded, histone-like HC protein has been confirmed in red algae (Kobayashi et al. [", "@CR46]).", "\n\n200--300 identical DNA molecules exist in the chloroplast. ", "Plastome size usually varies from 100 to 200 kbp. ", "The biggest size variation can be observed in green algae chloroplast genomes. ", "The smallest ones have been identified in *Helicosporidium* sp. *", "Simulium jonesie*---37.4 kbp and *Ostreococcus tauri* (71.6 kbp), while the largest ones were found in *Nephroselmis olivacea* (200.8 kbp) and *Dunaliella salina* (269 kbp) (Smith et al. [", "@CR76]). ", "Such differences have not been observed among land plants---their plastome size usually is within 120--160 kbp. (", "Table [1](#Tab1){ref-type=\"table\"}).Table 1Examples of selected parameters of the plastomes in different speciesSpeciesSequence length (kbp)Number of genesNumber of intronsTotal plastomeIR (A and B)SSCLSCProteinRNA*Arabidopsis thaliana*154.526.317.884.2854472*Nicotiana tabacum*155.825.318.486.7984575*Vitis vinifera*160.926.619.189.1845316*Phaseolus vulgaris*150.326.417.679.8834410*Triticum aestivum*134.520.712.880.3835063*Pinus thunbergii*119.70.653.065.712339nd*Zea mays*140.422.712.582.311146nd*Chlamydomonas reinhardtii*203.422.278.180.96940nd*Dunaliella salina*269.014.4112.9127.38236nd*Ostreococcus tauri*71.76.822.335.96133nd*Helicosporidium* sp. *", "ex Simulium*37.5ababab2628nd*Euglena gracilis*143.2ababab6748399*Nephroselmis olivacea*200.846.116.492.115545ab*Gracilaria tenuistipitata*183.8ababab20333ndAll data comes from NCBI and the Chloroplast Genome Database*IR* inverted repeats, *SSC* small single copy, *LSC* large single copy, *ab* absence, *nd* no data\n\nTypical plastomes have a pair of identical inverted repeats (IRs), 5--76 kbp each (although in *Pinus thunbergii* they are just 600 bp long), separated by small and large single copy regions (SSC and LSC, respectively) (Fig.", " [1](#Fig1){ref-type=\"fig\"}). ", "IRs usually contain three highly conservative regions coding rRNAs and some tRNAs and are very similar to each other. ", "Exceptions from this rule were discovered in *Pisum sativum*, *Vicia faba*, *Medicago sativa* (which contains a single IR-like sequence), and *Euglena gracilis* (3 direct repeats). ", "Some plastomes do not have inverted repeats (e.g., *Helicosporidium* sp. *", "ex Simulium*, *Euglena gracilis*, *Gracilaria tenuistipitata*).", "\n\nSequences separating IRs, short and long single copy regions, are unique. ", "Size of the latter has major influence on size of the entire plastome (Shaw et al. [", "@CR71]). ", "One of the largest LSCs (127.3 kbp) has been found in *Dunaliella salina* (Table [1](#Tab1){ref-type=\"table\"}).", "\n\nPlastome usually contains 100--120 functional genes, and their size does not directly correlate with plastome size. ", "All chloroplast genomes contain genes encoding proteins, tRNA and rRNA (De Las Rivas et al. [", "@CR22]; Cui et al. [", "@CR13]; Wicke et al. [", "@CR93]). ", "Among species with more genes, some genes (mostly protein-encoding ones) still need to be analyzed. ", "For example, *Chlorella vulgaris* is estimated to have 174 genes (including 63 of hypothetical or uncharacterized proteins) (Cui et al. [", "@CR13]). ", "Vast majority of telomic plants has 80--100 defined protein coding genes (and only a few undefined, whose products participate in: translation, transcription, photosynthesis, energy metabolism, fatty acid metabolism, transport, and cofactor biosynthesis (Barkan [@CR2]; Green [@CR34]). ", "RNA genes are defined more accurately---6--8 rRNA genes are present in IRs, and 36--40 tRNA genes are spread across the entire plastome (Wicke et al. [", "@CR93]).", "\n\nAside from aforementioned genes, many conserved hypothetical ORFs (ycfs) were discovered, but their functions remained unknown until recent years. ", "For a long time, *ycf1* gene remained the biggest mystery---while its presence was necessary for survival of researched organisms (*Nicotiana tabaccum* and *Chlamydomonas reinhardtii*), its function was unknown, and its absence in plastomes of *Poaceae* posed more questions (Boudreau et al. [", "@CR7]; Drescher et al. [", "@CR28]; Guisinger et al. [", "@CR36]; de Vries et al. [", "@CR23]). ", "However, in 2013, it has been discovered that in *Arabidopsis thaliana,* this gene encodes Tic214, which is a part of general TIC translocon, necessary for transfer of nuclear proteins into the chloroplast (Kikuchi et al. [", "@CR44]). ", "Currently, *ycf2* remains as the only hypothetical ORF whose protein has an unknown function.", "\n\nAn interesting parameter of plastomes is their number of introns. ", "In land plant plastomes, group I and II introns have been identified (with the latter representing over 90 % of intron pool) (Eckard [@CR30]). ", "However, plastomes of genus *Euglena* also contain 73--119 nt long group III introns, derived from group II introns, but lacking their D2--D5 domains (Sheveleva and Hallick [@CR73]). ", "Introns are present both in protein-coding and RNA genes.", "\n\nAmong selected species representing the monocots, the intron number is as follows: *Oryza sativa*---60; *Hordeum vulgare*---14; *Triticum aestivum*---63; among dicots: *Vitis vinifera*---16; *Solanum tuberosum*---22; *Nicotiana tabacum*---75; *Populus trichocarpa*---26; *Pinus koraiensis*---36; and *Arabidopsis thaliana*---72 (Cui et al. [", "@CR13]). *", "Euglena gracilis* has a distinctively high number of introns (399---over 40 % of total ctDNA). ", "Its special trait is the presence of 15 twintrons---group II and III introns present within other introns from these groups. ", "Simple and complex twintrons can be distinguished---in the former, a single intron is inserted into another, while the representatives of the latter group consist of at least two introns inserted into another intron (Hallick et al. [", "@CR38]).", "\n\nHowever, in most of species, the number of introns varies between one and few dozen, with no regularity among species from the same taxon---Solanaceae (*Solanum tuberosum*---22, *Nicotiana tabacum*---75, and *Lycopersicon esculentum cultivar LA3023*---17) and Fabaceae (*Lotus corniculatus*---69, *Glycine max*---25, and *Phaseolus vulgaris*---10) are a prime example. ", "On the other hand, some species have no introns whatsoever (*Cyanidioschyzon merolae*, *Cyanidium caldarium*, *Gracilaria tenuistipitata*, *Nephroselmis olivacea*, and *Porphyra purpurea*) (Cui et al. [", "@CR13]).", "\n\nA different content of GC pairs is a trait strongly distinguishing plastomes from nuclear genomes. ", "In former, GC pairs represent just \\~30 % of total base pairs---it is caused by multiple traits of chloroplast, such as specific properties of chloroplast DNA polymerase and repair systems (Nielsen et al. [", "@CR62]).", "\n\nChloroplast gene expression {#Sec3}\n===========================\n\nTranscription: PEP and NEP polymerases {#Sec4}\n--------------------------------------\n\nDespite heavily depending on nucleus-derived proteins, chloroplasts possess their own system responsible for expression of genes, which originate from ancestral cyanobacteria (Yagi and Shiina [@CR94]). ", "RNA polymerases, responsible for transcription, are a crucial part of this machinery. ", "Two types of them can be found in a chloroplast---bacterial-type plastid-encoded RNA polymerase known as PEP and nuclear-encoded RNA polymerase (NEP), characteristic for angiosperms and *Physcomitrella* moss (Barkan [@CR2], Yagi and Shiina [@CR94], Liere et al. [", "@CR51]). ", "PEP consists of four subunits, α-, β-, β′-, and β″, which are encoded by *rpoA*, *rpoB*, *rpoC1*, and *rpoC2* plastid genes, respectively (Serino and Maliga [@CR69]). ", "It shares multiple traits, such as need for sigma factors in promoter recognition, with eubacterial RNA polymerases (however, it is worth noting that plant sigma factors are encoded in nucleus) (Tiller and Bock [@CR81]). ", "There are multiple types of sigma factors, which grant promoter specificity and take part in transcription of different groups of genes (Lerbs-Mache [@CR50]; Yagi and Shiina [@CR94]). ", "Meanwhile, NEP is a single-subunit polymerase, which shares many similarities with its counterparts in mitochondria and T3/7-type bacteriophage (Liere et al. [", "@CR51]). ", "Chloroplasts of higher plants contain two types of NEP (RPOTp and RPOTmp), which are capable of aiding PEP with transcription of plastome genes (Swiatecka-Hagenbruch et al. [", "@CR80]).", "\n\nPEP and NEP also recognize different promoters. ", "PEP promoters usually contain consensus sequences, −35 (TTGaca) and −10 (TAtaaT), and resemble bacterial σ70 promoters (Gruissem and Zurawski [@CR35]; Yagi and Shiina [@CR94]). ", "On the other hand, NEP has two main types of promoters---type I has an YRTA motif, which bears many similarities to mitochondrial promoters, and sequences crucial for type II promoters are placed downstream of the transcription initiation site (Sriraman et al. [", "@CR77]; Swiatecka-Hagenbruch et al. [", "@CR80]).", "\n\nPost-transcriptional processing and translation {#Sec5}\n-----------------------------------------------\n\nAfter transcription, initial transcripts undergo a multi-step processing, which includes splicing, transforming primary RNA molecules into mono- or oligocistronic mRNAs, formation and maturation of 5′ and 3′ ends, and finally RNA editing (Stern et al. [", "@CR78]; Tiller and Bock [@CR81]). ", "Most of components of translation in plastids (including 70S ribosomes) have cyanobacterial homologues (Tiller and Bock [@CR81]). ", "However, plastid translation also involves plenty of protein translation factors and positive regulatory mRNA elements, which do not have bacterial counterparts and increase the overall complexity of the process (Manuell et al. [", "@CR56]).", "\n\nThe process usually is initiated by small subunit (30S) of the ribosome and transfer RNA (tRNA), which selects the initiation site on the 5′ end of mRNA (usually starting from AUG triplet, although in some cases, GUG and UUG can also serve that role) (Sugiura et al. [", "@CR79]). ", "Once the site is selected, 50S subunit is attached to the complex, resulting in activation of initiation complex and start of elongation phase (Manuell et al. [", "@CR56]). ", "During this stage, ribosome progresses toward 3′ end of mRNA and adds amino acids carried by tRNA to the growing polypeptide. ", "This process is supported by translation elongation factors: eEF1A, eEF1B, eEF2, and eEF5 (Doerfel et al. [", "@CR27]; Gutierrez et al. [", "@CR37]; Browning and Bailey-Serres [@CR9]). ", "Each of these factors has a different purpose: eEF1A is responsible for delivering tRNA to the peptidyl transferase center, eEF1B serves as exchange factor for eEF1A in recycling GDP for GTP, eEF2 plays a role in moving tRNA that already dropped its amino acid off from P-site to E-site and eEF5 increases the efficacy of proline and glycine-rich protein elongation (Browning and Bailey-Serres [@CR9]).", "\n\nTermination of translation is caused by the ribosome reaching one of STOP codons (UAA, UAG, UGA). ", "Once it happens, two release factors (eRF1 and eRF3) bind the STOP codon and cut the newly created peptide off, paving the way for recycling of the ribosome (Dever and Green [@CR25]).", "\n\nPlastid genome sequencing {#Sec6}\n=========================\n\nThe research focused on learning the primary structure of plastomes has begun significantly earlier than similar studies regarding nuclear genomes. ", "First, complete chloroplast genome sequences were published in second half of 1980s (Shinozaki et al. [", "@CR74]), while the analogous data about eukaryotic nuclear genomes and prokaryotic genomes emerged over a decade later. ", "It was caused by a major difference in genome size and the level of advancement of sequencing techniques. ", "These two factors are the main reason for current abundance of knowledge about structure and functioning of plastomes. ", "At first, it had a purely cognitive character, but with time, it also gained a major applicational importance. ", "Referential databases (such as NCBI) currently contain information about chloroplast DNA of over 1000 plant species. ", "Most of them represent *Viridiplantae*---a clade of green plants, containing Chlorophyta and telome plants (Cocquyt et al. [", "@CR12]). ", "However, representatives of other taxons can also be found there, providing multiple opportunities of performing multi-directional comparative analyses. ", "Knowledge regarding organization and mechanisms of functioning of these genomes has drawn increasing attention of scientists. ", "This interest is expressed in form of constantly growing number of analyzed species. ", "Plastomes became an attractive target of intentional modifications, whose purpose is utilizing their capabilities in many fields of modern biotechnology---this trend is reflected by the amount of realized sequencing projects. ", "Genome engineering includes transfer of new genes (or other specific elements, such as promoters) and changes aimed at controlling expression of endogenous genes. ", "Creation of new construct and precise control of results is easier in plastomes than in nuclear genome. ", "The following chapters describe selected aspects of plastome modification.", "\n\nPlastid genome engineering {#Sec7}\n==========================\n\nIn recent years, plastid transformation has emerged as an attractive alternative for nuclear gene transformation. ", "However, the specific nature of chloroplasts posed multiple challenges in designing techniques that could be utilized in this process.", "\n\nDesigning plastid transformation {#Sec8}\n--------------------------------\n\nThe first and biggest obstacle was selecting DNA vectors. ", "Contrary to a random, *Agrobacterium*-mediated T-DNA integration in nuclear transgenes, chloroplast transgene integration is targeted due to homologous recombination of vector's flanking sequences and target DNA (Verma and Daniell [@CR86]; Meyers et al. [", "@CR59]). ", "Because of that, transgene must be flanked by two targeting sequences, each around 1--2 kb in size (Meyers et al. [", "@CR59]). ", "Currently, *Escherichia coli* plasmids incapable of replication in plastids are the most popular vectors. ", "However, maintaining efficiency of transplastomic plant generation requires reconstructing the vectors when a different plant species is chosen (Verma and Daniell [@CR86]). ", "Depending on the state of a target, DNA is introduced either via polyethylene glycol treatment (when protoplasts are targeted) or gene gun (when plastids are in an undamaged tissue) (Dix and Kavanagh [@CR26]; Maliga and Bock [@CR55]). ", "Selection of transformed plants is usually done by utilizing marker genes encoding resistance to antibiotics. ", "Currently, the most popular choice is *aadA*, a gene from *E. coli* responsible for encoding aminoglycoside 3″-adenylyl transferase, which grants resistance to spectinomycin (Bock [@CR4]).", "\n\nIt must be remembered that usually no more than a few plastomes undergo transformation. ", "To prevent the subsequent loss of transplastomes, propagation of transplastomic cell lines under selection pressure has to be maintained until all the wild-type genomes perish (Bock [@CR5]).", "\n\nPlastid engineering: pros and cons {#Sec9}\n----------------------------------\n\nPlastid engineering holds some important advantages over its nuclear counterpart. ", "First, vast majority of angiosperms inherits chloroplasts maternally, thus significantly reducing the risk of transgenic plants outcrossing with weeds via pollen---in turn, reduction of that risk means that transgene silencing, utilized in commercially used transgenic plants to prevent outcrossing, is no longer necessary (Wani et al. [", "@CR90]). ", "Transformed plastids are also capable of producing a significantly higher amount of target protein, reaching from 4 to 46.1 % (or, in most extreme cases, over 70 %) of total soluble protein (TSP), compared with 1--2 % in plants where nuclear genome underwent transformation (De Cosa et al. [", "@CR21]; Daniell [@CR14]; Oey et al. [", "@CR63]; Meyers et al. [", "@CR59]). ", "Usefulness of plastome transformation is further boosted by lack of silencing mechanisms which can interfere with the process and the ability to transfer full metabolic pathways into the plastome while maintaining their efficiency (Meyers et al. [", "@CR59]).", "\n\nWhile plastome engineering seems promising, it is important to remember that this technique is not free of limitations. ", "Most importantly, multiple economically important plants lack feasible protocols for plastid transformation; the alternative is to transfer transgenic plastid from transformable plants to the species of choice (Sigeno et al. [", "@CR75]; Ovcharenko et al. [", "@CR65]). ", "Unfortunately, this method is costly and time-consuming, which significantly limits its application in comparison to nuclear transformation. ", "However, it has been discovered that movement of cpDNA between cells of grafted plants is possible and can potentially improve efficiency of the whole process (however, it happens at a cost of increased likelihood of mutations and is limited to closely related species) (Bock [@CR4]). ", "It is also worth noting that proteins do not undergo glycosylation in transformed chloroplasts, although the impact of lack of this process depends on the protein of interest (McCabe et al. [", "@CR58]).", "\n\nPotential use of plastome analysis and modification {#Sec10}\n===================================================\n\nThanks to significant progress in plastome research, a potential range of ways to utilize plastome analysis and modification has greatly increased. ", "Here, we present the most promising types of current plastome research.", "\n\nProduction of antigens, vaccines, and therapeutic proteins {#Sec11}\n----------------------------------------------------------\n\nOne of the most promising potential uses of plastome engineering is the production of recombinant proteins. ", "High yield of target protein in transformed plastids and, among many positive traits, ability to apply post-translational modifications combined with lack of silencing, makes using chloroplast modification for production of antigens, enzymes, therapeutic proteins and vaccines, and intriguing prospect.", "\n\nOver the last 15 years, we have witnessed the emergence of multiple reports on production of bacterial and viral antigens that can be used in vaccines directed against the most dangerous human diseases. ", "However, most of them have only been tested on mice so far, which means that developing effective vaccines for humans will still take time (Daniell et al. [", "@CR18]). ", "Initially, most of vaccine antigens were expressed in tobacco leaves. ", "The first antigen expressed in tobacco was the cholera toxin B subunit (CTB), whose accumulation reached 4.1 % of total soluble leaf protein (TLP) (Daniell et al. [", "@CR16]). ", "Fusing CTB with merozoite surface protein-1 (MSP1) and apical membrane antigen-1 (AMA1) further increased TSP values (to 10.11 and 13.17 %, respectively) and isolated antigens provided inoculated mice with long-time protection against *Vibrio cholerae* (Davoodi-Semiromi et al. [", "@CR20]). ", "Other bacterial antigens successfully accumulated in tobacco include: heat-labile enterotoxin subunit B of *E. coli* responsible for diarrhea (Kang et al. [", "@CR42]), tetanus toxin fragment C (Tregoning et al. [", "@CR82]), and anthrax protective antigen (Watson et al. [", "@CR92]; Ruhlman et al. [", "@CR68]).", "\n\nTobacco has also proved to be a promising platform for production of viral antigens. ", "In 2004, rotavirus VP6 protein was successfully accumulated in seedlings and young leaves of tobacco, reaching 3 % TSP, but it lacked stability and was never tested on animals (Birch-Machin et al. [", "@CR3]). ", "Since then, most of research focused on antigens of three viruses---cervical cancer-causing human papillomavirus (HPV), human immunodeficiency virus (HIV), and hepatitis virus. ", "Eventually, antigens derived from all of these viruses were produced in tobacco. ", "As it turned out, the target proteins maintained their effectiveness---human papillomavirus antigens (L1 and E7) induced systemic immune response in mice (Fernández-San Millán et al. [", "@CR32]; Venuti et al. [", "@CR85]), and so did p24 and C4V3 polypeptides isolated from HIV, which successfully elicited antibody responses in mice (Gonzalez-Rabade et al. [", "@CR33]; Rubio-Infante et al. [", "@CR67]).", "\n\nWhile the yield and stability of target proteins were satisfactory, tobacco's usefulness was limited by its high alkaloid content, which made it unsuitable for oral delivery. ", "Because of that, scientists have searched for more suitable plants for antigen accumulation, and they have found them in form of lettuce and tomatoes. ", "Both of them turned out to be effective for production and oral administration of target proteins, although it is worth noting that ripening of tomatoes reduced their transgene expression (Zhou et al. [", "@CR97]; Davoodi-Semiromi et al. [", "@CR20]; Lössl and Waheed [@CR53]). ", "Research on lettuce already resulted in successful production of multiple important therapeutic proteins; the first successful attempt was accumulating proinsulin, where old leaves of plants with chloroplasts transformed with human proinsulin--CTB complex managed to accumulate proinsulin up to 53 % of TLF, compared with 47 % in old tobacco leaves and just 1 % of total seed protein in *Arabidopsis* (Boothe et al. [", "@CR6]; Boyhan and Daniell [@CR8]). ", "Some algae have also proved to be capable of producing vaccine antigens---in 2010 *Chlamydomonas reinhardtii* was successfully utilized to accumulate AMA1 and MSP1, two potential candidates for vaccine against malaria-causing protozoa from *Plasmodium* genus (Dauvillée et al. [", "@CR19]).", "\n\nEnzyme production: obtaining biomass and raw material {#Sec12}\n-----------------------------------------------------\n\nTransplastomes can also be used to synthesize enzymes, which can be utilized to obtain material for biofuel. ", "Currently, biofuel production is an expensive process, which results in wasting of large amounts of potentially useful biomaterial. ", "Big part of expenses comes from obtaining enzymes necessary for degradation of cell walls---cellulases, hemicellulases, and accessory enzymes (Agrawal et al. [", "@CR1]). ", "That is why in recent year's utilization of modified plants as a source of enzymes became a popular field of research. ", "So far, none of the enzymes derived from transgenic plants are produced on a mass scale, but current results show immense promise. ", "For example, endoglucanase (cellulase) and pectate lyases (hemicellulases) from one of experimental cultivars of transplastomic tobacco were significantly less expensive than commercial enzymes (production was 3100-fold and 1057/1480-fold cheaper, respectively) (Verma et al. [", "@CR87]).", "\n\nAnother enzyme expressed in transformed tobacco chloroplasts is β-mannanase, a hemicellulase of *Trichoderma reesei.* ", "Once again, the results gave reasons to be optimistic---mannase produced in chloroplasts had wider pH optima and thermostability than its counterpart obtained from *E. coli* and displayed notable activity even without purification, potentially opening a route for its easier and cheaper utilization in the future (Agrawal et al. [", "@CR1]). ", "Another examples of fungal enzymes successfully obtained from transplastomic tobacco are swollenin and cutinase; however, it is unlikely for them to find any practical use soon, as they caused severe damage to plant cells---it included damaged thylakoid membranes, disruption of pigment-protein complexes, loss of chloroplasts, and decreased galactolipids content (Verma et al. [", "@CR88]). ", "Tobacco chloroplasts are also capable of producing bacterial enzymes, such as thermostable cellulases (Cel6A and Cel6B) of thermophilic actinobacteria, *Thermobifida fusca* (Yu et al. [", "@CR96]).", "\n\nCrop improvement {#Sec13}\n----------------\n\nEvery plant is exposed to a variety of biotic and abiotic stressors, which are capable of negatively impacting plant's development, size, and quality of its yield. ", "Because of that, plastome modifications introducing improved resistance to common stress factors are a popular field of research, which has potential to improve the yield, reduce the amount of used pesticides and insecticides, and give a chance to grow the crop in areas where wild-type plants would struggle to survive.", "\n\n### Herbicide resistance {#Sec14}\n\nThe increasing use of herbicides has resulted in the need for plants capable of surviving exposure to non-selective chemicals used against the weeds. ", "However, providing it by nuclear transformation of crops is a risky approach, as herbicide immunity genes can be transferred with pollen, potentially resulting in outcrossing with weeds and subsequent creation of superweeds, immune to herbicides. ", "While it is possible to significantly reduce that threat by silencing transgenes, this process further increases the cost of the whole operation. ", "This is why chloroplast transformation, free of risk coming with outcrossing, is being looked into.", "\n\nFirst successes in providing herbicide resistance through genetic engineering of plastome came in 1998. ", "The research focused on finding a way to reduce or remove the negative influence of glyphosate. ", "This objective was achieved by transferring to tobacco's chloroplast the petunia gene engineered to overexpress glyphosate's target, 5-enol-pyruvyl shikimate-3-phosphate synthase (EPSPS), catalyst of one of the key steps of aromatic amino acid biosynthesis, (Daniell et al. [", "@CR15]). ", "In the following years, it has been shown that prokaryotic EPSPS can also be successfully used in this procedure, although its accumulation and glyphosate tolerance did not correlate (Ye et al. [", "@CR95]).", "\n\nAnother example of successful induction of herbicide resistance includes improving resistance to some of the triketone herbicides by introducing barley's 4-hydroxyphenylpyruvate dioxygenase-synthesizing *hppd* gene, which is a part of plastoquinone and vitamin E biosynthesis pathway, into tobacco plastomes (Falk et al. [", "@CR31]; Venkatesh and Park [@CR84]). ", "In 2007, *hpdd* from *Pseudomonas fluorescens* was introduced into soybean plastomes; this experiment is especially noteworthy, as it was the first case of obtaining herbicide immunity in an economically important crop without utilizing antibiotic resistance markers (Dufourmantel et al. [", "@CR29]).", "\n\n### Pest and disease resistance {#Sec15}\n\nPests and diseases are some of the biggest problems for modern agriculture. ", "Their influence is capable of severely reducing the crop yield and forces the use of chemicals, which represent an environmental hazard and increase the overall cost of crop growth. ", "While nuclear transformation has managed to reduce the impact of these factors, chloroplast transformation can still provide additional biosafety and play a role when higher gene expression is needed (Venkatesh and Park [@CR84]).", "\n\nThe first discoveries in this field were made in 1995, when crylA(c) coding sequence of *Bacillus thuringiensis* (Bt) was used to produce Bt toxins in tobacco in concentrations which made it harmful for attacking insects, such as *Helicoverpa zea*, *Heliothis virescens,* and *Spodoptera exigua* larvae (McBride et al. [", "@CR57]). ", "Since then, Bt toxins were introduced into other transplastomic plants, such as cabbage (*Brassica oleracea*), but they never entered commercial production, mainly due to plenty of available alternatives obtained by nuclear tranformation (Liu et al. [", "@CR52]; Jin and Daniell [@CR40]).", "\n\nDisease-resistant tobacco was first created in 2001 by inserting the sequence encoding an antimicrobial peptide MSI-99, analog of magianin 2, defensive peptide secreted from the skin of *Xenopus laevis* (African clawed frog) (DeGray et al. [", "@CR24]). ", "Transplastomic plants significantly inhibited growth of pre-germinated *Aspergillus flavus*, *Fusarium moniliforme*, and *Verticillium dahlia* fungi, and *Pseudomonas syringae* pv. ", "tabaci bacteria (DeGray et al. [", "@CR24]). ", "Recent research also shows that MSI-99 expressed by tobacco chloroplasts is capable of suppressing the effects of rice blast, one of the most dangerous fungal rice diseases (Wang et al. [", "@CR89]).", "\n\n### Simultaneous resistance to herbcides, pests, and diseases {#Sec16}\n\nIn recent years, a number of transplastomic plants capable of simultaneously improving resistance to insects and diseases have emerged. ", "While this kind of immunity would usually require multi-gene engineering, transforming tobacco chloroplasts with agglutinin gene from *Pinellia ternata,* a popular Chinese medicinal herb, is enough to singlehandedly reduce the survival rate of a wide array of pests (*Bemisia tabaci* whitefly, *Myzus persicae* aphid, *Spodoptera exigua* armyworm, *Helicoverpa zea*, *Heliothis virescens,* and *Lepidopteran* insects) by 90--100 %; also, agglutinin displayed significant anti-viral activity (Jin et al. [", "@CR41]). ", "Another example of transplastomic plant immune to insects and phytopathogens is *Nicotiana benthamiana* whose plastids included genes encoding chitinase from *Paecilomyces javanicus*, sporamin from sweet potato and cystatin from *Colocasia esculenta* (Chen et al. [", "@CR11]). ", "Bioassays have confirmed that the transformation reduced the symptoms of soft rot caused by *Pectobacterium carotovorum* subsp. *", "carotovorum* and leaf spot disease associated with *Alternaria alternata* and caused growth retardation and death of *Spodoptera exigua* and *S. litura* larvae that ingested the leaves (Chen et al. [", "@CR11]).", "\n\n### Abiotic stress resistance {#Sec17}\n\nGrowing demand for plants capable of growing and giving yield in unfavorable conditions, combined with human exploitation and extreme weather phenomena lead to an increased need for plants with increased immunity to drought, extreme temperatures and salinity.", "\n\nTo increase immunity to salt stress and drought, osmoprotectants are necessary due to their role in stabilizing membranes and proteins during osmotic stress. ", "As most of plants cannot metabolize sugar alcohols, introducing genes encoding a product capable of that is a viable way to improve osmoprotection (Khan et al. [", "@CR43]). ", "One of such genes is *ArDH*, which encodes arabitol dehydrogenase, responsible for reduction of [d]{.smallcaps}-ribulose to [d]{.smallcaps}-arabitol, which accumulates in chloroplasts and increases tolerance to high NaCl concentrations. ", "Its expression in tobacco chloroplasts allows plants to grow normally on soil with up to 350-mM NaCl concentration (Khan et al. [", "@CR43]). ", "Another example is a betaine dehydrogenase (BADH) gene transformed into *Daucus carota* (carrot), which resulted in transformed plants accumulating 50- to 54-fold more betalaine than their untransformed counterparts in medium with 100-mM NaCl concentration (Kumar et al., [", "@CR47]). ", "Transplastomic *N. benthamiana* with genes encoding chitinase, sporamin, and cystatin, mentioned before due to its increased immunity to insects and diseases, also shows increased immunity to osmotic stress (Chen et al. [", "@CR11]). ", "Meanwhile, temperature stress resistance can be achieved by enhancing antioxidant defense, increasing the unsaturation of fatty acids or by the use of *E. colipanD* gene encoding [l]{.smallcaps}-aspartate-α-decarboxylase---the enzyme decarboxylating [l]{.smallcaps}-aspartate to β-alanine and carbon dioxide (Wani et al. [", "@CR91]).", "\n\nConclusions {#Sec18}\n===========\n\nOnce the most important issues related to mass cultivation of tranplastomic plants are solved, they are likely to become a viable alternative for plants with nuclear transgenes, because of their higher production of protein of interest, lack of silencing mechanism, significantly higher biosafety, ability to engineer entire metabolic pathways, freedom of applying desired posttranslational modifications to the protein of interest, and potentially, no need for purification of protein target. ", "At the moment, it is unclear whether transplastomic plants can become more important for agriculture or biopharmaceutics, as we still failed to get anywhere close to uncovering their real potential. ", "However, it is worth remembering that there are some exciting subjects related to both worlds, such as edible vaccines. ", "For this reason, cooperation between scientists, agricultural and biotechnological companies will be necessary for steady development of transplastomics.", "\n\nCurrently, the biggest challenges ahead are related to the lack of protocols for transforming plastomes of other plants than tobacco. ", "While attempts to express foreign genes in some important agricultural plants, such as lettuce and tomato, have already succeeded, their number is still too low, the protocols contain many flaws, and the need to create a separate protocol for every cultivar makes the whole process more expensive. ", "On top of that, there are still no successful attempts of creating transplastomic staple food crops, such as cereal, and expressing foreign genes in non-green plastids remains a challenge due to our poor understanding of their genetic structure and expression (Wani et al. [", "@CR91]). ", "It is very unlikely for any transplastomic plants to be commercially used in the near future due to the reasons mentioned above combined with low plant regeneration efficiency and widespread use of antibiotic resistance genes as markers. ", "At this time, it appears that the problem of markers is the closest to the solution, as safer, although not widespread markers unrelated to antibiotic resistance already exist and some of them, such as *BADH*, are even capable of improving the target plant (Daniell et al. [", "@CR17]).", "\n\nInformation about plastome structure can also be very valuable in phylogenetic analyses and is an efficient molecular tool due to low mutation rate, easy amplification and conservative sequences of chloroplast genome (Hu et al. [", "@CR39]). ", "To this day, plastomes have been used in multiple analyses on different taxonomy levels---from species of the same genus to clades (Moore et al. [", "@CR60], [@CR61], Hu et al. [", "@CR39]). ", "Until now, the biggest issue was a low number of sequenced plastomes, which negatively affected the quality of phylogenetic analysis (Rogalski et al. [", "@CR66]). ", "However, recent major progress in realization of such projects means that the aforementioned analyses have a chance to become more reliable.", "\n\n*Author contribution statement* {#d30e1556}\n-------------------------------\n\nSO, EŁ, TK and TS wrote the manuscript. ", "EŁ provided the tables and figures. ", "SO did final revisions of the manuscript. ", "All authors read and approved this manuscript.", "\n" ]

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[ "I found chimney pipe that somebody removed a wood stove and wants to get rid of. ", "Will this work? ", "This is all the info I have.", "\n\nI have 2 sections of stainless steel insulted stove pipe. ", "30 inches long 8 inch INSIDE DIAMETER. ", "Also cap and cone that sits on the roof. ", "Took out wood stove and no longer need it. ", "Its in really good shape. ", "I can't find any markings on the pipe. ", "I purchased it from some place that deals with insulated pipe and stuff. ", "I don't remember the name, however, this was/is the best that you could buy. ", "I just want rid of it\n\n__________________I don't care what folks say behind my back........They are either braggin or.......lyinTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts..\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\n__________________I don't care what folks say behind my back........They are either braggin or.......lyinTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts..\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nI had talked to the building dept last fall, I haven't started my oven yet. ", "At that time the inspector told me it was just a general permit needed and there were no real requirements as I had lots of questions. ", "I have been looking on Craigslist and have sourced lots of materials for free or very cheap. ", "I have been looking for a god deal on the chimney as I like that style best and finally found this one. ", "I just wanted to check to make sure this would be acceptable as I know absolutely nothing about chimneys. ", "Thanks for the quick reply, since it looks like this will work I'm going to email him right now. ", "Thanks again!", "\n\nI think you will be all right. ", "As for as \"depending on the application\" is conserned as long as you are not building inside your home or something attached to it. ", "That is where building codes get real sticky, for a real good reason though .", "\n\n__________________I don't care what folks say behind my back........They are either braggin or.......lyinTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts..\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nI bought one section of 8\" double wall SS double wall and the cap for 60 bucks (from a local salvage store) and just thought that I got a great deal. ", "I haven't totally ruled out using it if I need to extend my chimney in the future, but it is on stand by if I need it. ", "I want try to give a value of the 2 sections and cap that you purchased but the only local source which I priced was 250 bucks per section of 3 wall. ", "I think that you are getting a good deal.", "\n\n__________________I don't care what folks say behind my back........They are either braggin or.......lyinTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts..\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nTo view links or images in signatures your post count must be 0 or greater. ", "You currently have 0 posts.", "\n\nNo part of this website or content thereof may be reproduced, distributed or transmitted in any form or by any means, nor may any part of this website be stored in a database or other electronic retrieval system, or any other website, without the prior written permission of Forno Bravo." ]

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[ "“Green Room” star Callum Turner is in talks to play Newt Scamander’s brother in the next installment of Warner Bros.’ “Fantastic Beasts and Where to Find Them.”", "\n\nEddie Redmayne will return to the sequel as Scamander. ", "Jude Law is on board to play young Dumbledore, and Johnny Depp is attached to play Grindelwald. ", "David Yates is returning to direct.", "\n\nRowling, who made her screenwriting debut on “Fantastic Beasts and Where to Find Them,” has also written the script for the second installment. ", "The film is set in an increasingly dark time for the Wizarding World where Newt Scamander and company have to decide on their allegiances.", "\n\nPlot details are unknown at this time other than the film being set in Paris.", "\n\nThe first movie in the planned five-part “Fantastic Beasts” series grossed more than $813 million at the box office.", "\n\nThe sequel, which begins production this summer, also reunites producers Rowling, David Heyman, Steve Kloves and Lionel Wigram. ", "Neil Blair, Rick Senat and Danny Cohen are serving as executive producers.", "\n\nAfter a breakout role in the A24 thriller “Green Room,” Turner followed up with a critically acclaimed performance in Adam Leon’s “Tramps,” which bowed at the Toronto Film Festival. ", "He has since landed the lead in Marc Webb’s “The Only Living Boy in New York” opposite Jeff Bridges, which opens in August.", "\n\nTurner is repped by WME and Curtis Brown Group. “", "Fantastic Beasts 2” hits theaters on Nov. 16, 2018." ]

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[ "Q:\n\nCheck if two items are equal after replacing\n\nLet's say that an item is either a natural number or a list of items. ", "Examples of items are:\n\n1\n[2]\n[4, [3, 1], 3, 4]\n\nA rule states that two items are equal. ", "For example:\n\n1 = 2\n3 = [3, 1]\n[4, 3] = [1, 5]\n\nWhen using these example rules, we can transform [4, [3, 2]] into [4, [3, 1]] into [4, 3] into [1, 5] and we can say that [4, [3, 2]] equals [1, 5].", "\nI want to find an algorithm that, given items $a$ and $b$ and a finite set of rules, determines if $a = b$.\nI already thought of an algorithm that works in some cases. ", "But I hope to find an efficient algorithm that works in all cases. ", "It would also be nice if the algorithm can detect $a \\not= b$ instead of infinitely searching for ways to let $a = b$. Is this a known problem? ", "Any help is appreciated.", "\nNote: We can simplify the problem by only allowing the number 1 instead of every natural number. ", "This is equivalent, because we can transform 1 into [1], 2 into [1, 1], 3 into [1, 1, 1], etcetera.", "\n\nA:\n\nI found a solution to my problem. ", "Let's look at the simpler but equivalent problem in which an item is recursively defined as an empty list or a list of items. ", "I'll summarize the algorithm.", "\nVariables:\n\nInt counter starting at 0\nHash map: list of integers $\\to$ integer.", "\nThe integers represent equivalence classes.", "\n\nFunction find(item) $\\to$ int:\nFinds the equivalence class of an item. ", "Recursively call find on all the children of item. ", "Now you have a list of ints. ", "If this list of ints is contained in the hash map, return the corresponding value. ", "If not, add the list to the hash map with the counter as value. ", "Increase the counter and return the value.", "\nFunction merge(int a, int b):\nMerges two equivalence classes a and b. In the hash map, replace all occurences (both in keys and in values) of a by b. Now it can happen that one key is mapped to multiple values. ", "If that happens, again merge those values. ", " Repeat this until every key maps to a unique value.", "\nAlgorithm:\nFor every rule c = d, call merge(find(c), find(d)). ", "Then to see if a = b, check if find(a) = find(b).", "\n\n" ]

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[ "Gov’t completes computerised land registry\n\nGovernment has completed the noble project of computerising Uganda’s land registry which will greatly minimise the so many land conflicts in the country.", "\n\nGovernment has completed the noble project of computerising Uganda’s land registry which will greatly minimise the so many land conflicts in the country.", "\n\nBy Moses Mulondo\n\nGovernment has completed the noble project of computerising Uganda’s land registry which will greatly minimise the so many land conflicts in the country.", "\n\nIn an exclusive interview with New Vision on Thursday, lands minister Daudi Migereko revealed that the ministry had started using the computerised registry.", "\n\n“A few days ago, we started using the computerised land registry. ", "People can now get their computerised land titles in the land offices and communicate to us if they face any problem,” Migereko said.", "\n\nThe minister also revealed that in the course of computerising the registry, they discovered so many forgeries of land titles and investigations aimed at prosecuting the culprits have already commenced.", "\n\nMigereko said the project has cost government US$23.5m which was a grant by World Bank.", "\n\nWorld Bank is also supporting similar projects of computeriSing land registry in Ghana and Tanzania.", "\n\n“The computerised national land information will solve problems of forging titles, missing files AND the red tape in searching land information. ", "Storage and retrieval of information will be easier and faster,” Migereko stated with a smile of relief.", "\n\nHe however clarified that the first phase has dealt with land information in the six zonal (sub-region) areas of Kampala, Mukono, Wakiso, Masaka, Mbarara and Jinja.", "\n\nThe minister explained that unlike in the past when issuance of land leases and land tiles has been at the ministry headquarters in Kampala, the services will be provided in the zonal offices.", "\n\nThe coordinator for land sector reform, Richard Oput, explained that the ministry chose to begin with the above mentioned six zonal offices because 60%-70% of land transactions take place in those areas.", "\n\nOput reported that the second phase of computeriSing the land registry will commence in July.", "\n\nThe other zonal offices where offices have been built and equipped with computers, surveying equipment and other requirements but whose land information is yet to be computeriSed include Mbale, Kibaale, Fort Portal, Masindi, Arua, Gulu and Lira.", "\n\nOput stated that in those sub-regional offices which have been completed, residents will only have to go with references like the block, plot number and where the land is located to quickly get any information they want regarding their land.", "\n\nHe revealed that the other land reforms the ministry is working on include drafting a Bill seeking to regulate the activities of real estate dealers, and another new land law of land information system to guide the operations of the computerised land registry.", "\n\nThe ministry has also embarked on reviewing Uganda’s old land laws to undertake their amendment reconcile them with the modern changes in the society.", "\n\nThe ministry has also just re-opened the school of surveying and land management and equipped it with a modern resource center involving a computer laboratory, library, and modern surveying equipment.", "\n\nThe completion of computerising land registry in the areas where most land transactions take place will greatly minimise land wrangles and simplify the judicial process of adjudicating land cases in courts of law.", "\n\nMigereko revealed that the number of land titles in the country is slightly above 500,000 most of which are in the central region, Ankole,\nTooro, Busoga and Mbale but which constitute only 18% of the entire land in Uganda.", "\n\nThe rest of the other parts of Uganda there are no land titles as land is owned in clans and communal arrangements" ]

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[ "When life reaches rock bottom, it has no where to go but up. ", "Gary Oak, Pokemon Master for fifteen minutes, grandson of a too famous researcher, eternal rival of Ash Ketchum, loser in everything that matters, is about to find out. ", "egoshipping edited\n\nDisclaimer: Pokemon and its respective characters do not belong to me.", "\n\nEditted Version.", "\n\nChapter Three - An Eye for an Eye, A Book for a ShirtI woke to the sound of muffled voices.", "\n\nSlowly, deliberately, the fine veil of sleep lifted. ", "In vain, I clung desperately on the fleeting threads of dream. ", "Yet, unconsciousness, like water, quickly slid out of my reach and reality coagulated around me. ", "I opened my eyes only to meet blinding sunlight. ", "How unusual, I thought, as I lifted a hand to cover my eyes. ", "I, a perpetual insomniac, seldom wake up later than seven-thirty. ", "By the intensity of the sun, it must be at least nine.", "\n\nThrough a crack between two fingers I glanced at my bedside clock. ", "I found none. ", "The absence propelled my heavy mind into complete panic. ", "My eyes shot opened but I calmed when a frantic survey informed me that in fact Iwas not in my room at all. ", "As the series of sleep-laced thoughts gave way to clearer, morecoherent stream of consciousness, I recognized the room as one of Blaine's guestrooms, to be precise, the room across the living room. ", "Memories of the night before hit me in full: I was depressed, I drank more than I ought, I got more depressed, I completely drank myself silly, and then… I sprang up but a massive headache forced me back into the bed.", "\n\nI groaned.", "\n\nAt that particular moment, the muffled voices caught my attention again. ", "Too soft to comprehend, too loud to ignore, really, the worst sort of muffled voices. ", "The noise must be from the living room, which is next to the dining room, which is next to the kitchen…\n\nThe kitchen… for a moment my mind dwelled fondly on the Tylenol in the kitchen cupboard. ", "The thought of such an incentive gave me the boost of energy I needed to overcome my headache and get out of bed. ", "My legs wobbled under me – think Tylenol - My head ache multiplied in strength each step I took – think Tylenol - My hand felt heavy as I lifted it to the door knob – You need the Tylenol – Oh the world is spinning – Tylenol.", "\n\nSuch was my pattern of thoughts as I made my way to the kitchen with Tylenol as the carrot at the end of the stick. ", "The thirty feet of mahogany flooring separating my room from the kitchen felt like the longest thirty feet in the world. ", "When I reached my destination, I could not help but feel most accomplished.", "\n\nI navigated expertly around Blaine's kitchen, gathering a cup from a cupboard, hot water from the electronic kettle and of course, my due reward: the pack of Tylenol from the medicine box. ", "Two pills and a nice long drink of hot water later, my god-awful headache felt somewhat better, completely psychological I am sure, but nevertheless better. ", "I settled myself on a stool at the kitchen counter and ate plain white bread, the only food lying at hand length from where I sat, not exactly my choice of breakfast but definitely filling enough.", "\n\nHalf way through the piece of bread, my brain began registering a conversation, also known as the muffled voices I heard earlier, that the miserable head-ache had successfully shut out for five whole minutes.", "\n\n\"—am flattered you phoned me for an interview. ", "I was quite surprised really,\" a voice, most probably Miss Waterflower's said.", "\n\n\"Should you be, Ms. Waterflower? ", "You are the most esteemed water pokémon gym leader in the world,\" came the shameless flattery from an alien feminine voice, disturbingly high pitched, \"Of course you must be part of my research.\"", "\n\nI glanced with disdain at the closed door behind the doorway I came in from earlier, I wondered about the identity of the stranger. ", "A journalist from a local newspaper or a magazine perhaps? ", "An overly enthusiastic water pokémon trainer? ", "An aspiring to-be gym leader? ", "An obsessive fan? ", "I took another dry bite at my bread and listened on.", "\n\n\"What degree are you studying for again, Cassy?\"", "\n\n\"Master in marine biology.\"", "\n\nAh, so a student researching for her thesis then. ", "I nodded thoughtfully, recalling the interviews I have conducted for my own thesis during my days in university. ", "I have fond memories of university, a playground for educated hypothesis and free thoughts. ", "A place where at least some people would recognize me for my own work and not what my grandfather did. ", "A pity I had to do most of my degree through correspondence because of my gym responsibilities and freelance researching.", "\n\n\"I suppose I should start with a general question. ", "What is your favorite water pokémon and why?\"", "\n\n\"I love all water pokémon, of course, but I have a certain weakness for Tentacruels. ", "Not only are they strong, but the jewels on their heads are just very pretty.\"", "\n\nI almost gagged out loud. ", "Tentacruel of all things? ", "Pretty? ", "I stuck my tongue out at the thought. ", "I have always considered beautiful Tentacruel as an oxymoron. ", "I can understand why so many girls squeal at the sight of an Azumarill, Marill, or Azurill. ", "I can even understand why May loves the juvenile forms of water pokémon like Horsea, Mudkip and Wooper. ", "Those creatures are bubbly and cute. ", "They are huggable. ", "But Tentacruel? ", "Nor can I say Tentacruels are all that strong. ", "They are not especially weak, of course, being a mature form of a duo typed pokemon, but I would rather have a Gyarado or Dewgong on my team any day and I am not even trying to name the strongest water pokémon here.", "\n\nCassy laughed, alas a slightly nervous laugh. ", "Even she did not know what to make of the answer. \"", "I suppose Tentacruels do have their own kind of beauty…\" she said slowly and quickly steered the conversation away from the said monster, \"From your vast experience with water pokémon, which is the most memorable, extraordinary, unique, so to speak?\"", "\n\n\"All 380 odd pokémons,\" 386 to be exact – I noted in my mind. \"…", "are unique in their own ways. ", "The 63 water pokémon,\" 64 – I corrected silently. \"...", "in the world are no different. ", "Even pokémon of the same species are never the same. ", "But I think by far the most memorable water pokémon I have encountered is Suicune.\" ", "Ah… Suicune, I have seen a Suicune once, a rather magnificent, beautiful creature…\n\nThe phone rang. ", "Once, twice, three times. ", "No one picked up. ", "Blaine must be out. ", "At the forth ring I grudgingly gave in and picked up the phone. \"", "Hello, Blaine's residence speaking.\"", "\n\n\" Gary!\" ", "the voice at the other end sounded like he just met God. ", "To my horror, I recognized the voice as that of my lab supervisor, Steven.", "\n\n\"Steven!\" ", "I mimicked his excitement, less than please. ", "Honestly! ", "One cannot have time off even during vacation these days.", "\n\nA strained laugher. ", "I blenched, Steven, usually a calm and stoic man, would never laugh so nervously unless something went dreadfully wrong to the atomic level. ", "I prayed to God I was wrong. \"", "Timothy,\" he laughed that nervous laugh again, \"you know, that new assistant I hired—\"\n\n\"The one I hired only because he was your nephew?\" ", "I interrupted pointedly.", "\n\n\"Er… Yeah him... He just blew up something big.\"", "\n\nI bit my lips. \"", "How big?\"", "\n\n\"A back up water-pump.\"", "\n\n\"WHAT?\" ", "I practically screamed. ", "Hearing fearful whimper at the other end, I froze and closed my eyes. ", "Calm down, Gary, nothing can be solved if you scream at the panicking Steven. ", "Don't shoot the messenger. ", "Breath in in in out. ", "Breath in in in out…\n\nA minute of silence later, I finally spoke with a respectable amount of composure. \"", "Which one, Steven, and can it be fixed?\"", "\n\n\"The one responsible for the north end and no, it is a total lost.\" ", "Steven squeaked out.", "\n\n\"Alright,\" I said slowly, trying to remember what the insurance on my lab covered. \"", "Steven how did this happen?\"", "\n\n\"Timothy smoked in the non-smoking area and –\" he broke off, anxiety laced his voice, \"Oh I am sorry Mr. Oak, please don't fire me, you know I need this job a lot, and you have absolutely no idea how much it means to me and my family and—\" He was completely babbling.", "\n\n\"Steven, calm down. ", "You are not going to be fired, but Timothy has to go.\" ", "That affectively quieted him down and gave me the silence I needed to think. ", "If I remember correctly, my insurance only covers flood, mechanical failures, and pokemon related accidents, meaning this man-made accident would most likely not be covered. ", "I rubbed my temple gingerly. ", "The circumstance was definitely against me. ", "A new water pump of that size would cost about a hundred fifty thousand. ", "My emergency funding can offset half of that. ", "This leaves about eighty thousand unaccounted for.", "\n\nMy mind churned for possible solutions but found none completely to my liking. ", "Finally I gave up and sighed. \"", "Set up a meeting with the Dean of Science at Burkely for me, Steven.\"", "\n\n\"But that would mean--\"\n\nI cut him off irritably, \"I know what that means, Steven, but desperate time calls for desperate measures. ", "Even if we empty our emergency account, we still won't have enough to cover the pump. ", "We would have to prospone phase four of the research by at least a year if we are to earn the funding ourselves. ", "I rather publish my research through Burkely than delay any of part of the research plans for that long.\" ", "I paused to let my words sink in.", "\n\nSteven took a deep breath. \"", "I am sorry,\" he repeated in a low voice.", "\n\nI ran my fingers through my hair. \"", "It's not your fault,\" I pointed out, knowing blmaing him would not help the situation. \"", "Besides, it's not that bad,\" I added, more to convince myself than the lab supervisor, \"Burkely is a respectable univeristy and I have heard they have one of the least intrusive policy regarding external researches.\"", "\n\nI repeated a list of procedures to take seven times before I hung up. ", "The phone call left me in a rotten mood and even more horrible headache, in an effort to clear my mind I decided to head to my room and ready myself for a walk. ", "My mind, as full and heavy as lead, only led me out of the kitchen before betraying me completely. ", "In a moment of thoughtlessness, I confused the door to the living room with the door to the guest room: a fatal mistake.", "\n\nThe door edged opens soundlessly, a perfect imitation of a swinging door at the climax of a movie. ", "The two occupants of the room instantly froze. ", "For a moment they stared at me and I at them.", "\n\nMiss Waterflower maintained her unreadable stare and said nothing. ", "The stranger Cassy, a brunette in somewhat immodest clothing, corrected with an impish grin, \"Good afternoon, mister, it is past twelve.\"", "\n\nI glanced at the wall clock above the fifty two inch television and found, my eyes wide in disbelieve, that it was almost one. ", "That would mean I woke up at almost twelve, and that would mean I slept almost thirteen hours as oppose to my usual five. ", "I must have really over drunk myself. \"", "Forgive me. ", "I am still half asleep.\"", "\n\n\"I am really sorry about last night,\" I apologized genuinely, recalling the less than pleasant circumstances in which we met yesterday night as I added, \"Tell me how much your shirt cost. ", "I will pay for it.\"", "\n\nMisty snorted, \"You can't buy everything, Gary Oak, that was a very special shirt and no amount of your dirty money can replace it.\"", "\n\nI flinched at the accusation. ", "I did not expect her to bring up such an uneasy topic in front of a guest. \"", "Miss Waterflower, let's discuss this later,\" I eyed Cassy the student to ensure she understood my concern, \"I don't want to keep this Miss waiting.\"", "\n\n\"Do you mind, Cassy?\" ", "The edge in Misty's voice left the woman no choice but to shake her head.", "\n\nMy eyes narrowed. ", "She had every right to be angry, but that did not give her the right to humiliate me in front of a stranger. \"", "I am very sorry about what happened last night, Miss Waterflower, but I couldn't stop the force of nature when I am drunk.\"", "\n\n\"You call throwing up all over me natural?\"", "\n\nI rolled my eyes in exasperation. \"", "You know that was not what I meant and I said sorry!\"", "\n\n\"Sorry just doesn't cut it.\" ", "She glared.", "\n\nI glared back. ", "She was not the one who had to worry about gathering over a hundred thousand to replace water pump that an idiot blew up admist a throbbing headache. ", "I felt my temper rising dangerously, but not wanting to say anything I may seriously regret later, I decided to ignore her and march out of the room.", "\n\nUnfortunately, I got no farther than a step out of the living room before Misty caught up and blocked my way. \"", "What do you want, Waterflower?\"", "\n\n\"Oh? ", "No more 'Miss Waterflower' and fake civility?\"", "\n\n\"Believe me, civility is far too much of a hassle to fake for anyone let alone for the undeserving.\" ", "I sneered privately at the sight of her flaming eyes.", "\n\nShocked at the sudden address, alas formal address, my mouth remained opened agape while Misty Waterflower looked at me like I grew a second head before suddenly bursting out in laughter. \"", "You must be mistaken, Gary Oak is no doctor.\"", "\n\n\"Yes I am,\" I corrected coolly, secretly offended and hurt, \"I have a doctoral degree in pokémon genetics.\" ", "Knowledge has always been one of my prides. ", "Her comment was a direct attack on my self-esteem and any sort of attack on my ego, even those unintentional, could not be forgiven without retaliation. \"", "This reminds me,\" I spoke, my mouth curling into a smirk, \"just so you know, there are 64 water pokémon discovered so far, not 63 as you said, Great Water Pokémon Expert Misty Waterflower.\"", "\n\n\"You!\" ", "Misty Waterflower's face made me think of ripe tomatoes and autumn fire. ", "She was angry. ", "No, she was furious. ", "I felt strangely accomplished.", "\n\n\"The truth hurts, doesn't it? ", "Everyone calls you the Great Water Pokémon Expert and yet 'stupid jerk' me actually has to correct you on the number of water pokémon discovered in the world. ", "Disappointing, don't you think?\" ", "Those were not the kindest of words, but one with injured pride cared little for the feelings of the injurer. ", "My thoughts traveled in a rather straight forward and immature line: she humiliated me and I want to humiliate her back – an eye for an eye, a foot for a foot.", "\n\n\"You are such a—\"\n\nI pointedly ignored Misty Waterflower and turned to Cassy with a wide smile and an extended hand. \"", "Hello, nice to meet you, I am Gary Oak.\"", "\n\n\"I am Cassy White,\" she introduced herself enthusiastically, her old interest in Misty Waterflower cruelly forgotten, \"My professor, Doctor Andrea Lawlor, calls you one of the most talented researchers in the world! ", "I am so honored to see you in person.\"", "\n\nThe name of one of my all time favorite mentors, Doctor Lawlor, lifted my mood. \"", "Doctor Lawlor tends to grossly exaggerate praises. ", "She still specializes in marine life form genetics I heard?\"", "\n\n\"Yeah she still does. ", "But I don't think she exaggerated anything. ", "She showed us your thesis on Kyogre the first week of class and it was absolutely brilliant.\"", "\n\nI grinned at her compliments. ", "They sounded especially nice after everything Misty Waterflower said. \"", "Kyogre, the 64th water pokémon,\" I added with a glance at the Cerulean gym leader, who, if possible, looked more infuriated than even before, \"is indeed one of nature's great wonders.\"", "\n\n\"It is indeed,\" chipped Cassy, completely oblivious to, or at least chose to completely ignore, the stifling tension in the air. ", "Entirely unaware of anything outside of direct interest is a common trait among scientists after all, I suppose, afore all other roles Cassy is a scholar in biology.", "\n\nFrom the far corner of my eyes I saw Misty Waterflower stomped away after giving me one last lethal glare. ", "I did not turn to watch her leave. ", "Next to me, I vaguely registered Cassy speaking. \"", "You are much younger than I ever imagined…\" she blundered before her voice faded into the background. ", "My senses were so well tuned to Misty Waterflower's every movement that I felt and heard, even though I could not see, her walked out of the room, down the hall way, through the reception room and out the door with an angry slam.", "\n\nSo much for our first real conversation, I lamented as I turned my attention back to Cassy, suddenly regretting everything I have said. ", "I could only imagine her opinion of me after this episode.", "\n\nMy heart quivered.", "\n\nHow odd, I thought, that a man could fear losing what he could not even identify.", "\n\nWhen Cassy left at around two thirty, Blaine has yet return home and the magnitude of my still throbbing headache overrode my lurking hunger. ", "After taking yet another Tylenol, I headed to Blaine's study with a cup of hot Earl Gray. ", "The study has always been my favorite room in Blaine's house for its excellent view and the library, my library, all the old books I inherited from my parents and the new books I added on my own. ", "When I first moved out of my grandfather's house I spent almost ten percent of my wages on storage space for my books, a rather heavy financial burden, and the dire price for being stubborn. ", "Some may think my break from my grandfather illogical, of course it was, but like I mentioned before angry people don't make the wisest decisions and once I moved out my pride kept me from moving back in.", "\n\nBlaine has never been much of a reader but he has a spacious house and upon mentioning my hefty storage fees one day, he generously offered free space for my books. ", "I gradually transferred most of the books away when I acquired the gym and later on an apartment, but still a fair number of them remained on the forged vintage bookshelves in his study for my own enjoyment when I visit. ", "Blaine did not mind at all, he never read any of them but he considers those books home decor, after all, bookshelves full of well preserved hard cover books look rather impressive in any studies.", "\n\nI pulled out a small notebook containing a directory of the books on the shelves from the bottom draw of the desk. ", "I ran my finger down the list until I reached a title without a check mark: The Strange Case of Dr. Jekkyll and Mr. Hyde. ", "I took my pen out of my shirt pocket and marked the title with a new check before putting the notebook away again. ", "Then, standing up, I walked up to the bookshelves and found the said book, one of my parents', under the \"S\" section. ", "A few years ago I have anally reorganized my books by alphabetical order.", "\n\nSo, at three o'clock sharp I settled down in the comfortable leather sofa facing the bookshelves and began to reread the book. \"", "Mr. Utterson, the lawyer, was a man of a rugged countenance, that was never lighted by a smile; cold, scanty and embarrassed in discourse…\"\n\nI was just about to read the last chapter of the book when Blaine called me down to dinner at six-thirty. ", "The first clause of our mutually beneficial deal: he cooks and I wash dishes when ever I visit him or he visits me. ", "Living alone for the last five years have taught me to cook decently but knowing how to cook does not equate to wanting to cook. ", "In truth, I am usually too lazy to cook any more than one meal a day – a rather unhealthy habit but one that I cannot break despite Blaine's constant nagging.", "\n\nI marked my page with a bookmark and I walked down stairs with the book in hand in case Blaine called me down early as he does whenever he wants company. ", "In such a case I would be sitting across the counter from him in silence because Blaine never talks when he cooks. ", "Or so I thought.", "\n\nI first heard their laughter when I reached the bottom of the stairs. ", "I have never heard Blaine laughed quite like that. ", "With me, he often gives throaty, deep laughs, genuine but somewhat restrained, always held back. ", "But there and then his laughter contained an unreserved lightness that I never knew he processed. ", "I sometimes wonder how many single serving friends thirty years of gym leading on a remote tourist island brought to Blaine. ", "I often thought how lonely it must be for Blaine to be one of the few constants in the midst of an ever flowing river of people. ", "How comforting it was to know he has a friend that can make him laugh like that! ", "Unwilling to break the moment, I stood next to the door out of sight, simply listening and being glad.", "\n\nWhen their bantering finally died down, I let myself into the kitchen. \"", "Dinner smells good,\" I complemented, letting my presence be known.", "\n\nBlaine, still chuckling from the last joke turned and in a mismatching I-told-you-so tone he lectured, \"Enjoying your hangover?\" ", "He placed a meaningful glance at the bottle of Tylenol I left on the counter, \"Didn't you say you know your limits?\"", "\n\n\"Shut up, Blaine,\" I tried my best to ignore the unnatural stiffness of Miss Waterflower's back up on my entrance. \"", "Of course I revel in hangovers.\"", "\n\nThe exchange died with Blaine's throaty chuckle. ", "I at once began to regret walking into the room, but knowing nothing could change past deeds, I sat down on one of the kitchen stools behind the counter and reopened my book. ", "I intended to finish reading the novel but I could barely take in a word before my eyes found their way to Miss Waterflower and Blaine, the former tossing a salad and the latter stirring a pot of soup. ", "Eventually I gave up, closed the book, and attempted to start a conversation, \"What's for dinner?\" ", "I mentally slapped myself for the lame question.", "\n\nMiss Waterflower continued with her silent treatment but Blaine responded quite willingly, \"Clam chowder for soup, lamb rib with garlic bread and greens for our main course, and chocolate mousse cake for dessert,\" here my stomach gave an appropriate grumble. ", "Blaine gave a knowing smile, \"You didn't eat lunch, did you?\"", "\n\n\"It was too much of a headache,\" I returned, pun intended.", "\n\n\"Or you are too lazy,\" he accused rather bluntly. ", "I shrugged, sheepish smile glazed over my face. \"", "Did you even eat breakfast?\"", "\n\n\"I had a piece of white bread at twelve something.\"", "\n\nBlaine slapped his forehead with his hand. \"", "Good lord, you really don't take care of yourself well enough. ", "Good thing I cooked a big meal today.\"", "\n\nMiss Waterflower snorted, turned to Blaine with a look of utter horror, and finally joined the chitchat. \"", "You just realized, Blaine? ", "Anyone who would drink himself as drunk as he did does not care for health.\"", "\n\nBlaine laughed in good humor before the atmosphere could grow heavy, \"You really did see the kid at his worst didn't you?\" ", "He lifted the pot off the stove and turned off the gas. ", "Then, he walked toward me with his hands on his waist in a most mediator-like manner, \"Did you apologize, Gary?\"", "\n\nI sulked indignantly, \"I did already.\"", "\n\n\"Good.\" ", "He turned back to Miss Waterflower in a melodramatic way that made Misty giggle, \"Don't be too harsh on that kid, Misty,\" he pleaded with a bow, \"That boy was just having a bad day, I promise he is usually a lot more agreeable and intelligent than last night.\" ", "Subsequently, he elbowed me on the stomach in a not-so-subtle fashion.", "\n\nI glared at Blaine as I nursing my stomach and my back with gentle fingers but decided to take the opportunity to make amends anyway, \"I am sorry, Miss Waterflower.\" ", "It was the more sophisticated way of dealing with the situation especially when I have to coexist comfortably with her in the same house for a few more days.", "\n\nMiss Waterflower half heartedly turned back to the salad, for a few moments clearly in deep contemplation. \"", "I am sorry too, Gary, I spoke unfairly this afternoon.\"", "\n\n\"Good! ", "Now that stupid tension is gone we can start dinner!\" ", "Blaine announced with a clap of his hand.", "\n\nWe all grinned and set the table together. ", "I took care of the utensils, Blaine went down to the basement for wine, and Miss Waterflower brought the food to the table. ", "Everything seemed well again, we let our guards down, perhaps we should not have. ", "Storms brew under sunny skies, but who would anticipate a storm in perfect weather? ", "Who would expect what happened after this calm before the storm?", "\n\nI was getting the cutleries when I suddenly remembered about the book I have left on the counter unattended, begging for an accident. ", "I instantly swirled around, intending to quickly bring the book back up to the study, but I turned too late. ", "The book was already in danger: Miss Waterflower's wet fingers hovered only one inch away. ", "I reacted badly. \"", "Don't touch that!\"", "\n\nAt once Miss Waterflower's reaching hand retreated, confusion clear in her eyes. \"", "I just want to look at it,\" she hastily explained before her stubborn fingers advanced for the book a second time.", "\n\nKnives and forks forgotten, I strode to her just in time to snatch her hand away before any lasting damage occur. \"", "Looking does not involve hands, Miss Waterflower,\" I reprimanded, my voice harsh, my eyes narrow, \"When I said don't touch the book, I meant don't touch the book.\"", "\n\n\"It's not like I would have ruined it!\" ", "she exclaimed, her temper flared and she twisted her wrist out of my grip.", "\n\n\"Yes you would have,\" I corrected in a dry voice, \"your fingers are wet.\"", "\n\n\"My fingers are not wet enough to ruin any book,\" she insisted after one look at her fingers. \"", "What's your problem? ", "That's not even your book. ", "I saw it in Blaine's study a few days ago.\" ", "I opened my mouth to explain but she rambled on, \"Just because I forgave you for yesterday doesn't mean you can just be an unreasonable ass, you know.\" ", "She grabbed the book with lightning speed and before I could stop myself I let out an unmanly pained gasp.", "\n\n\"Give it back!\" ", "I demanded, reaching for the book.", "\n\nShe held the book up high: a challenge. \"", "No.\"", "\n\n\"Give it back!\" ", "I tried to grab the book again just to find her move the book away. ", "For some time we fought for the book, somewhat childishly as I later reflected, until finally she hid the book behind her back.", "\n\n\"NO!\"", "\n\nI scowled but withstood my temptation to reach for the book in front of her lest she wanted an excuse to call me a pervert on top of unreasonable ass and egotistic jerk.", "\n\nClosing my eyes, and after breathing deeply, I tried a more diplomatic approach, \"Miss Waterflower, please.\"", "\n\n\"Again, your fake civility!\"", "\n\nI could not believe Misty Waterflower and her twisted logic. \"", "You only think I faked my civility because you have none yourself! ", "Now for the last time, please give me the book Miss Waterflower.\" ", "She dashed around me but I was faster and I grabbed her wrist before she could escape. \"", "Are you deaf?\"", "\n\nShe shot me a glare and tried to pull her arm free but I tightened my grip and reached for the book with my other hand. ", "I would have gotten it too if not for what she did next.", "\n\nShe threw the book: an unforgivable act.", "\n\nI screamed a soundless scream as the book soar into the air in one smooth arc right into the sink. ", "I ran over to where the book landed only to verify what I already knew: the book was ruined.", "\n\n\"You guys are in luck! ", "I found a 1970 bottle… Hey, what's wrong? ", "Gary?\" ", "I turned, slowly, deliberately, to face Blaine. ", "He instantly noticed the wet book in my shaky hand. \"", "Oh Lord…\"\n\nNext to me, Misty Waterflower made a frantic apology, undeniably shaken, \" Blaine, I am sorry!\"", "\n\n\"Misty, what did you do?\" ", "Blaine asked in a melancholic whisper.", "\n\n\"I was fighting with Gary over your book and… and I accidentally dropped the book into the sink, I am really sorry.\"", "\n\nBlaine shook his head once. \"", "You really should not be apologizing to me,\" he muttered, wiping his face with his hand, \"That book is not mine.\"", "\n\n\"I hope, with that in mind, I am not as 'unreasonable' as you said, Misty Waterflower?\" ", "I questioned, my voice soft and eerily calm. ", "Misty Waterflower covered her mouth and for once in her life stayed silent at the right moment. \"", "You know best whether or not that was an accident. ", "You wanted revenge for the shirt? ", "You've got it. ", "A book for a shirt. ", "You win. ", "Excuse me,\" I gave a short nod to Blaine and made my way to the door.", "\n\nWhen I was young, before I took my first research project or considered science as a career, before I gain and lost my place as the pokémon master, before I watched Lance battle on television or met Ash, before I moved in with my grandfather, before I learned to hold back my tears, before I had any reasons to cry, before that one accident, my mother and father took turns reading to me at my bed side.", "\n\nOn Monday, Wednesday, Friday, and every other Sunday father read me articles from the Times as well as chapters of his novel of the month that always revolved around politics and intrigues. ", "I did not truly understand what he read, those passages were not written for children, but I loved the sound of his voice, a strange mix of knowledge, authority and gentleness. ", "I used to interrupt him with questions every time he hit a long word or abstract concept and he used to patiently give answers. ", "At a young age I knew words like pacifism, dystopian, totalitarianism, and liberalist. ", "I used to throw these large words around at school. ", "When a teacher tried to force me into a game of cop and robber, a game I hated with a passion, I would say, \"Sorry, I can't play because that's against my beliefs as a pacifist.\" ", "When I saw the schools geeks getting cornered by the school bullies I would say, \"You autocrats should stop terrorizing him.\" ", "By the miraculous the power of popularity I got away with all those lines, people liked me back then.", "\n\nOn Tuesday, Thursday, Saturday, and every other Sunday mother told me ancient myths and read me chapters from her novel of the week that always revolved around gods, princes, and dragons. ", "I did not truly understand what she read, she liked reading the unabridged versions of books way beyond my comprehension level but I loved the sound of her voice, so melodic, smooth, and exquisite like the finest Persian silk. ", "She did not like being interrupted when she read so she made me write down the words I did not understand and wait till she was finished to check those words in the dictionary. ", "At a young age I heard about twenty chapters from Lord of the Rings, random chapters from Le Morte D'Arthur, a few from Odyssey, and many other chapters from a long list of classics. ", "From her I learned about characters like Zeus, Isis, Morgan le Fay, and the three Fates. ", "I used to allude to them with lines like, \"Tragic like Oedipus?\" ", "or \"He is plain stupid, if you are going to nasty then you should at least have a brain like Loki.\" ", "I liked demonstrating my knowledge, proving to the world that I knew more than other average elementary school students.", "\n\nThen one night I found my bed-side empty and my room in a perfect dreadful silence.", "\n\nThat night Doctor Faustus and the Cat's Cradle, the two books my parents were reading, lied motionless on the shelves filled with books. ", "That night I drifted into fitful sleep.", "\n\nThe next afternoon I found myself, a seven and a bit year old boy, at the front door of a foreign house, a solemn, unfamiliar man, my grandfather, awaiting behind the door.", "\n\nBlaine has a habit of talking to his fish when he thinks no one can hear. \"", "Come on, little one, swim up there for some, don't let fatty – that's the way! ", "There's one more---\"\n\nI interrupted him with a cough. ", "I find that habit extremely depressing because of my preconception that only lonely old men talk to gold fish. ", "I never thought it my place to comment on how sad I find his conversations with fish but I always stop him when I do see him at it.", "\n\n\"Ah Gary,\" He swirled around at my voice. \"", "You are leaving now?\"", "\n\nHe always knows without me speaking, I snorted in private amusement, \"Your sixth sense told you?\" ", "I meant that as a joke so I laughed.", "\n\nHe did not laugh with me. \"", "No, just your bags,\" he spoke, his lips tilted into a light smirk.", "\n\nI shook my head and looked away, the saying 'parting is such sweet sorrow' swam in my mind. ", "Then, I remembered Miss Waterflower will keep him company after I leave and the knowledge lent me comfort. \"", "I just need to get away for a bit, there's an emergency in the lab.\" ", "It was not a lie. ", "An exploded water pump is definately considered an emergency.", "\n\n\"I hope that goes well,\" he responded in a deceptively kind tone but his eyes gave away his true feelings: he did not believe me at all.", "\n\n\"Me too.\"", "\n\n\"Gary, Misty she…\" Blaine started but when words failed him he resorted to a simple earnest, apologetic gaze.", "\n\nI combed my hair with my hand, \"Miss Waterflower keeps seeing me at my worst and I at hers,\" I bowed my head and traced the tiles with my foot, \"Perhaps we are just not meant to be friends.\"", "\n\n\"Don't say that…\"\n\n\"I need to go,\" I interrupted, suddenly feeling desperate to end the conversation, \"The last ferry off the island leaves in forty five minutes.\"", "\n\n\"I won't keep you then,\" Blaine sighed in defeat as he turned back to his goldfish, \"I saved some dinner for you, take the lunch box on the counter with you.\"", "\n\nI thanked him, grabbed the box, and walked into the night. ", "As I walked, alone and quiet, I contemplated on void, loneliness, and the all consuming empty darkness.", "\n\nChapter Three Ends\n\nOri: Well that took a while. ", "I had tons of trouble writing the second half. ", "I sent my first draft to Maia Pen a very long time ago, all the way back in April, you can ask her. ", "In my first draft the chapter was half the current length, but I realized I must end Gary's visit to Blaine's in this chapter for the story to have the same pace as what I have in mind. ", "Thus, I had to write on despite frustration and the temptation to just give up.", "\n\nThis story will be a Gary/Misty story, turmoil and obstacles are food for love.", "\n\nNext chapter, there will be reconciliation, a better explanation to Misty's bias against Gary, May's second appearance, good food, shopping spree, old vendetta, and more!", "\n\nReview if you have time! ", "I would love you if you do!", "\n\nThe author would like to thank you for your continued support. ", "Your review has been posted." ]

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[ "Regulation of biofilm formation and cellular buoyancy through modulating intracellular cyclic di-GMP levels in engineered cyanobacteria.", "\nThe second messenger cyclic dimeric (3'→5') GMP (cyclic di-GMP or c-di-GMP) has been implicated in the transition between motile and sessile lifestyles in bacteria. ", "In this study, we demonstrate that biofilm formation, cellular aggregation or flocculation, and cellular buoyancy are under the control of c-di-GMP in Synechocystis sp. ", "PCC 6803 (Synechocystis) and Fremyella diplosiphon. ", "Synechocystis is a unicellular cyanobacterium and displays lower levels of c-di-GMP; F. diplosiphon is filamentous and displays higher intracellular c-di-GMP levels. ", "We transformed Synechocystis and F. diplosiphon with a plasmid for constitutive expression of genes encoding diguanylate cylase (DGC) and phosphodiesterase (PDE) proteins from Vibrio cholerae or Escherichia coli, respectively. ", "These engineered strains allowed us to modulate intracellular c-di-GMP levels. ", "Biofilm formation and cellular deposition were induced in the DGC-expressing Synechocystis strain which exhibited high intracellular levels of c-di-GMP; whereas strains expressing PDE in Synechocystis and F. diplosiphon to drive low intracellular levels of c-di-GMP exhibited enhanced cellular buoyancy. ", "In addition, the PDE-expressing F. diplosiphon strain showed elevated chlorophyll levels. ", "These results imply roles for coordinating c-di-GMP homeostasis in regulating native cyanobacterial phenotypes. ", "Engineering exogenous DGC or PDE proteins to regulate intracellular c-di-GMP levels represents an effective tool for uncovering cryptic phenotypes or modulating phenotypes in cyanobacteria for practical applications in biotechnology applicable in photobioreactors and in green biotechnologies, such as energy-efficient harvesting of cellular biomass or the treatment of metal-containing wastewaters." ]

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[ "Loyola students receive national scholarships to study abroad\n\nLoyola University New Orleans junior Juli Smith is intrigued by Taiwan’s language and culture and has a special interest in studying Taiwanese Sign Language. ", "Malaika Lucien, also a junior, wants to spend a year studying business and perfecting her French, which she has grown up speaking. ", "Junior Sarah Willey seeks to immerse herself in Rabat, Morocco studying in both French and Arabic. ", "Those hopes will now become reality thanks to three prestigious Benjamin A. Gilman International Scholarships awarded to the Loyola students.", "\n\n\"Many Loyola students are prime candidates to apply for this outstanding award from the U.S. Department of State,\" said Alisa Jackson, study abroad adviser in the Center for International Education at Loyola. \"", "I am thrilled that three of our students were selected for the prestigious honor this year.\"", "\n\nThe Gilman scholarship program offers awards for undergraduate study abroad to students who are receiving Federal Pell Grant funding at a two- or four-year college or university. ", "Since its inception in 2001, more than 16,000 students nationwide have used the Gilman scholarship to study in 142 countries. ", "The program encourages students to choose non-traditional study abroad destinations outside of Western Europe, Australia and New Zealand. ", "The Gilman scholarship program is funded through the International Academic Opportunity Act of 2000 and is sponsored by the Bureau of Educational and Cultural Affairs at the U.S. Department of State.", "\n\nThe three Loyola students were selected from among 860 applicants from 332 colleges and universities across the U.S., Jackson said.", "\n\nSmith, an international business major, was awarded $5,000 to study in Taiwan during the full 2015-16 academic year. ", "She will study at Providence University, through International Student Exchange Program (ISEP). ", "Additionally, she was one of only three students selected to receive the Fund for Education Abroad’s Academic Year Scholarship of $10,000. ", "The mission of the Fund for Education Abroad (FEA) is to increase opportunities for dedicated American students to participate in high-quality, rigorous education abroad programs by reducing financial restrictions through the provision of grants and scholarships.", "\n\nLucien, a finance and political science double major, was also awarded $5,000 to study at the ESCE, a prestigious business school in Paris for the full year. ", "She also hopes to intern at a French company in the spring semester.", "\n\nWilley, a contract major in international development, was awarded $5,000 to study in Morocco through the Council on International Educational Exchange .", "\n\nMore information on the Gilman and FEA Scholarship programs and study abroad is available online." ]

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[ "Flag Springs, Missouri\n\nFlag Springs is an unincorporated community in Andrew County, in the U.S. state of Missouri.", "\n\nHistory\nA post office called Flag Springs was established in 1870, and remained in operation until 1907. ", "The community took its name from a nearby spring noted for the flag irises along its course.", "\n\nReferences\n\nCategory:Unincorporated communities in Andrew County, Missouri\nCategory:Unincorporated communities in Missouri" ]

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[ "Australian-born forward Chris McQueen is the surprise name in England's 20-man squad for the mid-season international against Samoa.", "\n\nCoach Wayne Bennett has handed the 29-year-old Wests Tigers back-rower his first call-up ahead of the one-off Test in Sydney on Saturday May 6.", "\n\nFormer South Sydney and Gold Coast Titans star McQueen's selection is something of a controversial choice having represented Queensland six times in State of Origin but qualifies for England through his father.", "\n\nThe move has echoes of Ben Te'o's call-up to this summer's British and Irish Lions' tour of his native New Zealand.", "\n\nMcQueen was approached to play for England in the 2013 World Cup but rejected it in the hope of winning Origin honours and he went on to play in six consecutive matches for the Maroons from 2013-14 and make a second appearance for an Australian Prime Minister's XIII against Papua New Guinea.", "\n\nMcQueen was the surprise name in Wayne Bennett's 20-man squad (Getty)\n\nThere is also a recall for another Australia-born forward, Chris Heighington, who was last selected under Steve McNamara in 2011, while Wigan loose forward Sean O'Loughlin returns to the squad as captain after missing the 2016 Four Nations tournament through injury.", "\n\nFull squad:" ]

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[ "Q:\n\nJava 5: java.util.concurrent.", "FutureTask - Semantics of cancel() and done()\n\nI am currently hunting a nasty bug in a multi-threaded environment using FutureTasks and Executors. ", "The basic idea is this to have a fixed number of threads execute individual FutureTasks that compute a result that is to be displayed in a a table (never mind the GUI aspect here). ", "\nI have been looking at this for so long, I am beginning to doubt my sanity.", "\nConsider this piece of code:\npublic class MyTask extends FutureTask<Result> {\n private String cellId;\n ...\n protected void done() {\n if (isCancelled()) return;\n try {\n Result r = get(); // should not wait, because we are done\n ... // some processing with r\n sendMessage(cellId, r);\n } catch (ExecutionException e) { // thrown from get\n ... \n } catch (InterruptedException e) { // thrown from get\n ... \n }\n }\n ...\n}\n\nWhen done() is called by an Executor handling an instance of MyTask, I check if I got there, because the task was cancelled. ", "If so, I skip all remaining activities, especially I do not call sendMessage().", "\nThe documentation for FutureTask.done() says:\n\nProtected method invoked when this task transitions to state isDone (whether normally or via cancellation). ", "The default implementation does nothing. ", "Subclasses may override this method to invoke completion callbacks or perform bookkeeping. ", "Note that you can query status inside the implementation of this method to determine whether this task has been cancelled.", "\n (API Reference)\n\nBut what I do not get from the documentation of FutureTask are the semantics while done() is being executed. ", "What if I pass the isCancelled() check at the beginning, but right after that some other thread calls my cancel() method? ", "Will that cause my task to change its mind and reply isCancelled() == true from then on?", "\nIf so, how would I later know if the the message was sent? ", "Looking at isDone() would just tell me that execution of the task was finished, but as isCancelled() were true then as well, I could not know if it got to send the message out in time. ", "\nMaybe this is obvious, but I do not really see it right now.", "\n\nA:\n\nFutureTask#done() is called no more than once for any given instance, and it's only called for one reason -- run() completed either with or without error, or cancel() ran before either of the preceding events occurred. ", "The record of completion by any of these outcomes is latching. ", "The reason a FutureTask completed can't change, regardless of competing events seemingly happening \"at the same time.\"", "\nHence, within FutureTask#done() only one of isCancelled() or isDone() will return true then and forever more. ", "It's difficult to distinguish between isDone() reporting true by way of error or successful completion. ", "You can't override set() or setException(Throwable) decisively, as both delegate to the inner AQS to decide whether the attempt to record a successful yielding of a value or encountering an exception should stick. ", "Overriding either method only lets you know that it was called, but you can't observe the decision made by the base implementation. ", "If either event occurs \"too late\"—say, after cancellation—the attempt to record the value or the exception will be ignored.", "\nStudying the implementation, the only way I see to discern a non-canceled successful outcome from an error is to bite the bullet and call get().", "\n\nA:\n\nFrom the API (emphasis mine):\n\npublic boolean cancel(boolean mayInterruptIfRunning)\nDescription copied from interface: Future\nAttempts to cancel execution of this task. ", "This attempt will fail if the task has already completed, already been cancelled, or could not be cancelled for some other reason.", "\n\nSo FutureTask is working off the assumption that you cannot cancel a task when it has transitioned to the isDone stage.", "\n\nA:\n\nWhy not send the message \"outside\" of the task, based on the outcome of the Future<V> object returned by an ExecutorService? ", "I've used this pattern and it seems to work well: Submit a bunch of Callable<V> tasks through an ExecutorService. ", "Then, for each primary task, submit a secondary task that waits on the Future<V> of the primary task and does some follow-up action (like send a message) only if the Future<V> indicates that the primary task completed successfully. ", "There is no guesswork with this approach. ", "When the call to Future<V>.get() returns, you're guaranteed that the task has reached a terminal state, as long as you don't call the version of get that takes a timeout argument.", "\nIf you take this approach, you should use two separate ExecutorService instances: one for the primary tasks and one for the secondary ones. ", "This is to prevent deadlocks. ", "You don't want secondary tasks to start up and potentially block primary tasks from starting when the thread pool size is limited.", "\nThere's no need to extend FutureTask<V> at all. ", "Just implement your tasks as Callable<V> objects. ", "But if for some reason you want to detect if the task was canceled from within the Callable<V> code, just check the interrupt status of the thread with Thread.interrupted().", "\n\n" ]

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[ "First completed model of 2020 – a Phobos Lieutenant for my Raptors army. ", "This is another model from the Shadowspear box that I’m slowly (but happily!) ", "working my way through. ", "I did a very minor conversion to swap the head with the captain from the same box." ]

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[ "g*2/(-3) a composite number?", "\nTrue\nSuppose -4*b + i = -23, -2*i + 1 = 5*b - 18. ", "Let o(l) = l**3 + 2. ", "Is o(b) a prime number?", "\nTrue\nIs (-108)/(-10) - (-4)/(-5) a prime number?", "\nFalse\nIs 77/2*(-2)/(-1) composite?", "\nTrue\nLet k(d) = -2*d. ", "Let s be k(-5). ", "Suppose 3*h - s = -y + 2*h, -3*y + 2*h = -55. ", "Suppose 2*w - 3*w = -y. ", "Is w composite?", "\nTrue\nSuppose -230 - 505 = -b. ", "Suppose 5*t - 350 - b = 0. ", "Is t prime?", "\nFalse\nLet u = -12 + 14. ", "Let k(t) = 17*t + 1. ", "Is k(u) composite?", "\nTrue\nSuppose -554 = -2*b + 3*d, -5*d + 0*d + 812 = 3*b. ", "Is b prime?", "\nFalse\nLet b(y) = -126*y - 6. ", "Let w be b(-5). ", "Suppose w = 4*j - 1224. ", "Let u = j + -319. ", "Is u a prime number?", "\nFalse\nSuppose 4*y = -m + 307, 6*m - m = -2*y + 1553. ", "Is m a prime number?", "\nTrue\nIs ((-1388)/(-6))/((-40)/(-60)) prime?", "\nTrue\nLet w = -3097 - -4754. ", "Is w prime?", "\nTrue\nLet m = 96 + -137. ", "Let b = -16 - m. Let c = b + -15. ", "Is c composite?", "\nTrue\nLet p = 9 - -60. ", "Suppose -m + 4*i + p = 0, 4*m = i - 0*i + 261. ", "Is m prime?", "\nFalse\nIs (15/30)/((-1)/(-974)) a composite number?", "\nFalse\nSuppose -3 = -4*p + 5. ", "Suppose -293 = -o + 3*m, -p*o - 5*m + 753 = 167. ", "Is o a prime number?", "\nTrue\nIs (-11)/((1/2)/(610/(-20))) a prime number?", "\nFalse\nLet h(a) = a - 2. ", "Let i(l) = -l**2 - l. Let v(p) = -h(p) - i(p). ", "Let r be v(0). ", "Suppose -57 = r*d - 5*d. ", "Is d a prime number?", "\nTrue\nLet v(f) = 2148*f**3 - f**2 + 2*f. ", "Is v(1) prime?", "\nFalse\nLet p(k) = -2 - 3*k**3 + 4*k - 3*k**2 + 4 - 1 + 4*k**3. ", "Is p(6) a prime number?", "\nFalse\nSuppose 0 = z - 2*h - 561, 2*h = -z - 0*z + 553. ", "Is z prime?", "\nTrue\nLet o = -29 + 40. ", "Suppose -3*p = 3*b + 15, o + 6 = -5*b + 3*p. ", "Let n(f) = -9*f - 5. ", "Is n(b) a prime number?", "\nTrue\nLet i(l) = -l**3 + 16*l**2 + 12*l + 4. ", "Is i(9) a composite number?", "\nTrue\nLet q(v) = -v**2 + 5*v**3 - 1 + 6*v**3 + 4*v - 4*v. ", "Let b be ((-6)/(-4))/(6/8). ", "Is q(b) prime?", "\nTrue\nLet i be 0 - (-11)/((-3)/(-3)). ", "Let x = -20 + i. Let c = -2 - x. Is c prime?", "\nTrue\nLet k(f) be the third derivative of -f**4/24 + 13*f**3/6 - 2*f**2. ", "Is k(6) prime?", "\nTrue\nLet v = 20 - 15. ", "Suppose 5*k - v*n = 1045, -k = -6*k - 2*n + 1059. ", "Is k composite?", "\nFalse\nLet u be 10231/7 + (-8)/14. ", "Suppose -4*k + 3*m = k - u, -5*k - 5*m + 1445 = 0. ", "Is k a prime number?", "\nFalse\nLet h(v) = 317*v + 29. ", "Is h(6) a prime number?", "\nTrue\nIs (-2990)/(-3) + (6/(-9) - -1) a composite number?", "\nFalse\nLet l(z) = -z**3 + 4*z**2 - 4. ", "Let k = -7 + 11. ", "Let a be l(k). ", "Let f = a - -23. ", "Is f a composite number?", "\nFalse\nLet q(r) = -3 + 19*r + 4 - 7 + 2. ", "Let i be 2*(-3)/4*-2. ", "Is q(i) a composite number?", "\nFalse\nLet d = 532 - 375. ", "Is d a composite number?", "\nFalse\nLet u(a) = -7*a - 5. ", "Let b be (4 + 0/2)*-2. ", "Is u(b) composite?", "\nTrue\nSuppose r + 3*d = d - 10, 0 = -2*r + 5*d + 16. ", "Is (-3)/r*46/3 a composite number?", "\nFalse\nSuppose -3*o = -4*p - 805, -5*p - 426 = -4*o + 647. ", "Is o composite?", "\nTrue\nLet t be (3 + 0)*32/6. ", "Is (-4)/t + 3354/8 a composite number?", "\nFalse\nLet g(u) = 234*u**2 + 8*u + 3. ", "Is g(-4) a prime number?", "\nFalse\nSuppose 2*w - 3*w = -2, 2*s - 2*w + 28 = 0. ", "Let f = -21 - -34. ", "Let y = f - s. Is y prime?", "\nFalse\nSuppose 2*s + 3*s - 433 = p, -2*p = 5*s - 439. ", "Is (20/(-6))/((-2)/s) a prime number?", "\nFalse\nLet f(g) = 63*g + 14. ", "Let a(m) = 21*m + 5. ", "Let z(o) = 17*a(o) - 6*f(o). ", "Let j be 2/(-1) + 3 + -2. ", "Is z(j) composite?", "\nTrue\nSuppose 0*o + 3*o - 483 = 0. ", "Is o prime?", "\nFalse\nLet n(z) = 1 + 2*z**3 + 8*z + 5*z**2 + 0*z**2 - 15*z**2. ", "Let f(y) = -y**2 + 8*y. ", "Let o be f(7). ", "Is n(o) prime?", "\nFalse\nLet w be 4/(-6) + 143/3. ", "Let u = w - 16. ", "Is u a prime number?", "\nTrue\nLet y = 40 + 1155. ", "Is y prime?", "\nFalse\nLet u be (-24)/108 - (-1012)/18. ", "Suppose 5*m - 3*i = 271, 5*i + 7 = m - u. Is m composite?", "\nFalse\nLet m be ((-1)/4)/((-10)/7960). ", "Suppose -5*d - 281 = -3*u, 2*u = 2*d - 9 + m. Is u composite?", "\nFalse\nIs (1/4)/(2 - 5061/2532) prime?", "\nTrue\nLet s(n) = 4*n + 1. ", "Let m(l) = l**2 - 8*l - 2. ", "Let f be m(6). ", "Let i be (-1)/(2 + f/6). ", "Is s(i) composite?", "\nFalse\nLet k = 1090 - 683. ", "Is k prime?", "\nFalse\nLet p = 3 - 1. ", "Let a be (-5)/10 + (-39)/p. ", "Is (-17)/(-4) + 5/a a prime number?", "\nFalse\nSuppose -407 = -5*p + 308. ", "Is p a prime number?", "\nFalse\nSuppose -2*n - 5*l + 209 = 0, 155 + 320 = 5*n + 3*l. ", "Let x be 1 + (0 - -2) + 1. ", "Suppose -x*u + n = -32. ", "Is u prime?", "\nTrue\nLet c(f) = -93*f - 17. ", "Is c(-6) a prime number?", "\nTrue\nLet y(t) = -13*t**2 + 12. ", "Let l be y(4). ", "Let b = 195 - -128. ", "Let r = l + b. Is r prime?", "\nTrue\nSuppose -14 = -3*q - m, -m = q - 5*m + 17. ", "Suppose 181 = q*o - 59. ", "Suppose 3*i = 2*p + 187, o = -3*i + 5*p + 255. ", "Is i prime?", "\nFalse\nLet i be 8 + (-4 - -2) + -1. ", "Suppose v = -3*x + 25, 3*x - i*x + 3*v = -24. ", "Suppose 4*k + x = 5*k. ", "Is k a composite number?", "\nTrue\nIs (4388/(-16))/(2/(-8)) a composite number?", "\nFalse\nSuppose 0*t = 2*t - 186. ", "Suppose n + 3*r - t = 0, -3*n + 2*r + 2*r = -214. ", "Let j = n - 39. ", "Is j a prime number?", "\nFalse\nLet k(q) = -5*q + 3. ", "Let j = -3 - -1. ", "Let c(x) = 6*x - 2. ", "Let s(b) = j*c(b) - 3*k(b). ", "Is s(4) prime?", "\nTrue\nLet g(r) be the third derivative of 1/24*r**4 - r**2 + 0 + 0*r**3 + 1/12*r**5 + 0*r. ", "Is g(-1) a composite number?", "\nTrue\nLet w(c) = c - 6. ", "Let i be w(9). ", "Suppose i*n - 354 + 117 = 0. ", "Is n prime?", "\nTrue\nSuppose 0*v + 376 = -4*v + c, 0 = v - 5*c + 94. ", "Let j be v/((-1)/(1/2)). ", "Suppose -2*l - 4*x + 63 = -j, -5*l = -4*x - 219. ", "Is l prime?", "\nTrue\nLet n(z) = 3*z**2 - 1. ", "Is n(10) composite?", "\nTrue\nSuppose 0 = 6*o - 4*o - 382. ", "Is o a prime number?", "\nTrue\nIs (948/8)/((-4)/(-8)) composite?", "\nTrue\nLet x(a) = a**3 + 7*a**2 + 5*a + 1. ", "Let f = 11 - 17. ", "Is x(f) composite?", "\nFalse\nLet v be (2*(-1 - -2))/(-2). ", "Let k = 18 - v. Is k prime?", "\nTrue\nLet q(p) = -p**3 - p**2 - p - 2. ", "Is q(-3) prime?", "\nTrue\nLet j = -4 + -11. ", "Let g be j/(-2)*(0 + 2). ", "Suppose -10 = -u + g. Is u composite?", "\nTrue\nLet n(i) = i**3 + 6*i**2 - 24*i - 23. ", "Is n(12) composite?", "\nFalse\nLet c(x) = 3*x + 1. ", "Let n = -31 + 43. ", "Is c(n) prime?", "\nTrue\nLet i(a) be the first derivative of 10*a - 1 + 10/3*a**3 + 1/4*a**4 + 3*a**2. ", "Is i(-9) prime?", "\nTrue\nLet g be 1 + 0 + 0/(-2). ", "Suppose 107 = 3*y - g. Suppose 0 = 7*i - 3*i - y. Is i prime?", "\nFalse\nSuppose 2*r + 0*r + 10 = 0, -3 = 3*j + 3*r. ", "Suppose z = -j*z. ", "Suppose z = -3*h - 20 + 62. ", "Is h composite?", "\nTrue\nSuppose 0 = 2*u - 0*u - 238. ", "Is u prime?", "\nFalse\nLet l(r) = 59*r**2 - 3*r + 5. ", "Is l(-4) a prime number?", "\nFalse\nLet c be (8/20)/((-2)/(-10)). ", "Suppose c*y + 3 = 7. ", "Is y/3*(-159)/(-2) a prime number?", "\nTrue\nSuppose -127 = -4*n + d, 90 = -0*n + 3*n + d. Is n a prime number?", "\nTrue\nSuppose -s - 69 = -3*i + 2*s, -3*i + 4*s + 68 = 0. ", "Suppose 3*q + 0*q - i = -f, 4*f = 3*q - 9. ", "Is q prime?", "\nTrue\nSuppose -2*l = -1 + 3. ", "Is (-1168 - l)*(-2)/6 prime?", "\nTrue\nLet g = -6 - -8. ", "Suppose 1 + g = l. Suppose -2*n = l*n - 955. ", "Is n prime?", "\nTrue\nSuppose 2*g + 25 = 7*g + 2*l, -3*g - 3*l = -24. ", "Suppose -1 = -u - c, 4*u + 3*c - g = 1. ", "Is u*(3 + -5) + 97 composite?", "\nTrue\nSuppose 0 = -0*h - h + 2. ", "Suppose -3*b + 10 = 3*c - 2*c, h*b + c - 6 = 0. ", "Is (-49)/(-2)*(b - 2) a prime number?", "\nFalse\nIs 3 - (0 - 83/1) a composite number?", "\nTrue\nLet n(c) = -32*c - 3. ", "Let h be (4/1)/2 - 4. ", "Let l be n(h). ", "Suppose 4*j = l - 9. ", "Is j a prime number?", "\nTrue\nSuppose 0 = 2*i - 0*i - 6. ", "Suppose 5*f - i*f - 74 = 0. ", "Is f a prime number?", "\nTrue\nSuppose 0 = -4*a + 5*a - 269. ", "Is a a prime number?", "\nTrue\nSuppose 8*l - 12*l + 19088 = 0. ", "Suppose -5*r = -r - l. Is r a composite number?", "\nFalse\nSuppose -3*l + 2*c = -0*c - 18, 2*l + 4*c = 12. ", "Let d(s) = 7*s - 9. ", "Is d(l) a prime number?", "\nFalse\nSuppose -36 = 2*m + 2*h, 0 = -m - 0*m + 4*h - 28. ", "Let s = m + 33. ", "Is s a prime number?", "\nTrue\nLet s(x) = 2*x**2 + 15*x + 9. ", "Is s(-10) a prime number?", "\nTrue\nSuppose 0*x - x = -5*t - 46, 74 = 2*x - 4*t. ", "Is x a prime number?", "\nTrue\nLet d(n) = -n**3 + 12*n**2 - 5*n + 3. ", "Let q be (22/(-8))/((-3)/12). ", "Is d(q) a prime number?", "\nFalse\nLet u = -343 + 560. ", "Is u a prime number?", "\nFalse\nLet j(o) = -o**2 - 7*o + 1. ", "Let p = -16 + 10. ", "Let c be j(p). ", "Is (c - 0) + (-2)/2 prime?", "\nFalse\nLet w be 30*1 - (4 + -6). ", "Let k = -18 + w. Is k a prime number?", "\nFalse\nLet i(x) = 4 - 4*x**2 + 0*x + 3*x + 3*x**2. ", "Let y be i(3). ", "Suppose -4*n = -3*v + y*v - 17, -14 = 2*n - 4*v. ", "Is n a prime number?", "\nTrue\nSuppose 0 = 6*t - 2*t - 2392. ", "Suppose 0 = -5*l + 5*s + 1000, -3*l + 6*l - s - t = 0. ", "Is l a prime number?", "\nTrue\nSuppose i + 2*o + 8 = 0, 0 = 3*i - i + 5*o + 21. ", "Suppose i*r - 96 = 62. ", "Is r a prime number?", "\nTrue\nLet u(c) = 6*c**2 + 8*c - 14. ", "Let v(d) = -5*d**2 - 7*d + 13. ", "Let i(z) = -4*u(z) - 5*v(z). ", "Suppose -h - 5*g = 27, 7*g = -3*h + 5*g - 29." ]

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[ "Psychological conditions diagnosed among veterans seeking Department of Defense Care for Gulf War-related health concerns.", "\nThe Comprehensive Clinical Evaluation Program is a US military program that provides a voluntary, clinically oriented evaluation for Gulf War health concerns. ", "This article presents administrative data on psychological conditions (as coded using the International Classification of Diseases, 9th Revision) from the first year of the program. ", "The most commonly diagnosed psychological conditions were medically unexplained physical-symptom syndromes; depression and anxiety, including post-traumatic stress disorder; and alcohol abuse or dependence. ", "Psychological conditions were significantly related to a higher number of workdays lost, and the 19% of veterans with a primary diagnosis of a psychological condition reported 28% of the lost workdays among veteran who participated. ", "Stressful Gulf War experiences were weakly but significantly related to psychological conditions. ", "We conclude that among Gulf War veterans seeking evaluation for Gulf War-related health concerns, psychological conditions are common and are associated with important occupational morbidity." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Forty years after its debut, the whole designated hitter thing is no less odd than it was when Ron Blomberg drew a bases-loaded walk off Luis Tiant in the first plate appearance by a DH on April 6, 1973.", "\n\nOdd because David Ortiz, the last great designated hitter, will play first base when the World Series shifts to St. Louis after the first two games in Boston.", "\n\nOdd because Allen Craig, who missed St. Louis' first two rounds of the playoffs with a foot injury, will DH for the Cardinals despite being a DH just twice in his career.", "\n\nTo DH or not to DH has been debated for as long as owners thought about keeping pitchers out of batters' boxes, and every October the debate takes on a different angle because nobody quite knows what to do in the World Series.", "\n\nThe current World Series setup - DH in American League parks, not National League parks - began in 1986. ", "From 1976 to 1985, it was used in all World Series games in even-numbered years - talk about odd.", "\n\nHideki Matsui had the most relevant World Series for a DH, winning MVP honors in 2009 despite starting three of six games for the Yankees. ", "The most irrelevant? ", "A case can be made for the Giants' three DHs in 2002, if only because all batted ninth.", "\n\nIt's the time of year when NL managers must invent DHs from their bench players and AL managers must make sure their pitchers reintroduce themselves to the bat rack. ", "It's not the norm from the regular season, but everyone must live with it.", "\n\nUniformity is better, but neither league is ready to budge, especially the AL, if only because the players' union wouldn't let go of the DH. ", "The pressure is beginning to mount for NL teams to consider a change now that season-long interleague play is here, but nothing's in the works.", "\n\nFor now, Ortiz is taking grounders and Craig is taking hacks. ", "We'll have two quality DHs for Games 1, 2 and, if necessary, 6 and 7, but iffy propositions in other games with Ortiz fielding (six starts at first during the season) and Boston pitchers hitting (1-for-26).", "\n\nThe World Series is baseball's biggest stage, yet two sets of rules apply. ", "It's odd, but that's nothing new." ]

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[ "Franklin MLB PHILLIES Kids Team Baseball Set Uniform. ", "The Franklin Sports MLB Kid's Team set will make any aspiring athlete feel like a part of their favorite team! ", "Complete with a team jersey, team wristbands and team helmet, this set is perfect for dress-up or a day in the park!", "\n\nTestimonials:\n\nL. FOSTER (PA)\n\n\"Omg what can I said. ", "I love it. ", "I love the prompt and courtesy service.", "And the quality is outstanding. ", "You have got a happy new customer for life.\" (", "E60969)\n\nS. SCHNEIDER (NC)\n\n\"This is the first year our private school has a cheer and dance team. ", "We needed uniforms and since they have a boy (Me) on the team we wanted to find something that we could all wear and look the same.", "\nThese shorts are fantastic and wear really well. ", "They also a really really good with E16436, which is a cheerleader football T-shirt. ", "We got red and white shorts with white and red T-shirts and socks and it looks totally fab. ", "And being shorts, I really like it. ", "They seem to wash well, but you need to be careful the first time they are washed.", "\n\" (E18344)\n\nProduct Description\n\nFranklin MLB PHILLIES Kids Team Baseball Set Uniform\n\nFeatures:The Franklin Sports MLB Kid's Team set will make any aspiring athlete feel like a part of their favorite team! ", "Complete with a team jersey, team wristbands and team helmet, this set is perfect for dress-up or a day in the park!", "\n\nEach set includes a 100% polyester team jersey, team wristbands and team helmet. ", "Jersey and wristbands are both machine washable.", "\n\nSize: One Size Fits Most - Ages 5-9\n\nNOTE: Team designs and logos subject to changeWARNING: Helmet must not be used as protective equipment in baseball or any other contact sport." ]

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[ "Foodies Read + TBR Pile Challenge | Cooking for Geeks by Jeff Potter\n\nPlease note: This review is for the FIRST edition of this title. ", "There is now a 2nd edition, which incl. ", "an additional 150 pages of new content!", "\n\nThis book includes an interesting combination of super basic recipes (hard boiled eggs, no-knead bread) and complicated or time-intensive recipes (duck confit sugo, 48-hour brisket). ", "The focus in all the recipes, regardless of required skill/interest level, is how the cooking techniques work.", "\n\nFor example, Potter doesn't just tell you that the \"shock and awe\" method of hard boiling eggs produces better-tasting eggs with shells that are easier to peel off; he walks you through the thermal gradient of the egg and what the shock of hot/cold water will do to the insides as well as the shell.", "\n\nThat being said, I have to confess that I have not actually tried any of the recipes in this book yet (no, not even the supposedly super-scientific perfect eggs). ", "I hesitate to \"review\" a cookbook without having tried the recipes, but here's why I went ahead and did it anyway:\n\n1. ", "Cooking for Geeks isn't just a collection of recipes. ", "It includes interviews, lots of tips for beginners, kitchen organization + equipment advice, and all kinds of science-y info on topics like taste, heat conduction methods, and food safety.", "\n\nSince reason number 2 is boring, let's talk some more about reason number 1.", "\n\n- - -\n\nI especially liked the sections on tastes (like bitter, sweet, sour, etc.) ", "and the kitchen organization + equipment info. ", "These are not topics that most \"cookbooks\" delve into but they're still very important to successful cooking. ", "I would recommend this book to beginner cooks, despite some of the more complicated recipes, simply because these sections are so dang helpful.", "\n\nPotter encourages experimentation. ", "There's a lot of \"What happens if we... ?\" ", "and \"Try X, Y, or Z instead and see how it turns out!\" ", "going on here. ", "That's cool with me, but if you're looking for extremely precise or strict recipes (and some people do prefer that!) ", "you'll just want to be aware that this is more of an experiment-friendly book.", "\n\nThe recipes themselves aren't even written in the traditional cooking time | ingredients list | steps | notes kind of way, nor will you find a lot of big glossy photos of pretty dishes. ", "The focus is all on figuring out how stuff works and how you can make it work even better.", "\n\n(That said, I love cookbooks with pretty pictures and would have appreciated some more illustrations/photos. ", "Still, since I was reading this on my Nook + phone, I wouldn't have been able to fully appreciate them anyway!)", "\n\n- - -\n\nAlso, keep in mind that a lot of the \"geek\" references are geared more towards developer/hacker types. ", "Like, if you think of yourself as a geek or nerd or whatever because you read a lot of comics and play tabletop RPGs, cool, let's be friends, but also you might miss out on some of the references meant for the more computer-y species of geek.", "\n\nDespite those geek species-specific references, this book covers a lot of science and techniques that you don't have to know anything about coding to get. ", "I'm saying that with a background in the natural sciences so basic household chemistry doesn't scare me anyway, but I truly think that as long as you have an interest in the subject of kitchen science you'll be able to understand all or most of the topics in this book." ]

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[ "Some Spider-Man fans really want Tobey Maguire to come back\n\nJust to be clear, this is not happening. ", "Not in a million years.", "\n\nHope is a beautiful thing. ", "For Spider-Man fans, hope is what kept them going through the horrors of Spider-Man 3 and its dancing goth Peter Parker, the mediocrity of the Amazing Spider-Man reboot, and Sony‘s endless back-and-forth as they desperately tried to work out what to do with the franchise.", "\n\nThe good news is, all that hoping and waiting has finally paid off. ", "Sony and Marvel have worked out a crossover deal where Spider-Man will appear in the Marvel Cinematic Universe, most likely in Captain America: Civil War. ", "This news inspired a near-religious fervor among Marvel aficionados, many of whom are treating it more like the second coming than what it actually is: a corporate merger.", "\n\nMarvel never needed Sony, Marvel just wanted to give us what us fans have always dreamed of. ", "Because Marvel is love... Marvel is life.", "\n\nAnyway, now that we’ve got that first flush of excitement out of the way, it’s time to get down to the nitty-gritty of baseless casting speculation. ", "And what better place to start than everyone’s first choice of Spider-Man, Tobey Maguire?", "\n\nWhile we are not an oracle imbued with the power to predict Marvel’s decisions, it feels safe to say that they will not be bringing back Tobey Maguire. ", "That is not a thing that will happen in the real world. ", "Although there is one instance in which we could get behind this idea, and that’s a movie where Tobey Maguire plays a middle-aged mentor figure to Miles Morales.", "\n\nhttps://twitter.com/Parkour3012/status/565091738327728128\n\nHowever, that is also not going to happen. ", "The Marvel–Sony agreement makes it slightly more likely that Miles Morales will appear at some point, but unfortunately, we doubt that he’s going to be the lead character.", "\n\nMarvel’s announcement implied that a new actor would be cast, saying “the new Spider-Man will first appear in a Marvel film” before appearing in the next installment of Sony’s franchise. ", "Whether that Sony film will be a sequel or another reboot is unclear, but either way, it won’t star Tobey Maguire.", "\n\nGavia Baker-Whitelaw is a staff writer at the Daily Dot, covering geek culture and fandom. ", "Specializing in sci-fi movies and superheroes, she also appears as a film and TV critic on BBC radio. ", "Elsewhere, she co-hosts the pop culture podcast Overinvested. ", "Follow her on Twitter: @Hello_Tailor" ]

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[ " 9:17 PM and 9:03 AM?", "\n706\nWhat is 103 minutes before 12:21 AM?", "\n10:38 PM\nWhat is 344 minutes after 6:16 AM?", "\n12:00 PM\nWhat is 126 minutes after 6:16 AM?", "\n8:22 AM\nWhat is 153 minutes before 7:23 PM?", "\n4:50 PM\nHow many minutes are there between 4:32 AM and 3:29 PM?", "\n657\nHow many minutes are there between 4:09 PM and 1:26 AM?", "\n557\nWhat is 665 minutes after 1:35 AM?", "\n12:40 PM\nWhat is 607 minutes after 7:52 AM?", "\n5:59 PM\nWhat is 110 minutes after 4:42 AM?", "\n6:32 AM\nHow many minutes are there between 10:40 AM and 12:43 PM?", "\n123\nWhat is 136 minutes after 7:35 PM?", "\n9:51 PM\nWhat is 158 minutes before 2:01 AM?", "\n11:23 PM\nWhat is 405 minutes before 5:42 PM?", "\n10:57 AM\nHow many minutes are there between 1:43 PM and 7:11 PM?", "\n328\nHow many minutes are there between 10:43 AM and 7:07 PM?", "\n504\nHow many minutes are there between 8:06 PM and 5:55 AM?", "\n589\nHow many minutes are there between 10:07 PM and 9:47 AM?", 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7:02 PM?", "\n9:17 AM\nWhat is 98 minutes after 11:16 AM?", "\n12:54 PM\nHow many minutes are there between 9:28 AM and 7:09 PM?", "\n581\nWhat is 300 minutes before 1:58 AM?", "\n8:58 PM\nWhat is 414 minutes after 12:35 PM?", "\n7:29 PM\nWhat is 49 minutes before 9:49 PM?", "\n9:00 PM\nHow many minutes are there between 9:22 PM and 11:54 PM?", "\n152\nHow many minutes are there between 3:50 PM and 5:21 PM?", "\n91\nHow many minutes are there between 2:24 AM and 10:10 AM?", "\n466\nWhat is 549 minutes before 2:44 PM?", "\n5:35 AM\nHow many minutes are there between 4:10 AM and 4:20 AM?", "\n10\nHow many minutes are there between 6:48 AM and 11:08 AM?", "\n260\nHow many minutes are there between 7:31 AM and 2:30 PM?", "\n419\nHow many minutes are there between 5:03 AM and 7:04 AM?", "\n121\nWhat is 203 minutes after 3:43 PM?", "\n7:06 PM\nHow many minutes are there between 1:24 AM and 8:48 AM?", "\n444\nHow many minutes are there between 3:07 PM and 4:07 PM?", "\n60\nWhat is 549 minutes 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700 minutes after 8:58 PM?", "\n8:38 AM\nHow many minutes are there between 6:23 PM and 12:49 AM?", "\n386\nHow many minutes are there between 3:58 AM and 2:22 PM?", "\n624\nHow many minutes are there between 11:46 AM and 7:34 PM?", "\n468\nHow many minutes are there between 4:14 PM and 9:17 PM?", "\n303\nHow many minutes are there between 5:42 PM and 7:24 PM?", "\n102\nWhat is 117 minutes after 8:10 PM?", "\n10:07 PM\nHow many minutes are there between 9:04 AM and 8:31 PM?", "\n687\nWhat is 570 minutes before 7:09 PM?", "\n9:39 AM\nWhat is 231 minutes before 11:44 AM?", "\n7:53 AM\nHow many minutes are there between 9:15 PM and 1:45 AM?", "\n270\nWhat is 505 minutes before 6:53 PM?", "\n10:28 AM\nHow many minutes are there between 10:22 PM and 2:46 AM?", "\n264\nWhat is 559 minutes after 2:22 AM?", "\n11:41 AM\nHow many minutes are there between 5:34 AM and 8:03 AM?", "\n149\nWhat is 186 minutes after 6:42 PM?", "\n9:48 PM\nWhat is 121 minutes before 5:43 PM?", "\n3:42 PM\nWhat is 703 minutes after 7:12 AM?", "\n6:55 PM\nHow many minutes are there between 8:02 AM and 10:41 AM?", "\n159\nWhat is 11 minutes after 2:10 PM?", "\n2:21 PM\nWhat is 597 minutes after 2:51 PM?", "\n12:48 AM\nWhat is 303 minutes after 11:49 PM?", "\n4:52 AM\nHow many minutes are there between 3:32 PM and 6:47 PM?", "\n195\nHow many minutes are there between 2:53 AM and 8:13 AM?", "\n320\nWhat is 662 minutes before 10:09 AM?", "\n11:07 PM\nHow many minutes are there between 4:06 PM and 2:53 AM?", "\n647\nHow many minutes are there between 5:44 PM and 5:34 AM?", "\n710\nWhat is 682 minutes before 4:48 AM?", "\n5:26 PM\nWhat is 610 minutes before 5:21 AM?", "\n7:11 PM\nHow many minutes are there between 7:04 PM and 12:13 AM?", "\n309\nHow many minutes are there between 1:22 AM and 4:44 AM?", "\n202\nWhat is 249 minutes after 11:19 PM?", "\n3:28 AM\nHow many minutes are there between 5:41 PM and 2:04 AM?", "\n503\nHow many minutes are there between 5:17 AM and 8:44 AM?", "\n207\nWhat is 253 minutes before 12:20 AM?", "\n8:07 PM\nHow many minutes are there between 9:14 AM and 11:21 AM?", "\n127\nHow many minutes are there between 4:54 AM and 12:32 PM?", "\n458\nHow many minutes are there between 6:52 AM and 6:23 PM?", "\n691\nHow many minutes are there between 6:40 PM and 11:31 PM?", "\n291\nWhat is 69 minutes before 9:06 PM?", "\n7:57 PM\nWhat is 238 minutes after 2:43 AM?", "\n6:41 AM\nWhat is 681 minutes before 3:51 PM?", "\n4:30 AM\nHow many minutes are there between 7:00 PM and 9:34 PM?", "\n154\nWhat is 549 minutes before 11:44 AM?", "\n2:35 AM\nWhat is 132 minutes after 10:52 AM?", "\n1:04 PM\nWhat is 678 minutes after 1:45 AM?", "\n1:03 PM\nWhat is 454 minutes after 6:49 AM?", "\n2:23 PM\nWhat is 665 minutes after 2:53 PM?", "\n1:58 AM\nWhat is 152 minutes after 7:06 PM?", "\n9:38 PM\nWhat is 700 minutes after 10:56 PM?", "\n10:36 AM\nHow many minutes are there between 6:19 AM and 6:29 AM?", "\n10\nWhat is 410 minutes after 3:24 AM?", "\n10:14 AM\nWhat is 630 minutes after 7:50 PM?", "\n6:20 AM\nWhat is 420 minutes before 7:51 PM?", "\n12:51 PM\nHow many minutes are there between 10:58 AM and 2:29 PM?", "\n211\nWhat is 345 minutes before 5:49 PM?", "\n12:04 PM\nWhat is 660 minutes after 8:25 AM?", "\n7:25 PM\nHow many minutes are there between 11:27 PM and 10:55 AM?", "\n688\nWhat is 631 minutes after 12:57 AM?", "\n11:28 AM\nHow many minutes are there between 3:43 PM and 2:08 AM?", "\n625\nHow many minutes are there between 6:05 AM and 3:53 PM?", "\n588\nWhat is 237 minutes before 2:19 PM?", "\n10:22 AM\nHow many minutes are there between 9:40 AM and 3:04 PM?", "\n324\nHow many minutes are there between 8:29 PM and 8:39 PM?", "\n10\nHow many minutes are there between 11:05 AM and 6:17 PM?", "\n432\nWhat is 191 minutes before 5:08 PM?", "\n1:57 PM\nHow many minutes are there between 4:48 PM and 2:58 AM?", "\n610\nWhat is 596 minutes after 12:10 AM?", "\n10:06 AM\nWhat is 609 minutes after 5:24 AM?", "\n3:33 PM\nWhat is 504 minutes before 11:18 AM?", "\n2:54 AM\nWhat is 332 minutes before 12:12 AM?", "\n6:40 PM\nHow many minutes are there between 7:06 AM and 6:43 PM?", "\n697\nHow many minutes are there between 7:" ]

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[ "Francis I. McKenna\n\nFrancis I. McKenna (February 25, 1859 – February 24, 1914) was a real estate and land developer, and architect from the 1890s to the 1920s in Portland, Oregon. ", "McKenna moved to Portland in 1889 and purchased the land now known as the University Park neighborhood. ", "He went on to establish the Portland Belt Line Company, which lobbied city officials to extend the cable car system to St. Johns, Oregon. ", "The project was constructed in 1905. ", "McKenna was also known as an advocate of civic improvement and industrialization. ", "\n\nBorn to farmers in Illinois, McKenna was orphaned at the age of 12. ", "This forced him to find work in labor, including farming and building railroads. ", "When he turned 18, McKenna had enough formal and informal education to ascertain a job at a rural Ohio public school. ", "Eventually, he was offered a job at Creighton University which he held for two years. ", "McKenna quit his profession and packed up for Oregon in 1889 with his wife Laura and son Coe. ", "North McKenna avenue and McKenna park were named in honor of the University Park developer. ", "His son, Coe, continued the family's real estate legacy.", "\n\nEarly and personal life\nFrancis I. McKenna was born on February 25, 1859 in Perry County, Illinois to William and Charity McKenna (née) Burgoon. ", "The McKenna family originally hailed from Belfast, Ireland. ", "Francis McKenna was educated in public schools from age six to 12 for three to six months a year until his parents died. ", "From there, McKenna was self-taught, taking odd jobs on farms and railroads until at 18 he was hired to educate at a public school in Ohio. ", "Two years later he took a job at Creighton University in Omaha, Nebraska. ", "He walked away from teaching in 1883.", "\n\nMcKenna married Laura Linebaugh in 1884 in Chicago, Illinois. ", "The couple had one child, a son, Coe A. McKenna. ", "Coe McKenna would go on to graduate from George Washington University in 1910.", "\n\nBusiness career\nMcKenna helped organize a Board of Trade amongst Portland's business community. ", "McKenna served as the board's first chairman and in his first annual address, laid out a plan to attract manufacturing plants to the city. ", "McKenna served as the president of the Portland Belt Company since its founding in 1893. ", "Their main purpose was advocating the construction of a cable car from East Portland, Oregon to St. Johns, Oregon along the Columbia Slough. ", "McKenna's project was originally approved, but when the Panic of 1893 came the line was canceled mid-construction. ", "A re-approval of the project came in 1905. ", "McKenna advocated for public control of the cable car, saying the city should construct the line and either contract the operation out or run it themselves. ", "In 1903, McKenna secured a double-track electric streetcar line to the peninsula with the Portland Railway Company.", "\n\nLand development\nIn 1889, McKenna moved to Portland, Oregon and invested in a large amount of land, the majority of which was in the University Park neighborhood. ", "With the rapid growth of the city came a growth in investments for McKenna. ", "His first newspaper advertisement appeared in 1890 where he was noted as the manager of the Conservative Real Estate & Trust Company. ", "By 1892, McKenna was advertising as the sole agent for the University Park neighborhood. ", "In 1894, McKenna constructed a three-story brick building in the heart of University Park. ", "When the Archdiocese of Portland purchased the land of the former Portland University to erect a new University of Portland, they went to McKenna to secure more 23 acres of more land for $20,000 ($ adjusted for inflation). ", "In 1910, McKenna purchased 1,280 acres of land for US$12,800 in a rural area near Chitwood, Oregon where he established a ranch. ", "\n\nMcKenna Park, named for the University Park developer, was created to accommodate the Portsmouth baseball team in the Tri-City League during the 1910 season. ", "Officially the park was fenced off five years before, but it was not being used during that time. ", "In 1919, the park was considered for the site of a new highschool, but eventually another plot was selected. ", "The sites original boundaries stretched from to Lombard street on the Northside, McKenna avenue to the east and Dawson street to the south. ", "McKenna owned land in other cities, including Bend, Oregon. ", "In 1909, he made a large land acquisition from the University Land Company, buying most of their plots. ", "McKenna's purchased included 500 lots for US$180,000 ($ adjusted for inflation).", "\n\nPolitical and civic advocacy\nEarly in his land development career, McKenna devoted portions of his advertising to his personal opinions on politics and civic matters. ", "His first opinion was published in his ad which appeared in the edition of April 2, 1893 of The Oregonian which stated his opposition to a miller regulation bill. ", "In 1894, McKenna lobbied the Albina, Oregon city council to construct wide boulevards, which was approved. ", "They were the first of the kind in the Portland area. ", "McKenna subscribed to the City Beautiful movement, which was a push in urban cities to beautify the community. ", "An early example of this was when McKenna worked for Dr. C. C. Stratton, then-president of Portland University, who advocated for Oregon to have an open immigration stance. ", "McKenna established the United Artisans club in Portland. ", "McKenna also founded the Initiative One Hundred, a community action committee. ", "He announced his resignation from office in 1903, and again planned to resign following some controversy in 1907, but reconsidered and kept the position. ", "He served as the Oregon Board of Trade chairman starting in 1901.", "\n\nDeath and legacy\nMcKenna died of a brain aneurysm on February 24, 1914 after battling severe mental health problems. ", "His funeral was held on February 26, 1914 and he was interred at Mount Cavalry Cemetery. ", "After his death, the McKenna estate was valued a US$187,748 ($ adjusted for inflation). ", "His wife and son had to pay $711 a piece in inheritance taxes. ", "Coe McKenna went on to take over the family development business. ", "He later served on the Multnomah County planning board and in the Oregon Senate.", "\n\nReferences \n\nCategory:1859 births\nCategory:1914 deaths\nCategory:People from Perry County, Illinois\nCategory:Businesspeople from Portland, Oregon\nCategory:American real estate businesspeople\nCategory:Creighton University faculty\nCategory:American schoolteachers\nCategory:Deaths from intracranial aneurysm" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Yuri Alberto\n\nYuri Alberto Monteiro da Silva (born 18 March 2001), known as Yuri Alberto, is a Brazilian footballer who plays for Santos as a forward.", "\n\nClub career\n\nSantos\nBorn in São José dos Campos, São Paulo, Yuri Alberto joined Santos' youth setup in 2013 at the age of twelve. ", "On 28 July 2017, he signed his first professional contract after agreeing to a signed a three-year deal.", "\n\nOn 1 November 2017, Yuri Alberto was promoted to the main squad by interim manager Elano. ", "He made his first team – and Série A – debut fifteen days later, coming on as a substitute for Renato in a 3–1 away loss against Bahia.", "\n\nYuri Alberto scored his first goal for the club on 7 March 2018, netting the equalizer in a 2–1 Campeonato Paulista away loss against Grêmio Novorizontino; aged 16 years, 11 months and 20 days, he became the sixth youngest to score for Peixe in their history. ", "He made his Copa Libertadores debut on 24 May, replacing Vitor Bueno in a 0–0 home draw against Real Garcilaso.", "\n\nInternational career\nOn 16 February 2017, Yuri Alberto was called up to Brazil under-17s for the year's South American Under-17 Football Championship. ", "He also featured in the Montaigu Tournament and in the FIFA U-17 World Cup.", "\n\nOn 7 March 2018, Yuri Alberto and Santos teammate Rodrygo were called up to the under-20s, but both were cut from the squad six days later after a request from his club's president.", "\n\nCareer statistics\n\nHonours\n\nInternational\nBrazil U17\nSouth American Under-17 Football Championship: 2017\n\nReferences\n\nExternal links\n\nCategory:2001 births\nCategory:Living people\nCategory:People from São Paulo (state)\nCategory:Brazilian footballers\nCategory:Association football forwards\nCategory:Campeonato Brasileiro Série A players\nCategory:Santos FC players\nCategory:Brazil youth international footballers" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "/*\n * DO NOT ALTER OR REMOVE COPYRIGHT NOTICES OR THIS HEADER.", "\n *\n * Copyright (c) YYYY Oracle and/or its affiliates. ", "All rights reserved.", "\n *\n * The contents of this file are subject to the terms of either the GNU\n * General Public License Version 2 only (\"GPL\") or the Common Development\n * and Distribution License(\"CDDL\") (collectively, the \"License\"). ", " You\n * may not use this file except in compliance with the License. ", " You can\n * obtain a copy of the License at\n * https://oss.oracle.com/licenses/CDDL+GPL-1.1\n * or LICENSE.txt. ", " See the License for the specific\n * language governing permissions and limitations under the License.", "\n *\n * When distributing the software, include this License Header Notice in each\n * file and include the License file at LICENSE.txt.", "\n *\n * GPL Classpath Exception:\n * Oracle designates this particular file as subject to the \"Classpath\"\n * exception as provided by Oracle in the GPL Version 2 section of the License\n * file that accompanied this code.", "\n *\n * Modifications:\n * If applicable, add the following below the License Header, with the fields\n * enclosed by brackets [] replaced by your own identifying information:\n * \"Portions Copyright [year] [name of copyright owner]\"\n *\n * Contributor(s):\n * If you wish your version of this file to be governed by only the CDDL or\n * only the GPL Version 2, indicate your decision by adding \"[Contributor]\n * elects to include this software in this distribution under the [CDDL or GPL\n * Version 2] license.\" ", " If you don't indicate a single choice of license, a\n * recipient has the option to distribute your version of this file under\n * either the CDDL, the GPL Version 2 or to extend the choice of license to\n * its licensees as provided above. ", " However, if you add GPL Version 2 code\n * and therefore, elected the GPL Version 2 license, then the option applies\n * only if the new code is made subject to such option by the copyright\n * holder.", "\n */\n" ]

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[ "Active (1877)\n\nActive was a wooden ketch that was wrecked on 19 January 1898 on the Oyster Bank at the entrance of Newcastle Harbour, New South Wales, Australia, near the previously wrecked schooner Colonist while carrying a cargo of ironbark to Morpeth, New South Wales, under the command of Captain P. Williams. ", "There were no casualties but the ship was lost. ", "The wreck has not been located, but the approximate co-ordinates of the shipwreck are .", "\n\nReferences\n\nFurther reading \nOnline databases\nAustralian National Shipwreck Database\nAustralian Shipping - Arrivals and Departures 1788-1968 including shipwrecks \nEncyclopaedia of Australian Shipwrecks - New South Wales Shipwrecks \n\nBooks\nWrecks on the New South Wales Coast. ", "By Loney, J. K. (Jack Kenneth), 1925–1995 Oceans Enterprises. ", "1993 . ", "\nAustralian Shipwrecks - Vol.1 1622-1850, Charles Bateson, AH and AW Reed, Sydney, 1972, , Call number 910.4530994 BAT \nAustralian shipwrecks Vol. ", "2 1851–1871 By Loney, J. K. (Jack Kenneth), 1925–1995. ", "Sydney. ", "Reed, 1980 910.4530994 LON\nAustralian shipwrecks Vol. ", "3 1871–1900 By Loney, J. K. (Jack Kenneth), 1925–1995. ", "Geelong Vic: List Publishing, 1982 910.4530994 LON\nAustralian shipwrecks Vol. ", "4 1901–1986 By Loney, J. K. (Jack Kenneth), 1925–1995. ", "Portarlington Vic. ", "Marine History Publications, 1987 910.4530994 LON\nAustralian shipwrecks Vol. ", "5 Update 1986 By Loney, J. K. (Jack Kenneth), 1925–1995. ", "Portarlington Vic. ", "Marine History Publications, 1991 910.4530994 LON\n\nCategory:Shipwrecks of the Hunter Region\nCategory:Ships built in New South Wales\nCategory:1877 ships\nCategory:Maritime incidents in 1898\nCategory:1871–1900 ships of Australia\nCategory:Merchant ships of Australia\nCategory:History of Newcastle, New South Wales" ]

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[ "1. ", "Field of the Invention\nThe present invention relates to an optical fiber for optical amplification, having a core portion doped with erbium as an optical amplification substance, and to an optical fiber amplifier and an optical-fiber laser.", "\n2. ", "Description of the Related Art\nIn recent years, optical fiber amplifiers using erbium doped optical fibers (EDF), which are optical fibers having core portions doped with erbium (Er) as an optical amplification substance, are used for various purposes.", "\nThe EDFs used in the optical fiber amplifiers are preferably those in which occurrence of nonlinear optical phenomena inside is suppressed so as to prevent degradation in the quality of amplified light. ", "For example, Japanese Laid-Open Patent Publication No. ", "2003-318473 discloses an EDF having a refractive index profile adjusted to be of a so-called W-type or α-type. ", "According to Japanese Laid-open Patent Publication No. ", "2003-318473, by making this adjustment to the refractive index profile, an absolute value of a wavelength dispersion of the EDF is increased and an overlap integral between an Er distribution in a core portion and a mode distribution of light propagated through the core portion is increased, thus increasing an absorption coefficient of the EDF and decreasing the length of the EDF to be used. ", "Consequently, occurrence of nonlinear optical phenomena such as four-wave mixing and cross-phase modulation in the EDF is suppressed.", "\nHowever, because optical fiber amplifiers have been used for more diverse purposes in recent years, intensities of light input to the EDFs tend to become higher. ", "When light input to such an EDF has a high intensity, nonlinear optical phenomena tend occur in the EDF. ", "Therefore, EDFs in which the occurrence of nonlinear optical phenomena is further suppressed have been demanded." ]

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[ "Longtime Businesses Invest in Precarious Block\n\nEdith Bello likes to tell her dad’s story — how Alfredo Bello immigrated to the United States from his native Guanajuato, Mexico, in the 1960s with $300 in his pocket. ", "Today he runs three restaurants in San Francisco, and now he’s the new owner of a building on one of the Mission’s most difficult blocks.", "\n\n“Even though I went to college, I don’t feel like I have accomplished as much as he has,” she said, noting that her father barely finished middle school. ", "He remains shy, and throughout a reporter’s visit, busied himself working in the restaurant.", "\n\nWhat’s clear is that he has a knack for attracting a broad-based clientele at his taquerias, which are often filled with workers during the day and the young hipster crowd and others at night.", "\n\nWhen Bello first arrived, he visited a family member who worked at Taqueria El Farolito on 24th Street. ", "He ended up putting on an apron, working his way up from line cook to cashier until he saved enough money to open his own place: Taqueria El Castillito at 2092 Mission St. Today he owns two taquerias (the other is in the Civic Center area), and now the Mayan restaurant Kúuup, housed in his new building at 2054 Mission St., between 16th and 17th streets.", "\n\nEdith Bello, who runs Kuuup on Mission Street, says hello to someone from the neighborhood.", "\n\nAlthough the blocks near the 16th Street BART station have long been problematic — the area has the Mission’s highest crime rate, according to police — Bello may be on to something. ", "Kúuup is one of four businesses that have opened in the last year on the west side of the 2000 block of Mission Street.", "\n\nMission Pizza is the latest business on the block.", "\n\nTaqueria Vallarta opened its third San Francisco location on the corner of 16th and Mission streets in August. ", "An insurance firm opened at the corner of 17th and Mission one-and-a-half years ago, and a pizzeria will soon open at 2074 Mission St.\n\nUnlike many of the new Mission restaurants, investment from Kúuup and Taqueria Vallarta comes from within the neighborhood. ", "Business owners said they hope it helps clean up the block.", "\n\nJuan Rosas, the owner of Taqueria Vallarta, said he knows the area has a bad reputation but sees potential.", "\n\n“There is a lot of clientele here. ", "It’s close to a BART station, it’s a commercial area,” Rosas said. “", "The area is getting cleaner and more tranquil.”", "\n\nSam Chavez, an employee at Fred Loya Insurance Company, said she feels safe during the day. ", "Besides, the people who hang out on the block mostly keep to themselves.", "\n\n“Businesses has been good,” Chavez said. “", "During the day it’s not so rough.”", "\n\nAn employee at a business on the block, who asked to remain anonymous because of fear of retribution, said the situation has not changed in the seven years he’s worked there.", "\n\n“It’s always the same people, the same druggies,” he said. “", "When the police comes they go to the hotels upstairs.”", "\n\nBut Rosas and Edith Bello said they’ve already seen an improvement in that people don’t hang out outside their restaurants. ", "Bello does her part: whenever someone is behaving badly near her restaurant, she tells them to move.", "\n\n“I go outside and tell them, ‘Excuse me, I am trying to do business here,’” she said. “", "And they move. ", "I am not scared of them, I’ve been living here my whole life.”", "\n\nThe business owners understand, however, that many before them have failed. ", "The soon-to-be pizzeria was formerly a Thai restaurant, Start 16. ", "It opened in June of last year and closed in the last few weeks. ", "The owners of the pizzeria could not be reached for comment.", "\n\nThe Bellos decided to open Kúuup after customers at Taqueria El Castillito requested that they serve Mayan food, and they remain optimistic that diners will recognize the quality of their food.", "\n\nEdith Bello said that her father “saw there was a need for it. ", "The food is part of who you are, it’s part of your culture.”", "\n\nShe noted that they spent two years working on the menu with cooks from the Yucatan, and import all their spices from there. ", "They are currently going through the permit process to obtain a beer and wine license.", "\n\n“Our dream is to have families come sit down and eat a good meal,” she said. ", "She noted that that’s what her father accomplished down the block. ", "On the weekends, families come to the El Castillito to eat menudo, a traditional soup that reminds them of home, she said." ]

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[ "Thyroid gland involvement in advanced laryngeal cancer: association with clinical and pathologic characteristics.", "\nIndications for thyroidectomy during laryngectomy are controversial. ", "We examined whether clinicopathologic features can predict thyroid gland involvement, and the prognostic effect of thyroid gland involvement in patients undergoing total laryngectomy. ", "The study set out to review preoperative assessment, operation findings, pathologic findings, and follow-up data. ", "Thyroid gland involvement was found in 11 of 53 patients (21%) undergoing total laryngectomy and thyroidectomy. ", "Preoperative work-up failed to predict thyroid gland involvement. ", "Thyroid gland involvement was associated with salvage procedures (p = .025), paratracheal metastases (p = .003), and poor overall survival (hazard ratio = 2.74, p = .008). ", "Thyroid gland involvement in patients undergoing total laryngectomy is frequent and is associated with poor prognosis. ", "Preoperative assessment failed to predict thyroid gland involvement. ", "We believe that thyroidectomy should be considered in cases with paratracheal lymphatic spread irrespective of tumor location within the larynx." ]

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[ "LEARN/CREATE (MT)\n\nNOTE: When the Idaho Legislature is in session, programming on the Learn/Create and World channels may be pre-empted for live coverage from the House and Senate floors.", "\n\n11:00 am\n\nTaste of Louisiana with Chef John Folse & Co.: Our Food Heritage\"German Immigration in the 1700s\"\nJohn Law, a Scottish financier, lured Germans to Louisiana with a propaganda campaign entitled \"The Magnificent Country of Louisiana.\" ", "When the Germans finally arrived after suffering grueling circumstances, they became fabulous farmers and saved the city of New Orleans from famine. ", "twice. ", "D\n\n11:30 am\n\nBake Decorate Celebrate!\"Fruity Treats\"\nFruit-from flavoring, to design and filling. ", "First is an edible arrangement featuring cookies and fruit dipped in chocolate. ", "Next, the decorating lesson is tip 102. ", "D\n\n12:00 pm\n\nGreat Conversations\"Azir Nafasi and Karl Fleming\"\nIn a 2005 interview, Azir Nafasi, teacher and author of Reading Lolita in Tehran: A Memoir in Books, talks with Karl Fleming, journalist and legendary civil rights reporter. ", "D\n\n1:00 pm\n\nFrench In Action\"Vacation In Brittany I\"\nMireille, her sisters, and cousins are playing a game of portraits when their game is interrupted by snack time, and by a minor accident.", "G\n\n1:30 pm\n\nFrench In Action\"Vacation In Brittany II\"\nOn a rainy day, Mireille, her sisters, and cousins are passing the time. ", "As they check to see what's playing at the movies, Cecile gets a surprise invitation for a sail.", "G\n\n2:00 pm\n\nUnfinished Nation\"Legacy of An Autocratic Ruler\"\nPresident Jackson's policy related to Native Americans. ", "The Veil of Tears. ", "Henry Clay's introduction of bill to renew charter of Bank of United States as ploy prior to presidential election of 1832. ", "Jackson's veto of bill and reelection victory. ", "Jackson's attempts to deplete power of bank after election. ", "Van Buren, Jackson's successor, and economic crises. ", "Political battles between the Whigs and Democrats; Harrison's election in 1840 and his brief tem in office; John Tyler, his successor.", "G\n\n2:30 pm\n\nUnfinished Nation\"Revolution of a Different Sort\"\nGrowth in population and surge in transportation and technology which occurs during the first half of the 18th century. ", "Rising immigration, and incidence of nativism. ", "Growth of canal system, emergence of railroads, and its priming of news industry. ", "Industrialists, the emerging factory system, and its effect on workers and artisans.", "G\n\n3:00 pm\n\nDiscovering Psychology - Updated Edition\"The Power of the Situation\"\nReveals how social psychologists attempt to understand behavior within its broader social context and how our beliefs and behavior can be influenced and manipulated by other people and by subtle situational forces.", "G\n\n3:30 pm\n\nDiscovering Psychology - Updated Edition\"Constructing Social Reality\"\nInvestigates the factors that contribute to our interpretation of reality and how understanding the psychological processes that govern our behavior can help us become more empathetic and independent members of society.", "G\n\n4:00 pm\n\nDesign Squad Nation\"One Giant Leap - Part 2\"\nJudy and Adam invite Felipe -- an accomplished 15-year-old pilot from Miami, FL -- to compete in the 2010 Red Bull Flugtag competition. ", "Together, they team up with NASA to design and build a human-powered flying machine. ", "With their NASA-inspired glider design, Team One Giant Leap soars off a 30-foot-high deck, impressing the judges with distance and style. ", "D\n\n4:30 pm\n\nBiz Kid$\"Sell, Sell, Sell (The Science of Sales)\"\nAll sales final. ", "Join the Biz Kids in sales training as they explore philosophy and sales techniques. ", "Discover the traits common to all good salespeople. ", "D\n\nCyberchase\"A Clean Sweep\"\nHacker makes Buzz's dream come true and gives him his very own donut shop in Radopolis. ", "But it's just part of Hacker's latest scheme. ", "Working out of the donut shop, Hacker makes confetti out of magnetite, and uses it to put all the Radsters to sleep, so he can take over the cybersite. ", "D\n\nPaint This with Jerry Yarnell\"Structuring Your Painting, Part 1\"\nThis instruction starts with the importance of reference material in developing any composition. ", "Other attributes - such as season and light source - also need to be established. ", "Jerry then discusses the use of eye stoppers, overlapping and negative space to arrive at a proper composition and maintain interest and excitement in the painting, Jerry completes the instruction by adding some do's and don'ts, featuring a special rule of how to create an entrance into a painting. ", "D\n\nThis Old House\"Jersey Shore Rebuilds 2013/Stories from Sea Level\"\nKevin surfs with pro Sam Hammer and cruises the bay with marine biologist Chris Wojcik. ", "Sea-level foundation footings go in in Bay Head, while stone veneer, fiber cement siding and composite decking dress up the Point Pleasant exterior. ", "Richard takes a victory lap in Manasquan as flooring and fixtures are in and Rita's house is finished. ", "D\n\nJoseph Rosendo's Travelscope\"A San Antonio Christmas\"\nSan Antonio is a festival town and Christmas is a most festive time of year. ", "Joseph joins the locals and visitors to celebrate the season along San Antonio's famous river walk surrounded by songs, decorations and plenty of holiday cheer. ", "Yet San Antonio is more than the River Walk, and Christmas in San Antonio means more than twinkling lights. ", "D\n\n9:30 pm\n\nLidia's Italy In America\"New England's Italy\"\nAs the Italian immigrants settled the Northeastern coast of the United States, they did what they knew from their homeland. ", "In many cases, this included fishing for the local catch. ", "In this episode, Lidia makes Calamari Fra Diavolo over Linguine and she also prepares a Salt Cod, Potato & String Bean Salad. ", "D\n\nSimply Ming\"Caramelization with Guest Jody Adams\"\nThis week on Simply Ming - Caramelization - a technique that enhances both savory and sweet cooking. ", "Done right it enhances a dish, and done wrong will turn it bitter. ", "Joining Ming in the kitchen is Chef Jody Adams. ", "D\n\n11:00 pm\n\nTaste of Louisiana with Chef John Folse & Co.: Our Food Heritage\"German Immigration in the 1700s\"\nJohn Law, a Scottish financier, lured Germans to Louisiana with a propaganda campaign entitled \"The Magnificent Country of Louisiana.\" ", "When the Germans finally arrived after suffering grueling circumstances, they became fabulous farmers and saved the city of New Orleans from famine. ", "twice. ", "D" ]

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[ "Yesterday's quote really hit home for me this week. ", "In the past couple weeks I haven't been feeling 100% about myself. ", "I think I was either working too hard, or my body was trying to get me sick, or my hormones were going crazy...but all in all, I was beginning to lose all hope about things that were important to me. ", "Namely, I was losing hope about my San Diego dream.", "\nEver since maybe Sophomore or Junior year of college, I had this dream that I wanted to move to San Diego, have my studio by the ocean, make art and give small workshops for adults on Fiber Art. ", "Or maybe not by the ocean, but close to it. ", "The closest I've ever felt to achieving this dream was when I was doing my internship during Summer 2012. ", "But in the last couple weeks, I felt as if everything was slipping. ", "I don't feel as if the connections I have there are strong enough to achieve anything. ", "I feel like bridges are being burned. ", "I'm not sure I could afford being there. ", "And the jobs I'd want, no one is hiring for or they can't afford to have me. ", "I know this is all negative thinking. ", "I feel stuck. ", "I just always thought that I might be in San Diego by now. ", "Maybe that's naive of me. ", "I've talked it over with various people and a lot of them have been saying that I don't need those connections. ", "The connections I had before don't matter right now, all that matters is that I go out there and try to achieve my dream. ", "Which I understand, but San Diego holds a lot of memory for me, good and bad. ", "Do I really want to be in that environment?", "\n\nAnd then I found the quote for yesterday:\n\n“Do not lose hold of your dreams or aspirations. ", "For if you do, you may still exist but you have ceased to live.” – ", "Henry David Thoreau\n\nExactly. ", "If I don't have San Diego, then what do I have? ", "Routine. ", "Monotonous routine. ", "I've seen myself start to fall into that. ", "I've created a chore list for myself that I try to repeat every week, and that's all I've been getting done. ", "At least the house is somewhat clean, but it's not really. ", "I have my knitting projects, and sometimes I sit down to read, but every weekend I'm off to work and I feel like that ruins my creative motivation. ", "I've considered looking for a new job, but it'd have to be here for a little while. ", "I feel like I'm holding myself back. ", "I try to take steps to get myself to my dream, but it's those steps that are stopping me. ", "Maybe I should just get up and go? ", "Just pack everything up, take Stella, and go? ", "There's a couple of Knitwear Designer jobs in Irvine which isn't too far from San Diego. ", "Maybe I should apply for them and see? ", "But I also am looking forward to moving into a house with Damian and Arlyn this summer. ", "I just don't know. ", "Timing is never right.", "\n\nBut again, going back to that quote, I need to keep my dream in mind, or else I don't have anything else to strive for right now. ", "So, that's my motivation for today. ", "Other motivation is to organize sewing patterns, clean and organize papers in the car, and work more on my Embrace Sweater I started last week. ", "Hooray!" ]

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[ "Got two beautiful dresses because they were on sale Don't know where I could appropriately wear them\n\n1,702 shares" ]

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[ "Emma Guy Cromwell\n\nEmma Guy Cromwell (September 28, 1865 – July 19, 1952) was a suffragist, women's rights activist, and early female Democratic Party politician from Kentucky in the United States. ", "Cromwell became the first woman to hold a statewide office in Kentucky when she was elected state librarian in 1896 by a vote of the Kentucky State Senate. ", "Later she won elections for the position of Secretary of State, Kentucky State Treasurer and she was appointed state park director, state bond commissioner, and State Librarian and Director of Archives.", "\n\nEarly life and education\nEmma Guy, the daughter of Ashley and Alice (Quisenberry) Guy, was born on September 28, 1865, in Simpson County, Kentucky and when her father died she spent most of her childhood in the neighboring Allen County, Kentucky. ", "She had one sister and two brothers.", "\n\nEmma attended Howard Female College at Gallatin in Sumner County, Tennessee. ", "She returned to Scottsville, Kentucky to teach at Allen Male and Female College. ", "Later she studied parliamentary law at the University of Michigan.", "\n\nEmma married Frankfort, Kentucky attorney William F. Cromwell on May 30, 1897 in a church ceremony in Bowling Green, Kentucky. ", "William Cromwell was Chief Clerk of the prior State Legislative session. ", "They had one son, William Foree Cromwell. ", "Her husband died in 1909.", "\n\nPolitical career\nIn 1896, Guy was appointed by the Kentucky General Assembly for the position of State Librarian making her the first female to hold a position in a Kentucky State Office. ", "Given that the state librarian then could not serve successive terms, she took on new roles in public service: serving as the enrolling clerk (1916 to 1918) and parliamentarian of the Kentucky House of Representatives and getting elected to the Frankfort School Board. ", "She also volunteered in women's clubs such as the Daughters of the American Revolution and the United Daughters of the Confederacy. ", "She also served on the state Parent Teacher Association.", "\n\nIn 1918 Cromwell published Cromwell's Compendium of Parliamentary Law. ", "She published in 1920 a booklet, \"Citizenship, A Manual for Voters,\" that was dedicated to the \"new voters in Kentucky\" -- women.", "\nA strong appeal is made to the women voters of our nation to prepare themselves for public life by keeping in touch with the issues of the day as well as the functions of government. ", "While it is a great privilege to take part in public affairs, and study the questions of the day, so that we can vote intelligently and criticize justly, let us not forget that the home is the most sacred refuge of life, the nucleus around which all pure and true civilization is formed, and that the chief end of all good government is to improve and protect the home, the church and the community.", "\n\nIn 1922 she was parliamentarian for the Kentucky House and Senate. ", "In 1923, Cromwell was elected Kentucky Secretary of State in elections that included two other females. ", "The Republicans had nominated Eleanor Wickliffe of Bardstown, and both Cromwell and Mary Elliott Flanery stood for the Democratic Party against three male candidates. ", "Cromwell won both in the primary and then in the general election. ", "She held the office from January 1, 1924 until January 1, 1928. ", "Cromwell discovered the records of previous administrations in the Capitol basement, and retrieved and categorized them. ", "Cromwell was the first woman to serve as acting governor of Kentucky when the two other officials in the line of succession -- Governor William J. Fields and Lt. ", "Gov. Henry Denhardt -- were attending the 1924 Democratic National Convention in New York City.", "\n\nCromwell went on to be elected Kentucky State Treasurer in 1927, and because of her conservative handling of state money, which was heavily criticized at the time, Kentucky 's state funds remained secure during the Great Depression.", "\n\nGovernor Ruby Laffoon appointed Cromwell as Kentucky State Park Director in 1932.", "\n\nIn 1937 Governor Happy Chandler named her State Librarian and Director of Archives, a post she then held for several more terms. ", "She arranged for the return of the Kentucky state constitution from the University of Chicago Archives.", "\n\nIn 1939, Cromwell published her autobiography, Woman in Politics which was republished in 1996 by The Kentucky Commission on Women. ", "In this book, she praises the suffragist Laura Clay as \"my main tutor and adviser (65)\" though there is not much detail in her memoir about any work she did for the Kentucky suffrage movement.", "\n\nLater life and death\nCromwell continued to be active in Democratic Party politics until she fell and broke a hip in 1949. ", "Cromwell died on July 19, 1952, of medical complications following a stroke. ", "She is buried in the Frankfort Cemetery, in Frankfort Kentucky.", "\n\nLegacy\nCromwell was one of seventeen women given a place of honor in the Kentucky State Capital when their portraits were placed in a permanent display called \"Kentucky Women Remembered\".", "\n\n\"Emma's List\", a new Political Action Committee created in 1993 to raise funds for female's campaigning for a Kentucky State office, was named in honor of Emma Cromwell.", "\n\nBibliography\n \n \n \n Research journal posts about Emma Guy Cromwell in History of Kentucky Women in the Civil Rights Era, University of Kentucky\n\nReferences\n\nExternal links\n \n \n\nCategory:Kentucky Democrats\nCategory:Politicians from Frankfort, Kentucky\nCategory:American non-fiction writers\nCategory:Secretaries of State of Kentucky\nCategory:1952 deaths\nCategory:State treasurers of Kentucky\nCategory:1865 births\nCategory:Women in Kentucky politics\nCategory:University of Michigan alumni\nCategory:American suffragists\nCategory:People from Simpson County, Kentucky\nCategory:Kentucky women in politics\nCategory:Kentucky women librarians\nCategory:Kentucky women activists" ]

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[ "The Netherlands-based Roosevelt Foundation on Thursday awarded the International Four Freedoms Medal to German Chancellor Angela Merkel for promoting the \"four freedoms\" enshrined in a famous 1941 speech by late US President Franklin D. Roosevelt.", "\n\nThe medal is given to leaders and organizations who promote freedom of speech, freedom of worship, freedom from want and freedom from fear.", "\n\n\"As a European leader she led the negotiations to reach a diplomatic solution in the Ukrainian crisis in the interest of peace and security in Europe. ", "She shows great moral leadership as chancellor of all Germans regardless of faith and ethnicity in the face of the start of the anti-Islam movement PEGIDA in 2014,\" the foundation said in a statement.", "\n\n\"In the current migrant and refugee crisis Merkel is committed to Europe's humanitarian duty to protect those fleeing war and conflict in the Middle East, Africa and Asia and to tackle the causes of the crisis by working for peace in Syria and the region,\" the foundation added.", "\n\nThe foundation also lauded her participating in the opposition political movement \"Democratic Awakening\" in the former German Democratic Republic.", "\n\n\"Franklin D. Roosevelt's four freedoms are more relevant than ever before,\" said Merkel after receiving the award.", "\n\nThe awardees hailed from Germany, Syria, Central African Republic and the Democratic Republic of Congo\n\nFrom Syria to Congo\n\nMerkel joins an illustrious list of leaders who received the prize, including former German Chancellor Helmut Schmidt, the late South African President Nelson Mandela, the Dalai Lama and the late US President John F. Kennedy.", "\n\nThe foundation on Thursday also awarded Syrian journalist Mazen Darwish the Freedom of Speech Medal for his commitment to independent news in Syria, which has witnessed five years of armed conflict.", "\n\nHuman Rights Watch was honored with the Freedom from Fear award, while three clergymen from the Central African Republic were granted the Freedom of Worship Medal.", "\n\nDenis Mukwege of the Democratic Republic of Congo was handed the Freedom from Want award for his \"dedication to help and protect survivors of sexual violence\" in the African nation.", "\n\nMeanwhile, Merkel's spokesman Steffen Seibert said the chancellor would continue on to Eindhoven, where Germany and the Netherlands would hold government consultations to deepen the neighbors' \"good relationship.\"" ]

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[ "Pont de la Tournelle\n\nThe (Tournelle Bridge in English), is an arch bridge spanning the river Seine in Paris.", "\n\nHistory\nThe location of the is the site of successive structures.", "\n\nThe first, a wooden bridge, was built in 1620. ", "This bridge connected the Eastern bank of the Seine (le quai Saint-Bernard) to . ", "It was subsequently washed away by ice in 1637, and again on 21 January 1651. ", "A stone bridge was erected in its place in 1654. ", "It was demolished in 1918 and replaced by the current bridge in 1928, after it suffered several natural disasters, especially the flood of 1910.", "\n\nThe was intentionally built lacking symmetry, in order to emphasize the shapeless landscape in the part of the Seine that it bestrides. ", "Consisting of a grand central arch that links the riverbanks via two smaller arches, one on each side, it's decorated on the Eastern bank with a pylon built on the left pier's cutwater, and a statue of Saint Geneviève, the patron saint of Paris, atop of the pylon, designed by Polish-French monumental sculptor Paul Landowski.", "\n\nThe term \"Tournelle\" traces its origin to a square turret () constructed at the end of the 12th Century on the fortress of Phillipe Auguste.", "\n\nNumerous scenes of Highlander: The Series were filmed along the Quai de la Tournelle near and underneath Pont de la Tournelle between 1992 and 1998.", "\n\nAccess\n\nSee also \n List of crossings of the River Seine\n\nReferences\n\nExternal links\n\n Bridge history\n More bridge history\n\nCategory:Bridges over the River Seine in Paris\nCategory:Bridges completed in 1658\nCategory:Bridges completed in 1928\nCategory:Buildings and structures in the 4th arrondissement of Paris\nCategory:1658 establishments in France" ]

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[ " by -704.", "\n0\nWhat is 6 divided by 1?", "\n6\nWhat is -3 divided by -2349?", "\n1/783\nCalculate -5304 divided by -51.", "\n104\nWhat is 6 divided by 35?", "\n6/35\nDivide -2373 by -7.", "\n339\nCalculate 1732 divided by 433.", "\n4\nWhat is 4316 divided by -1?", "\n-4316\nCalculate 175 divided by 5.", "\n35\nDivide 945 by -189.", "\n-5\nWhat is -3022 divided by -5?", "\n3022/5\n1 divided by 2875\n1/2875\nCalculate 274 divided by -274.", "\n-1\n-280 divided by -56\n5\nWhat is 5 divided by -70?", "\n-1/14\nWhat is 150 divided by 50?", "\n3\nCalculate 730 divided by -10.", "\n-73\nDivide 1716 by 44.", "\n39\nDivide 4771 by -5.", "\n-4771/5\n1548 divided by -4\n-387\nCalculate -1728 divided by -96.", "\n18\nCalculate 182 divided by -91.", "\n-2\nDivide 9 by 37.", "\n9/37\nCalculate 5 divided by 130.", "\n1/26\nCalculate 4 divided by 5.", "\n4/5\nCalculate 448 divided by -8.", "\n-56\nCalculate -15 divided by 2064.", "\n-5/688\nDivide -2433 by 2433.", "\n-1\n-11141 divided by -1\n11141\nWhat is -1174 divided by 5?", "\n-1174/5\nDivide 56 by -25.", "\n-56/25\nDivide -5 by -123.", "\n5/123\nDivide -34314 by 903.", "\n-38\nCalculate -595 divided by 119.", "\n-5\n-428 divided by -107\n4\nCalculate -5 divided by -54.", "\n5/54\n54 divided by 1\n54\nCalculate -112 divided by 2.", "\n-56\nWhat is -5011 divided by -1?", "\n5011\n-10296 divided by -26\n396\n387 divided by 8\n387/8\nDivide -193 by 16.", "\n-193/16\nCalculate -52110 divided by -3.", "\n17370\nDivide -2079 by 693.", "\n-3\nCalculate 4225 divided by 7.", "\n4225/7\nDivide -2 by 273.", "\n-2/273\nWhat is -3225 divided by 645?", "\n-5\nCalculate -33650 divided by 10.", "\n-3365\nDivide -1555 by 6.", "\n-1555/6\nDivide 25 by 25.", "\n1\nCalculate -858 divided by 6.", "\n-143\nDivide 3516 by -293.", "\n-12\nDivide -1750 by -7.", "\n250\nDivide 1239 by 1.", "\n1239\nCalculate -1 divided by 38.", "\n-1/38\n-152 divided by -6\n76/3\nWhat is -30294 divided by -54?", "\n561\nDivide 560 by -16.", "\n-35\nDivide 80 by 16.", "\n5\n35087 divided by 2699\n13\nWhat is 318 divided by 3?", "\n106\nWhat is 361 divided by -2?", "\n-361/2\n-4940 divided by 52\n-95\n2793 divided by -931\n-3\nCalculate 21820 divided by -5.", "\n-4364\nWhat is -843 divided by 281?", "\n-3\nCalculate 245 divided by 49.", "\n5\nDivide 5 by 197.", "\n5/197\n-3 divided by -1625\n3/1625\nCalculate 410 divided by 41.", "\n10\nCalculate -2538 divided by -846.", "\n3\nWhat is -2106 divided by -6?", "\n351\nDivide -5 by -22.", "\n5/22\nCalculate 1564 divided by 391.", "\n4\nDivide -2423 by 2423.", "\n-1\nCalculate -7456 divided by 3.", "\n-7456/3\nCalculate 149 divided by 149.", "\n1\nWhat is 5 divided by 28?", "\n5/28\nDivide 9 by 385.", "\n9/385\nDivide 420 by 3.", "\n140\nDivide 4056 by 3.", "\n1352\n-380 divided by 95\n-4\nCalculate -121 divided by 7.", "\n-121/7\nDivide 454 by -1.", "\n-454\nCalculate 2372 divided by 4.", "\n593\n48 divided by -1\n-48\n-1476 divided by 4\n-369\nDivide -2376 by 9.", "\n-264\nWhat is 288 divided by 4?", "\n72\nWhat is 5 divided by -1?", "\n-5\nDivide -3 by -156.", "\n1/52\nCalculate -516 divided by -6.", "\n86\nWhat is -279 divided by -4?", "\n279/4\nDivide 572 by 13.", "\n44\n376 divided by -8\n-47\nCalculate -1806 divided by 2.", "\n-903\nCalculate -194 divided by -1.", "\n194\nCalculate 770 divided by 5.", "\n154\n-3 divided by 157\n-3/157\n703 divided by -4\n-703/4\nWhat is -1528 divided by -382?", "\n4\nDivide 26 by 1.", "\n26\nWhat is -5 divided by 179?", "\n-5/179\nWhat is -1404 divided by -351?", "\n4\nWhat is 173 divided by 4?", "\n173/4\nCalculate -80 divided by 40.", "\n-2\nDivide 2 by 74.", "\n1/37\nWhat is 0 divided by -5732?", "\n0\nCalculate -2 divided by 525.", "\n-2/525\nDivide 31 by -2.", "\n-31/2\n-145 divided by 5\n-29\nCalculate 11 divided by -1.", "\n-11\nCalculate -18186 divided by -1.", "\n18186\nCalculate -1443 divided by 37.", "\n-39\n-4 divided by 192\n-1/48\nWhat is -5 divided by 934?", "\n-5/934\nDivide -4 by 117.", "\n-4/117\nDivide 1092 by -364.", "\n-3\nCalculate 5 divided by -174.", "\n-5/174\nCalculate 126 divided by -3.", "\n-42\nDivide 7 by -16.", "\n-7/16\nDivide -2 by 62.", "\n-1/31\n894 divided by -298\n-3\nCalculate -2901 divided by -967.", "\n3\nWhat is 4 divided by 2100?", "\n1/525\nDivide 2 by 36.", "\n1/18\nDivide 1 by 164.", "\n1/164\nCalculate 1058 divided by -3.", "\n-1058/3\nDivide -4 by -1312.", "\n1/328\nCalculate 16094 divided by 1238.", "\n13\nWhat is 858 divided by 286?", "\n3\n-245 divided by 49\n-5\nWhat is -1010 divided by 11?", "\n-1010/11\nWhat is -9895 divided by 5?", "\n-1979\nDivide -1605 by 1.", "\n-1605\n133 divided by -2\n-133/2\nWhat is -341880 divided by -6?", "\n56980\nDivide -5 by -41.", "\n5/41\nWhat is 0 divided by 128?", "\n0\nDivide 6367 by 5.", "\n6367/5\nWhat is 80 divided by -10?", "\n-8\nDivide 4212 by -156.", "\n-27\nCalculate 1 divided by -42.", "\n-1/42\nDivide 540 by 20.", "\n27\nDivide 1911 by 147.", "\n13\n-357 divided by 1\n-357\nCalculate -306 divided by 102.", "\n-3\nWhat is -296 divided by -8?", "\n37\n-5 divided by 2006\n-5/2006\n-1 divided by 788\n-1/788\nWhat is 45 divided by 1?", "\n45\nWhat is 1 divided by -34?", "\n-1/34\nCalculate -54 divided by -18.", "\n3\nDivide 6 by -97.", "\n-6/97\nDivide 2 by -123.", "\n-2/123\nWhat is 4 divided by -1469?", "\n-4/1469\n5406 divided by -6\n-901\nDivide 988 by 3.", "\n988/3\nDivide -1 by -416.", "\n1/416\nCalculate 660 divided by 132.", "\n5\n-60 divided by 5\n-12\n6 divided by 30\n1/5\nDivide -684 by 38.", "\n-18\nWhat is 568 divided by 8?", "\n71\nCalculate -184 divided by -8.", "\n23\nWhat is 52 divided by -5?", "\n-52/5\nDivide 8312 by 8.", "\n1039\n-1 divided by 4\n-1/4\nCalculate 3800 divided by 5.", "\n760\n15128 divided by 4\n3782\n399 divided by -3\n-133\nCalculate 3724 divided by 1862.", "\n2\nWhat is 8 divided by 152?", "\n1/19\nWhat is -25 divided by -9?", "\n25/9\n197 divided by 6\n197/6\n1054 divided by -62\n-17\n401 divided by -1\n-401\n-5020 divided by -7\n5020/7\nWhat is 810 divided by 90?", "\n9\nCalculate -303 divided by 6.", "\n-101/2\nDivide -614 by -6.", "\n307/3\nWhat is 932 divided by 6?", "\n466/3\n-26 divided by 118\n-13/59\nCalculate -202 divided by 4.", "\n-101/2\n1665 divided by -15\n-111\nDivide 5 by -7489.", "\n-5/7489\nWhat is -440 divided by -44?", "\n10\nDivide 369 by -41.", "\n-9\nWhat is 4 divided by 290?", "\n2/145\nCalculate 1161 divided by -129.", "\n-9\n1222 divided by -13\n-94\nWhat is -15 divided by 4?", "\n-15/4\nDivide -2 by -48.", "\n1/24\nDivide -302 by -6.", "\n151/3\nWhat is -21159 divided by 3?", "\n-7053\nWhat is 128 divided by -2?", "\n-64\nWhat is -2 divided by 4?", "\n-1/2\n5884 divided by 2942\n2\nDivide -1 by 2365.", "\n-1/2365\n-339 divided by 339\n-1\nWhat is 205 divided by -41?", "\n-5\nDivide 330 by 110.", "\n3\nDivide 45 by -149.", "\n-45/149\nWhat is -78 divided by 6?", "\n-13\nDivide 6 by -821.", "\n-6/821\nCalculate -8169 divided by 1167.", "\n-7\nCalculate -1 divided by 1320.", "\n-1/1320\n-1987 divided by -1\n1987\nWhat is 3114 divided by -6?", "\n-519\nWhat is -2448 divided by 612?", "\n-4\nCalculate -11046 divided by 3.", "\n-3682\nDivide -136 by 137.", "\n-136/137\n-216 divided by -18\n12\nCalculate 471 divided by -3.", "\n-157\nWhat is 19 divided by 1427?", "\n19/1427\nDivide -376 by 188.", "\n-2\nCalculate -964 divided by 25.", "\n-964/25\nCalculate 100 divided by -1.", "\n-100\n-1 divided by -254\n1/254\n-6 divided by 628\n-3/314\nWhat is 316 divided by 79?", "\n4\nWhat is -1740 divided by 3?", "\n-580\nCalculate 416 divided by 3.", "\n416/3\nDivide 1518 by -6.", "\n-253\nDivide 241 by -3.", "\n-241/3\nWhat is -1208 divided by -2?", "\n604\nWhat is -3934 divided by 6?", "\n-1967/3\n2124 divided by -6\n-354\nDivide -506 by -11.", "\n46\nCalculate 0 divided by -60.", "\n0\nWhat is 250 divided by -142?", "\n-125/71\nWhat is 1890 divided by -6?", "\n-315\n0 divided by -65\n0\nWhat is 4 divided by 8116?", "\n1/2029\nWhat is -5 divided by -557?", "\n5/557\nCalculate 210 divided by 6.", "\n35\nCalculate 13110 divided by -6.", "\n-2185\nWhat is -16029 divided by 3?", "\n-5343\nDivide 5 by -21.", "\n-5/21\nCalculate 9605 divided by -1921.", "\n-5\nWhat is -320 divided by -16?", "\n20\nCalculate 1040 divided by 16.", "\n65\n0 divided by -7677\n0\n-843 divided by -2\n843/2\nWhat is -2795 divided by 5?", "\n-559\nDivide 1 by -757.", "\n-1/757\nCalculate -10 divided by -41.", "\n10/41\n9549 divided by 1\n9549\n-645 divided by -5\n129\n-11 divided by 9\n-11/9\nDivide -468 by 7.", "\n-468/7\nWhat is 5 divided by 82?", "\n5/82\n465 divided by -155\n-3\nCalculate -14 divided by 385.", "\n-2/55\nWhat is -3480 divided by -120?", "\n29\n-5 divided by 960\n-1/192\nWhat is 4 divided by -81?", "\n-4/81\n29076 divided by -6\n-4846\nWhat is -316 divided by -79?", "\n4\n427 divided by 3\n427/3\n-128 divided by 29\n-128/29\n-9 divided by -1898\n9/1898\nWhat is -13027 divided by -1861?", "\n7\nDivide -13 by 87.", "\n-13/87\nCalculate 34 divided by -33.", "\n-34/33\nWhat is -10553 divided by -173?", "\n61\nDivide 4 by -279.", "\n-4/279\n23 divided by 55\n23/55\nCalculate -632 divided by -2.", "\n316\nCalculate -762 divided by -2.", "\n381\nCalculate -2018 divided by 1.", "\n-2018\n3728 divided by -4\n-932\nCalculate 278 divided by 278.", "\n1\n-40 divided by 20\n-2\nWhat is 43 divided by -103?", "\n-43/103\nWhat is 7 divided by 6?", "\n7/6\nCalculate 80 divided by -50.", "\n-8/5\nWhat is 144 divided by 36?", "\n4\nWhat is 105 divided by -42?", "\n-5/2\n-18 divided by -1\n18\nWhat is 1174 divided by 587?", "\n2\nWhat is -1300 divided by 260?", "\n-5\nCalculate 4923 divided by 6.", "\n1641/2\nWhat is -14 divided by 1?", "\n-14\n0 divided by 14\n0\nDivide" ]

{ "pile_set_name": "DM Mathematics" }

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[ "Player Grades: Thabo Sefolosha\n\nAn injury, a shooting slump, and a number change, three things that defined a subpar season from Thabo Sefolosha, a 2-guard who had previously cemented himself as a very capable perimeter defender for the Oklahoma City Thunder.", "\n\nSefolosha had the worst shooting season of his 8 year career, and one of the worst three-point shooting seasons since coming to Oklahoma City halfway through the 2008-2009 season, the franchise’s first season in the heartland. ", "Both his free throw rate and percentage were down considerably, and never gave fans the sense that he was finding his shooting groove. ", "Hesitancy with his shot, and a pass first mentality with open looks at the basket showed an overall lack of confidence in himself.", "\n\nAs the Thunder push for a championship, and as Sefolosha’s contract expires within the next few weeks, a full examination of the 30 year-old guard’s future contribution to the team will be necessary to determine if his services will be needed. ", "While his defensive abilities have proven to be valuable to the team, his best seasons may be behind him. ", "His defensive presence did not have the same effect on opponent’s offensive output, and show that Reggie Jackson and Jeremy Lamb may be just as capable defensively while being much better offensively.", "\n\nIt remains to be seen what will happen with Sefolosha. ", "While his time in Oklahoma City has been fantastic, and he has been a part of a growing team with championship capabilities, it may be time for the Thunder to cut ties with the veteran, and take chances with the youth that they have invested heavily in, or chase a new veteran that will add another scoring threat to this potent, yet at times unbalanced, roster. ", "Sefolosha still has a lot to add, and if he receives an extension could still be a viable asset for the Thunder.", "\n\nHis playoff performance was most notable when he was off the floor, when the Thunder’s offense had another spark, via the insertion of Caron Butler or Reggie Jackson into the starting line-up in Sefolosha’s stead. ", "The Thunder was 6-9 when Sefolosha played in the playoffs, but 4-0 when Sefolosha did not play (including both wins versus San Antonio). ", "Only 38% of his 236 playoff minutes this season were logged in wins.", "\n\nIn the spring of 2011, right as the Thunder were locked in a tough Western Conference Finals battle with the Dallas Mavericks, a silk tie was hand woven in a small mom and pop tie shop in western Italy. ", "A \"congratulations on making the Conference Finals\" gift from Sam Presti to Coach made what I do possible. ", "And the legend continues..." ]

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[ "At Gettysburg, Cyclorama is gone but not forgotten\n\nWorkers monitor progress in the restoration of Paul Philippoteaux's 1884 \"The Battle of Gettysburg\", a 360-degree oil painting, at the Cyclorama Center in Gettysburg, Pa. The Gettysburg Cyclorama underwent a $15 million restoration to repair more than a century's worth of serious damage. (", "AP Photo/Carolyn Kaster, File)\n\nGETTYSBURG — A drum-shaped building that once housed a circular painting of Pickett’s Charge has become another memory at Gettysburg. ", "Harry and Gloria Porter of Connellsville, Pa., on Tuesday sauntered to the grassy spot where the building stood.", "\n\n“We wanted to see where the Cyclorama was,” Gloria Porter said.", "\n\nThe Cyclorama building was demolished in March so the Gettysburg National Military Park grounds could appear as they did in the 1860s.", "\n\nThe Porters carry a small book of photographs to share with people they meet. ", "A snapshot of a younger Harry Porter with former Cyclorama director Troy Harman is included with pictures of Harry’s grandfather, who fought at Gettysburg; Thomas Jefferson Hartman, the Confederate who became William H. Porter’s best friend after the Civil War, and the tombstone Harry Porter erected on Hartman’s grave.", "\n\nAdvertisement\n\n“We enjoy the battlefield and the memories,” 89-year-old Harry Porter said. “", "I remember the Cyclorama. ", "I always thought they should bring back the electric map. ", "I always loved the map.”", "\n\nThe large panels of the Cyclorama painting were restored and moved in 2008 to the new National Park Service visitors’ center. ", "The $103 million Gettysburg Museum & Visitors Center was built off the main battlefield.", "\n\nThe plan for the center did not include the map, which had lights showing the key battles in July 1863 at Gettysburg. ", "The 1963 electric map was sold to Scott Roland, who is restoring it in Hanover.", "\n\nThe Cyclorama came down for $3.4 million, a quarter of the cost to repair it.", "\n\nLouise Matweecha, a visitor from Hazelton, said she liked having the Cyclorama on the battlefield.", "\n\n“Everything was right here,” she said. “", "You could come out and see the guns and everything. ", "I think it should be right where everything was.”", "\n\nThe location of the former Cyclorama was part of Cemetery Ridge, part of the Union line not far from Pickett’s Charge, according to Katie Lawhon of the National Park Service.", "\n\n“While the building was there, it was hard to visualize the fighting,” Lawhon said.", "\n\nVisitors can better see the fish-hook shape of the Union line at Gettysburg, she said.", "\n\nVisitors interviewed at the site on Tuesday had differing understandings of where the Union lines were, but they said the open space helps them visualize the battlefield.", "\n\n“We have more work to do,” Lawhon said.", "\n\nMonuments that war veterans dedicated on the site in the 1880s will be replaced, she said. ", "They are the 5th US Artillery Battery F tablet, the 90th Pa. Infantry monument, the 88th Pa. Infantry monument, 1st Mass. Sharpshooters position marker and the 12th Mass. Infantry monument.", "\n\nZiegler’s Ravine will be recreated. ", "The fence line of 1863 will be rebuilt. ", "More trees will be planted in Ziegler’s Grove.", "\n\nThe restoration, financed by the Gettysburg Foundation, is to start in January 2014. ", "An estimated cost was not available.", "\n\nNo signs mark the location of the building, designed by influential architect Richard Neutra. ", "Part of a $1 billion 1950s program to modernize the national park system, the $1 million building opened in 1963.", "\n\n“It was here?” ", "said Nate Barrington, a Gettysburg visitor from Rhode Island. “", "That’s why I feel a little disjointed. ", "It’s been 20 to 30 years.”", "\n\nPhil Dimick of Penn Run, Pa., was 14 when he attended the grand opening of the Cyclorama at the 100th commemoration of the Battle of Gettysburg. ", "He returned Tuesday for the 150th.", "\n\nDimick said he missed the Cyclorama. ", "He also preferred the former museum and visitors’ center that was demolished.", "\n\n“It was a bunch of stuff all crammed together,” Dimick said. “", "The cannons were next to each other and you could compare them all at one time. ", "They had cases and cases of muskets. ", "If you had items from the Civil War, you could find the item and figure out what it was. ", "If you looked around enough they had everything.”", "\n\nThat was when a teenager could buy a period cavalry saber for $20.", "\n\n“We rented a room in a woman’s house for five bucks a night,” he said. “", "Now it’s almost $300 a night just for this event.”", "\n\nGet more information on Gettysburg and news on 150th anniversary events on the Gettysburg 150th anniversary site: www.ydr.com/gettysburg150th" ]

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[ " \nEmanuele Neri, Davide Caramella, Mirco Cosottini, M. Anzidei, V. Battaglia, E. Belloni, F. Bianchi, P. Boraschi, G. Caproni, C. Catalano, A. Carriero, F. de Cobelli, M. Cosottini, F. Donati, L. Faggioni, R. Fossaceca, M. Francone, I. Iacucci, A. Laghi, M. Lombardi, P. Lucchesi, A. del Maschio, M. Milanesi, E. Neri, P. Paolantonio, I. Pesaresi, M. Rengo, A. Roberta, S. Salemi, M. di Terlizzi, F. Turini, V. Vallini, A. Vanzulli, C. Vignali, F. Vullo, V. Zampa and A. L. Baert (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3(C) Springer-Verlag Berlin Heidelberg 2010\n\nDiagnostic Imaging\n\nSeries EditorsA. L. Baert, M. F. Reiser, H. Hricak and M. Knauth\n\nContinuation of Handbuch der medizinischen Radiologie Encyclopedia of Medical Radiology\n\nEditors\n\nEmanuele Neri, Davide Caramella, Mirco Cosottini, M. Anzidei, V. Battaglia, E. Belloni, F. Bianchi, P. Boraschi, G. Caproni, C. Catalano, A. Carriero, F. de Cobelli, M. Cosottini, F. Donati, L. Faggioni, R. Fossaceca, M. Francone, I. Iacucci, A. Laghi, M. Lombardi, P. Lucchesi, A. del Maschio, M. Milanesi, E. Neri, P. Paolantonio, I. Pesaresi, M. Rengo, A. Roberta, S. Salemi, M. di Terlizzi, F. Turini, V. Vallini, A. Vanzulli, C. Vignali, F. Vullo, V. Zampa and A. L. Baert\n\nMR Angiography of the Body\n\nWith 91 Figures in 182 Separate Illustrations, 35 in Color and 5 Tables\n\nEditors\n\nEmanuele Neri\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Radiodiagnostica 1 Universitaria, Ospedale Cisanello. ", "Via Paradisa 2, Pisa, Italy\n\nDavide Caramella\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy\n\nMirco Cosottini\n\nUnit of Neuroradiology, Department of Neurosciences, University of Pisa, Via Roma 67, 56126 Pisa, Italy\n\nM. Anzidei\n\nV. Battaglia\n\nE. Belloni\n\nF. Bianchi\n\nP. Boraschi\n\nG. Caproni\n\nC. Catalano\n\nA. Carriero\n\nF. de Cobelli\n\nM. Cosottini\n\nF. Donati\n\nL. Faggioni\n\nR. Fossaceca\n\nM. Francone\n\nI. Iacucci\n\nA. Laghi\n\nM. Lombardi\n\nP. Lucchesi\n\nA. del Maschio\n\nM. Milanesi\n\nE. Neri\n\nP. Paolantonio\n\nI. Pesaresi\n\nM. Rengo\n\nA. Roberta\n\nS. Salemi\n\nM. di Terlizzi\n\nF. Turini\n\nV. Vallini\n\nA. Vanzulli\n\nC. Vignali\n\nF. Vullo\n\nV. Zampa\n\nA. L. Baert\n\nISSN 0942-5373\n\nISBN 978-3-540-79716-6e-ISBN 978-3-540-79717-3\n\nSpringer Heidelberg Dordrecht London New York\n\nLibrary of Congress Control Number: 2009930364\n\n(C) Springer-Verlag Berlin Heidelberg 2010\n\n9 8 7 6 5 4 3 2 1\n\nThis work is subject to copyright. ", "All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. ", "Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. ", "Violations are liable for prosecution under the German Copyright Law.", "\n\nThe use of general descriptive names, registered names, trademarks, etc. ", "in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.", "\n\nProduct liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. ", "In every individual case the user must check such information by consulting the relevant literature.", "\n\nCover design: Publishing Services Teichmann, 69256 Mauer, Germany\n\nPrinted on acid-free paper\n\nSpringer is part of Springer Science+Business Media (www.springer.com)\n\nForeword\n\nIndirect angiography following intravenous bolus injection of iodinated contrast media entered clinical practice as an alternative less-invasive method to direct (arterial) angiography when digital substraction X-ray techniques became available.", "\n\nBecause of its technical shortcomings, IVDSA was later replaced by CT angiography as another less-invasive modality for vascular imaging. ", "The introduction of multislice CT scanners and rapid progress in electronic image reconstruction allowed CT angiography to become the actually well-known, highly performing, and reliable radiological modality.", "\n\nMR angiography offers better patient safety than CT angiography because of the absence of ionizing irradiation. ", "As compared with ultrasound vascular imaging, it offers and superior accuracy as well as better contrast resolution.", "\n\nThis book offers a comprehensive overview of the latest technological advances in MR angiography, including up to date image acquisition techniques as well as optimal sequences. ", "Special attention is given to flow-based angiography, optimal and safe use of MR contrast media, rapid and reliable image procession, as well as to the correct interpretation of common artifacts.", "\n\nThe main section of this book is devoted to the current clinical applications of MR angiography in the different body organs and anatomic regions as well as to the important role of this method in the managing of transplant patients. ", "The book is exquisitely illustrated with multiple high-quality demonstrative cases and as always presented in technically impeccable printing and lay out\n\nThe editors are internationally well known for their superior and longstanding knowledge in MR angiography and image procession. ", "They are supported by a group of distinguished collaborating authors, who are also experts in the field.", "\n\nI am very much indebted to the editors and especially to E. Neri for preparing this outstanding volume in a record short time period, which enabled them to include the latest technical advances in this rapidly evolving important radiological method.", "\n\nIt is highly recommended to general and organ specialized radiologists as a most welcome update of their knowledge and as a practical guide in their daily practice. ", "I am convinced that this volume, which nicely completes the list of topics dealt with in our series, will meet appropriate interest and success with our readers.", "\n\nAlbert L. Baert\n\nLeuven, Belgium\n\nPreface\n\nMagnetic resonance angiography, in short MRA, is a fast growing imaging procedure that fills many sessions of our busy MR suites.", "\n\nHowever, at early introduction, when only unenhanced sequences could be acquired by using phase contrast and time-of-flight, MRA was considered just an optional tool that could be used to complement a standard MRI examination.", "\n\nNowadays, the technique is a well-established noninvasive angiographic examination, substitutive of conventional diagnostic angiography and of paramount importance in many clinical situations.", "\n\nThe use of contrast-enhanced sequences has improved both contrast and spatial resolution, making MRA a key imaging tool in the study of abdominal aorta and peripheral vessels, where it plays a significant role in the planning of interventional procedures.", "\n\nMoreover, MRA is increasingly moving toward the study of more complex clinical situations, as in the case of transplantation surgery.", "\n\nThis book was made possible because of the valuable contributions of many outstanding experts in this field, and it covers all the relevant clinical applications of MRA in the study of the whole body. ", "Starting from the basic imaging techniques, it moves to a detailed description of the vascular anatomy and deals with the most appropriate strategies for the diagnosis of vascular pathology.", "\n\nWe hope that this book may help practicing radiologists in making the best use of this exciting methodology, and encourage referring physicians to include MRA in the diagnostic work-up of their patients.", "\n\nEmanuele Neri\n\nMirco Cosottini\n\nDavide Caramella\n\nPisa, Italy\n\nContents\n\nImage Acquisition Technique and Sequences1\n\n1 Flow-Based MRA3\n\nAngelo Vanzulli\n\n2 MR Angiography Contrast Agents7\n\nIlaria Pesaresi and Mirco Cosottini\n\n3 Image Acquisition Technique and Sequences Contrast-Enhanced MRA17\n\nMarco Francone, Michele Anzidei, Ilaria Iacucci, Francesco Vullo and Carlo Catalano\n\n4 Artifacts in MR-Angiography27\n\nAndrea Laghi, Pasquale Paolantonio, Marco Rengo and Paola Lucchesi\n\n5 Image Processing35\n\nLorenzo Faggioni and Emanuele Neri\n\nClinical Applications45\n\n6 Radiologic Vascular Anatomy47\n\nClaudio Vignali, Valentina Vallini and Francesca Bianchi\n\n7 Neck Vessels73\n\nMirco Cosottini and Ilaria Pesaresi\n\n8 Thoracic Aorta and Pulmonary Vessels87\n\nMarco Di Terlizzi, Ambrosini Roberta, Rita Fossaceca and Alessandro Carriero\n\n9 Heart and Coronary Arteries105\n\nMassimo Lombardi and Matteo Milanesi\n\n10 Abdominal Aorta and Renal Arteries115\n\nVirna Zampa, Francesca Turini, Lorenzo Faggioni and Gabriele Caproni\n\n11 Peripheral Vessels127\n\nFrancesco De Cobelli, Elena Belloni and Alessandro Del Maschio\n\nSpecial Topics: Transplants143\n\n12 MRA in Liver and in Orthotopic Liver Transplants145\n\nPiero Boraschi, Francescamaria Donati, Simonetta Salemi and Francesca Turini\n\n13 MRA in Transplanted Pancreas and Kidneys157\n\nPiero Boraschi, Francescamaria Donati and Valentina Battaglia\n\nSubject Index169\n\nList of Contributors175\n\nList of Contributors\n\nMichele Anzidei\n\nDepartment of Radiology, University of Rome, \"La Sapienza,\" Policlinico Umberto I, viale Regina Elena 324, 00161 Roma, Italy\n\nValentina Battaglia\n\nDiagnostic and Interventional Radiology, Department of Oncology Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy\n\nElena Belloni\n\nRadiology Department, Vita-Salute University, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy\n\nbelloni.elena@hsr.it\n\nFrancesca Bianchi\n\nDiagnostic and Interventional Radiology, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nPiero Boraschi\n\nSecond Unit of Radiology, Department of Oncologic and Radiological Sciences, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy\n\np.boraschi@do.med.unipi.it\n\nGabriele Caproni\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nDavide Caramella\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\ncaramella@med.unipi.it\n\nAlessandro Carriero\n\nDiagnostic and Interventional Radiology Department, University del Piemonte Orientale \"A. AVOGADRO\", Corso Mazzini 18, 28100 Novara, Italy\n\nprofcarriero@virgilio.it\n\nCarlo Catalano\n\nDepartment of Radiology, University of Rome, \"La Sapienza,\" Policlinico Umberto I, viale Regina Elena 324, 00161 Roma, Italy\n\ncarlo.catalano@uniroma1.i\n\nMirco Cosottini\n\nUnit of Neuroradiology, Department of Neurosciences, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nmircocosottini@libero.it\n\nFrancesco De Cobelli\n\nRadiology Department, Vita-Salute University, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy\n\nfrancesco.decobelli@hsr.it\n\nAlessandro Del Maschio\n\nRadiology Department, Vita-Salute University, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy\n\nMarco Di Terlizzi\n\nDiagnostic and Interventional Radiology Department, Corso Mazzini 18, 28100 Novara, Italy\n\nFrancescamaria Donati\n\nSecond Unit of Radiology, Department of Oncologic and Radiological Sciences, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy\n\nLorenzo Faggioni\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Radiodiagnostica 1 Universitaria, Ospedale Cisanello. ", "Via Paradisa 2, 56100 Pisa, Italy\n\nRita Fossaceca\n\nDiagnostic and Interventional Radiology Department, Corso Mazzini 18, 28100 Novara, Italy\n\nMarco Francone\n\nDepartment of Radiology, University of Rome \"La Sapienza\", Policlinico Umberto I, viale Regina Elena 324, 00161 Roma, Italy\n\nIlaria Iacucci\n\nDepartment of Radiology, University of Rome \"La Sapienza\", Policlinico Umberto I, viale Regina Elena 324, 00161 Roma, Italy\n\nAndrea Laghi\n\nDepartment of Radiological Sciences \"Sapienza\" \\- University of Rome, Polo Pontino, I.C.O.T. Hospital, Viale Franco Fagiana 34, 04100 Latina, Italy\n\nandrea.laghi@uniroma1.it\n\nMassimo Lombardi\n\nU.O.C. Cardiovascular RM, C.N.R./\"G. Monasterio\" Foundation, Via Moruzzi 1, 56124 Pisa, Italy\n\nmassimo.lombardi@ifc.cnr.it\n\nPaola Lucchesi\n\nDepartment of Radiological Sciences \"Sapienza\" \\- University of Rome, Polo Pontino, I.C.O.T. Hospital, Viale Franco Fagiana 34, 04100 Latina, Italy\n\npaola.lucchesi@email.it\n\nMatteo Milanesi\n\nU.O.C. Cardiovascular RM, C.N.R./\"G. Monasterio\" Foundation, Via Moruzzi 1, 56124 Pisa, Italy\n\nEmanuele Neri\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Radiodiagnostica 1 Universitaria, Ospedale Cisanello. ", "Via Paradisa 2, 56100 Pisa, Italy\n\nneri@med.unipi.it\n\nPasquale Paolantonio\n\nDepartment of Radiological Sciences \"Sapienza\" \\- University of Rome, Polo Pontino, I.C.O.T. Hospital, Viale Franco Fagiana 34, 04100 Latina, Italy\n\npaolantonipasquale@hotmail.com\n\nIlaria Pesaresi\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nMarco Regno\n\nDepartment of Radiological Sciences, \"Sapienza\" \\- University of Rome, Polo Pontino, I.C.O.T. Hospital, Viale Franco Fagiana 34, 04100 Latina, Italy\n\nmarco.rengo@gmail.com\n\nAmbrosini Roberta\n\nDiagnostic and Interventional Radiology Department, Corso Mazzini 18, 28100 Novara, Italy\n\nSimonetta Salemi\n\nSecond Unit of Radiology, Department of Oncologic and Radiological Sciences, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy\n\nFrancesca Turini\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nValentina Vallini\n\nDiagnostic and Interventional Radiology, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nAngelo Vanzulli\n\nNiguarda Ca Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milano, Italy\n\nangelo.vanzulli@ospedaleniguarda.itangelo.vanzulli@fastwebnet.it\n\nClaudio Vignali\n\nDiagnostic and Interventional Radiology, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\ncvignali@med.unipi.it\n\nFrancesco Vullo\n\nDepartment of Radiology, University of Rome \"La Sapienza\", Policlinico Umberto I, viale Regina Elena, 324, 00161 Roma, Italy\n\nVirna Zampa\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nv.zampa@med.unipi.it\n\nFrancesco Vullo\n\nDepartment of Radiology, University of Rome \"La Sapienza\", Policlinico Umberto I, viale Regina Elena, 324, 00161 Roma, Italy\n\nVirna Zampa\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy\n\nv.zampa@med.unipi.it\n\n# Part 1 \nImage Acquisition Technique and Sequences\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_1(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 1. ", "Flow-Based MRA\n\nAngelo Vanzulli1\n\n(1)\n\nNiguarda Ca Granda Hospital, Piazza Ospedale Maggiore 3, Milano, 20162, Italy\n\n1.1 Time of Flight (TOF) MR Angiography\n\n1.2 Phase Contrast (PC) MR Angiography\n\n1.3 T2-Based MR Angiography\n\nReferences\n\nAbstract\n\nMR imaging is particularly suited to depict vessels and this can be obtained using sequences that highlight flow. ", "In the era of nephrogenic sistemic fibrosis these unenhanced sequences are used more frequently than in the past.", "\n\nThese sequences are based on three principles: time of flight, phase contrast, and fresh blood acquisitions. ", "The physical principles of these acquisitions are explained in order to understand the basis of MR angiography.", "\n\nIn the evaluation of vessel lumen, MR sequences can be applied in order to detect flow. ", "These sequences are based mainly on three principles: (a) using the inflow into the slab of fresh spins, which are not subjected to all the radiofrequency pulses, unlike the stationary tissue: time-of-flight phenomenon; (b) detecting the phase changes of moving spins subjected to a gradient: phase contrast; (c) optimizing an ultrafast spin echo or gradient echo sequence, in order to obtain bright signal from blood due to its T2 properties.", "\n\nIn all three techniques, the signal and resulting image are produced by physiological flow, and these methods will be degraded by artifacts in case of complex or turbulent flows [1].", "\n\nIn general, the MR angiography techniques use sequences derived from T1-weighted gradient echo sequences. ", "In fact vessels generally appear as hyposignals in spin echo sequences because of the outflow effect. ", "The spins in the blood are excited during the slice selection pulse. ", "At time TE/2, the flowing spins move out of the slice and are not subjected to the 180° pulse: therefore they do not give any signal in the original voxel (signal void). ", "When the flow is turbulent and not laminar, some spins are back in the original voxel at the time of the echo refocusing and give some signal (artifact) [2].", "\n\n## 1.1 Time of Flight (TOF) MR Angiography\n\nIn time-of-flight MR angiography [3], gradient-echo sequences are optimized to favor the vascular signal over that of the surrounding tissues by saturating the stationary tissue signal with very short TR (TR largely inferior to the tissues T1). ", "The longitudinal magnetization of these tissues does not have time to regrow after some 90° pulses and after their signal weakens. ", "The flowing spins coming into the slice volume have not been saturated yet, giving high signal intensity. ", "The strength of the vascular signal is proportional to the flow velocity (faster flow gives higher signal intensity) and depends on the length and orientation of the vessel (the vascular signal will be higher if the slice is perpendicular to the axis of the vessel) due to shorter travel of the spins into the slice volume. ", "In the case of a long vessel tract traveling into the slice, flowing spins will receive many saturating pulses, lowering the signal they can return from them. ", "The shorter the TR and the higher the flip angle, the stronger is the stationary tissues suppression, but slow flowing spins can also be suppressed. ", "A longer TE causes dephasing of the flowing spins, lowering vessel signal intensity. ", "An increased slice thickness also causes a longer travel of the flowing spins into the imaging plane with some degree of vessel signal loss due to the progressive saturation of the spins.", "\n\nThe main limitations of time-of-flight MRA are signal loss linked to spin dephasing when the flow is complex or turbulent (stenosis), when the flow is too slow or oriented parallel to the slice plane and poor signal suppression of the stationary tissues when substances with very short T1 relaxation time are present (fat, blood degradation products) [4]. ", "Vascular contrast can be improved by suppressing the signal coming from static tissues, by means of a magnetization transfer preparation pulse or by selective excitation of water, or by fat saturation [5].", "\n\nTo selectively visualize arterial or venous flow, presaturation bands can be applied upstream to the selected slice (arterial suppression to detect venous flow only) or dow nstream to the selected slice (venous suppression).", "\n\nTime of Flight MR angiography can be obtained in 2D or 3D mode.", "\n\nIn 2D acquisition, single thin slices are obtained in sequential order while in 3D acquisition, a thicker slice is excited and many single partitions are reconstructed from this thick slab by different phase encoding steps. ", "The main advantage of the 2D technique is better sensitivity to slow flows (shorter travel of the moving spins into the slice), with the possibility of using higher flip angles (giving better stationary tissue saturation). ", "The main drawback of 2D acquisition is poor through plane spatial resolution due to the thickness of the slices.", "\n\nContrary to the 2D TOF and 3D TOF, volumetric imaging gives good spatial resolution in all spatial directions, with a better signal-to-noise ratio, but the flowing spins travel through a thick volume, with progressive signal loss due to in-plane saturation. ", "The slowest flows are more sensitive to this artifact. ", "Flow saturation can be reduced by (a) dividing 3D acquisition into thinner slabs (MOTSA: multiple overlapping thin slab acquisition), (b) by using a variable excitation angle that is lower as the flow enters the volume and higher as it leaves the volume (TONE: tilted optimized nonsaturating excitation), thus compensating relaxation of short T1 tissues.", "\n\n## 1.2 Phase Contrast (PC) MR Angiography\n\nPhase contrast angiography relies on dephasing the moving spins submitted to a bipolar gradient in gradient echo acquisitions. ", "In the presence of a bipolar gradient of a given intensity and time, the moving spins will dephase in proportion to their velocity while stationary spins will be dephased and rephased by the opposite gradients, returning to their original status. ", "So the flow velocity is proportional to the phase shift and the stationary tissues phase shift is null.", "\n\nSimilar to spatial encoding in the phase direction, the possible phase values range from −π to +π. ", "Beyond this range of values, aliasing occurs, causing wrong velocity encoding [6].", "\n\nThe encoding gradient characteristics are thus defined in order to encode flows within a certain velocity range from −venc to +venc; this range has to be determined by the user before acquiring the data. ", "Any velocity outside this range will be poorly encoded (similar to what happens in pulsed and color Doppler with pulse repetition frequency-PRF). ", "The bipolar gradients are applied in a particular axis (x, y, or z) and the dephasing of the spins moving along the gradient axis is proportionate to their velocity, gradient intensity and the application time of a gradient lobe. ", "Magnetic field heterogeneities can cause stationary spin dephasing. ", "To compensate for these dephasings, a second acquisition is obtained, reversing the order of the encoding gradient lobes, and subtracting the two acquisitions: the moving spins will cumulate dephasings in the opposite direction, while dephas-ing of stationary spins due to field heterogeneities will be identical for both acquisitions, disappearing in subtraction.", "\n\nTo depict the movements in all the directions of space, the acquisitions are repeated with flow-encoding gradients in each of the three spatial directions. ", "An additional acquisition with no flow-encoding gradient will serve as a reference.", "\n\nThe images acquired with flow-encoding gradient are summed to depict flow in all directions and subtracted from the reference image without encoding gradient. ", "With this subtraction only vessels are depicted, as well as those that run parallel to the imaging plane.", "\n\nPhase data allow the measurement of flow velocity and direction [7].", "\n\nThe limitations of this technique relate to intra-voxel dephasing in case of complex or turbulent flow with loss of flow signal in the presence of vascular loops, bifurcations, or stenoses.", "\n\nPhase contrast MRA can be obtained from a thick slab 2D acquisition, allowing synchronization with ECG pulse (cine MR phase contrast angiography) or allowing to test different flow velocities for further 3D longer acquisitions.", "\n\nTo obtain a quantitative evaluation of flows, the slice plane has to be perpendicular to flow direction. ", "Thus a flow velocity curve can be obtained as a function of time, which, when coupled with the area of the vessel section, will permit one to calculate flow rate.", "\n\nIn phase contrast 3D MR angiography, each partition is encoded in three directions, resulting in long acquisition time.", "\n\nThe 3D acquisition gives thinner partitions with better image quality than in 2D single-slice technique.", "\n\nBecause Phase Contrast MR Angiography is more sensitive than time-of-flight to slow flow, its main application is cerebral venous imaging. ", "The scan time of these sequences can be greatly reduced by parallel imaging [8].", "\n\n## 1.3 T2-Based MR Angiography\n\nThese MR angiography techniques are based on two different sequences: a very short TR-TE gradient echo acquisition called balanced fast gradient echo (or tru-FISP) and a 3D half-fourier fast spin echo sequence prospectively synchronized with ECG pulse.", "\n\nThe first technique (balanced fast gradient echo) relies on an ultrafast gradient echo sequence in which the TR value is exactly equal to 2TE. ", "This causes the production of a stimulated spin echo signal every three gradient echo read-out which gives a particular high signal for fluids and blood (proportional to T2/T1).", "\n\nThis sequence allows the detection of the vessel, but fluids also have the same high signal intensity, preventing one from obtaining MIP images.", "\n\nThe other MRA technique based on T2 relaxation of blood is based on a 3D ultrafast half Fourier spin echo acquisition with prospective ECG synchronization and fat suppression with an inversion pulse (STIR) [9].", "\n\nThe half Fourier spin echo sequence is fast (less than 1 s per slice) and its movements are insensitive. ", "The center of k-space is filled by precocious echo (short effective TE) in which the flow-induced dephas-ing has not reduced the vascular signal yet. ", "The acquisition plane is parallel to the axes of the vessels. ", "The phase encoding direction is chosen parallel to the axes of the vessels in order to prevent the read-out gradient from weakening the vascular signal.", "\n\nProspective ECG synchronization triggers acquisitions at the same moment in the cardiac cycle. ", "The optimal interval between R wave of the ECG and acquisition is determined by a prior calibration sequence and optimized for the vessel of interest. ", "This interval is chosen with different 2D images obtained with different time delays.", "\n\nA 3D acquisition with a time delay adjusted to obtain signals from slow flowing venous vessels can be used as a reference and be subtracted from the arterial acquisition to depict only arteries.", "\n\nSTIR preparation reduces the signal from the surrounding fat tissues.", "\n\nReferences\n\n1.", "\n\nErsoy H, Zhang H (2006) Peripheral MR angiography. ", "J Cardiovasc Magn Reson 8(3):517-528CrossRefPubMed\n\n2.", "\n\nFoo TK, Polzin JA (2005) MR angiography physics: An update. ", "Magn Reson Imaging Clin N Am 13(1):1-22CrossRefPubMed\n\n3.", "\n\nAnderson CM, Lee RE (1993) Time-of-flight techniques: Pulse sequences and clinical protocols. ", "Magn Reson Imaging Clin N Am 1:217-227PubMed\n\n4.", "\n\nMcCauley TR, Monib A, Dickey KW, et al. (", "1994) Peripheral vascular occlusive disease: Accuracy and reliability of time-of-flight MR angiography. ", "Radiology 192:351-357PubMed\n\n5.", "\n\nAtkinson D, Brant-Zawadzki M, Gillan G, et al. (", "1994) Improved MR angiography: Magnetization transfer suppression with variable flip angle excitation and increased resolution. ", "Radiology 190(3):890-894PubMed\n\n6.", "\n\nO'Donnell M (1985) NMR blood flow imaging using multiecho, phase contrast sequences. ", "Med Phys 12:59-64CrossRefPubMed\n\n7.", "\n\nSteinberg FL, Yucel EK, Dumoulin CL, et al. (", "1990) Peripheral vascular and abdominal applications of MR flow imaging techniques. ", "Magn Reson Med 14:315-320CrossRefPubMed\n\n8.", "\n\nWilson GJ, Hoogeveen RM (2004) Parallel imaging in MR angiography. ", "Top Magn Reson Imaging 15(3):169-185CrossRefPubMed\n\n9.", "\n\nHo KY, de Haan MW, Oei TK, et al. (", "1997) MR angiography of the iliac and upper femoral arteries using four different inflow techniques. ", "AJR Am J Roentgenol 169:45-53 Miyazaki M, Sugiura S (2000) Non-contrast-enhanced MR angiography using 3D ECG-synchronized half-Fourier fast spin echo. ", "J Magn Reson Imaging 12(5):776-783PubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_2(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 2. ", "MR Angiography Contrast Agents\n\nIlaria Pesaresi1 and Mirco Cosottini2\n\n(1)\n\nDiagnostic and Interventional Radiology Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, Pisa, 56100, Italy\n\n(2)\n\nUnit of Neuroradiology Department of Neurosciences, University of Pisa, Via Roma 67, Pisa, 56100, Italy\n\n2.1 Magnetic Properties\n\n2.2 Relaxivity\n\n2.2.1 Paramagnetic Contrast Agents\n\n2.2.2 Superparamagnetic and Ferromagnetic Contrast Agents\n\n2.3 Susceptibility Effect\n\n2.4 Contrast Agents for Vascular Imaging\n\n2.4.1 Paramagnetic Gadolinium Agents\n\n2.4.1.1 Extracellular Fluid Agents\n\n2.4.1.2 Blood-Pool Agents\n\n2.4.2 Superparamagnetic Ultrasmall Iron Oxide Particles\n\n2.5 Safety\n\n2.6 Future Perspectives\n\n2.6.1 Contrast Agent Use at High Field\n\n2.6.2 Other Contrast Agents\n\n2.6.2.1 Gadolinium-Based Particulate Agents\n\n2.6.2.2 Hyperpolarized Contrast Agents\n\n2.6.2.3 Chemical Exchange Saturation Transfer (CEST)\n\nReferences\n\nAbstract\n\nGadolinium-based agents are the most widely employed agents for CE-MR angiography. ", "They act as positive paramagnetic substances, thus they increase the vascular signal by strongly reducing the T1 relaxation time of blood. ", "Several Gd-based agents have been approved for clinical application to date. ", "On the basis of their distribution, Gd-agents are subdivided into extra-cellular fluid (ECF) and blood-pool agents.", "\n\nConventional ECF agents have been employed for long time in vascular imaging. ", "Given their brief plasma half-life, they require a careful timing of the MRA acquisition in order to properly sample the contrast bolus first pass.", "\n\nBlood-pool agent have been recently introduced. ", "They are characterized by high relaxivity constants. ", "Since they persist in the vascular compartment for a quite long time, blood-pool agents allow the steady state acquisition of angiograms with higher spatial resolution.", "\n\nContrast agents for magnetic resonance imaging reached clinical validation in 1988 and were initially employed for the visualization of diseased tissues. ", "MR angiography imaging was related to flow-based phenomenon until the introduction of MRA with contrast agents in early 1990s (Creasy et al. ", "1990).", "\n\n## 2.1 Magnetic Properties\n\nMR contrast agents are represented by molecules endowed with not-null magnetic properties, which act by affecting the relaxation times of the surrounding water protons.", "\n\nThe magnetic property of a substance derives from the existence of unpaired electrons within the externals orbitals, a typical characteristic of transitional metal (e.g., iron, manganese) and lanthanide ions (e.g., gadolinium). ", "The number of unpaired electrons influences the magnetic moment of a substance, which reflects the efficiency of that substance to modify the environmental magnetic field (magnetic susceptibility).", "\n\nSubstances with not-null magnetic properties are divided into paramagnetic, ferromagnetic, and superparamagnetic. ", "Paramagnetic substances acquire a net magnetism only when exposed to an external magnetic field. ", "They are made of multiple ions which act as isolated magnetic dipoles without reciprocal magnetic interaction, so that the overall net magnetization is given by the sum of single ion magnetizations.", "\n\nFerromagnetic and superparamagnetic materials are characterized by a cooperative interaction among the constituting magnetic elements so that the resulting magnetic field is much higher than the sum of the single dipoles. ", "While superparamagnetic materials acquire a net magnetic field only when submitted to an external magnetic drift, ferromagnetic ones maintain a net magnetism even under neutral external conditions. ", "Iron oxides may exhibit either superparamagnetism (when arranged in small particles) or ferromagnetism (when organized in large crystals).", "\n\n## 2.2 Relaxivity\n\nAll contrast agents shorten both T1 and T2 relaxation times of surrounding protons. ", "This effect on proton relaxation is ruled by the relaxivity constant, which indicates the contrast agent's ability to decrease the T1 (longitudinal relaxivity, r1) and T2 (transversal relaxivity, r2) relaxation times of the water protons per unit (mM) concentration of metal ion.", "\n\nThe relaxation effect differs for paramagnetic, super-paramagnetic, and ferromagnetic contrast agents.", "\n\n### 2.2.1 Paramagnetic Contrast Agents\n\nThe relaxation effect of paramagnetic substances in solution is mainly realized through dipolar interactions between the paramagnetic ions and the hydrogen molecules of water belonging to the so-called inner sphere. ", "Indeed, paramagnetic contrasts can be modelled as isolated ions surrounded by an inner and an outer sphere of interacting water molecules. ", "While the energetic transfer between the metal ion and inner sphere water molecules is explained by dipolar interactions, the relaxation effect on outer-sphere molecules is explained by the Curie-spin relaxation theory (Gueron 1975; Muller et al. ", "2001; Caravan and Randall 2006).", "\n\nThe relaxation efficiency (i.e., relaxivity) of paramagnetic materials is governed by many factors such as the magnetic moment of the ion, the number of water molecules within the inner-sphere and the rate of exchange among the inner sphere and the bulk solvent. ", "Moreover, the local magnetic field generated by the ion must fluctuate at a rate (ωi) close to the hydrogen Larmor frequence (ωH) in order to stimulate hydrogen relaxation.", "\n\nAs free metal and lanthanide ions are embedded into chelates to avoid in vivo toxicity, contrast agent relaxivity is influenced by both paramagnetic ion and molecular ligands properties.", "\n\nIn particular, ligands influence the number of water molecules within the inner sphere and the fluctuation rate of the ionic magnetic field ωi..\n\nParamagnetic agents modify proton relaxation according to the following equations:\n\n(2.1)\n\n(2.2)\n\nwhere T1 and T2 identify the final relaxation times in the presence of the contrast agent, T10 e T20 the initial relaxation times, C the molar concentration of the contrast agent, r1 and r2 the longitudinal and transversal relaxivity respectively of the contrast agent.", "\n\nFor all medically used paramagnetic contrast agents r2 is higher than r1. ", "However, as 1/T10 is lower than 1/T20, a dominant effect on T1 relaxation is observed.", "\n\n### 2.2.2 Superparamagnetic and Ferromagnetic Contrast Agents\n\nThe relaxation effect of superparamagnetic and ferromagnetic agents is not based on direct dipolar interactions. ", "These agents are constituted by particles of variable dimension which form a stable suspension. ", "As no water molecules are admitted within the particles, direct interactions between ions and water molecules are prevented. ", "The relaxation effect is exerted on water molecules diffusing near the particles (the outer sphere) through the Curie-spin relaxation (Muller et al. ", "2001; Gueron 1975).", "\n\nMost superparamagnetic and ferromagnetic agents are made of iron oxide crystals enveloped by a dextran or siloxan coating which prevents agglomeration. ", "Each crystal is made of several thousands of magnetic ions which interact cooperatively so that the magnetic moment of the entire crystal tends to align with the external magnetic field.", "\n\nUltrasmall particles of iron oxides (USPIOs) contain a single iron oxides crystal within the particle core and show a superparamagnetic behavior. ", "Small particles of iron oxide (SPIOs) contain multiple iron oxide crystals within the particle core and behave as ferromagnetic agents.", "\n\nRelaxivity constants are strictly influenced by the particles core dimension. ", "In particular, r2/r1 ratio increases with increasing particle size; thus smaller particles are much better T1-shortening agents than larger ones (Roch et al. ", "1999).", "\n\nUSPIOs show high r1 and r2 values, so they can be employed to either increase signal intensity on T1-weighted images or decrease signal on T2-weighted images.", "\n\nSPIOs are characterized by the highest r2 constant, and then they cause a dramatic signal drop on T2-weighted images.", "\n\nTo sum up, paramagnetic substances are classified as T1 agents or positive agents because they relevantly increase signal intensity on T1-weighted images. ", "Ferromagnetic agents (SPIOs) are classified as T2 agents or negative agents as they cause a signal drop on T2-weighted images. ", "Superparamagnetic agents (USPIOs) can be classified as T1 or T2 agents as they can either increase signal intensity on T1-weighted images or decrease signal on T2-weighted images.", "\n\n## 2.3 Susceptibility Effect\n\nEven if contrast agents are generally exploited for their effect on proton relaxation, they can also exert a relevant susceptibility effect (T2* agents).", "\n\nAll contrast agents locally increase the static magnetic field (effective magnetic field). ", "If field inhomoge-neities reach a sufficient strength, they can significantly affect signal intensity by broadening the Larmor frequency and fastening the protons dephasing within a voxel. ", "This effect is most evident with long TE (on T2-weighetd images) as intravoxel dephasing and diffusion of water molecules through regions of variable magnetic field become more evident (Caravan and Randall 2006).", "\n\nThe existence of strong field inhomogeneities subsequent to contrast agent administration can be due to crystals aggregation, as observed with SPIOs, or due to compartmentalization.", "\n\nFerromagnetic, superparamagnetic, and paramagnetic agents can all undergo compartmentalization in tissues or vessels and manifest a medically relevant susceptibility effect.", "\n\n## 2.4 Contrast Agents for Vascular Imaging\n\nVascular MR contrast agents for clinical application are mainly represented by positive paramagnetic agents. ", "Few studies have dealt with superparamagnetic iron oxides for vascular imaging, however, to date these agents have generally been restricted to the investigation of the reticulo-endothelial-system (RES).", "\n\n### 2.4.1 Paramagnetic Gadolinium Agents\n\nMost contrast agents approved for human applications are gadolinium-based. ", "Gadolinium is a lanthanide ion endowed with a high magnetic moment and a proper magnetic field fluctuation rate which result in a high relaxivity constant. ", "Given its high toxicity, gadolinium needs to be embedded into che-lates to be administered in vivo. ", "Different gadolinium chelates show different relaxation properties and different biodistribution and must be subdivided into extracellular fluid (ECF) and blood-pool agents.", "\n\n#### 2.4.1.1 Extracellular Fluid Agents\n\nECF agents represent the first generation of clinically approved gadolinium contrast-agents and their role in contrast-enhanced magnetic resonance imaging is well established. ", "They are characterized by a brief vascular phase, then they rapidly equilibrate in the extracellular space (distribution half-life of about 5 min) reaching roughly the same concentration in the vascular and interstitial compartments.", "\n\nGiven their brief vascular phase, the adoption of ECF agents for MR angiography implies a careful timing and a fast imaging in order to capture the contrast bolus first pass in the arterial district.", "\n\nThe clearance of ECF agents is mainly mediated by the renal system, with an elimination half-life of about 80 min.", "\n\nAll gadolinium ECF agents are characterized by an eight-coordinate ligand binding to gadolinium (III) to prevent the release of ions in solution. ", "Gadolinium ligands are represented by small molecules (polyamin-ocarboxylate/phosphonate derivatives) which differ in their electrical charge, either neutral or negative, and in their chemical structure, either cyclic or linear (Table 2.1 and Fig. ", "2.1).", "\n\nTable 2.1.", "\n\nGadolinium-based extracellular fluid contrast agents approved for marketing\n\nType | Generic name | Trade name | Chemical abbreviation | Chemical structure | R1 (0.5 T, 37°C) (1/mM/s) | R2 (0.5 T, 37°C) (1/mM/s) | Osmolaritya (Osm/Kg)\n\n---|---|---|---|---|---|---|---\n\nIonic | Gadopentate dimeglumine | Magnevist (Bayer Schering) | Gd-DTPA | Linear | 3.8 | 3.8b | 1.96\n\n|\n\nGadoterate meglumine | Dotarem (Guerbet) | Gd-DOTA | Cyclic | 3.6 | 4.8 | 1.35\n\nNeutral | Gadodiamide | Omniscan (GE Healthcare) | Gd-DTPA-BMA | Linear | 3.9 | 4.3b | 0.79 - (1.90)\n\n|\n\nGadoteridol | Prohance (Bracco) | Gd-HP-DO3A | Cyclic | 3.7 | 4.8b | 0.63 - (1.91)\n\n|\n\nGadobutrol | Gadovist (Bayer Schering) | Gd-BT-DO3A | Cyclic | 3.6\n\n| |\n\n0.57 - (1.39)\n\n|\n\nGadoversetamide | OptiMARK (Mallinckrodt) | Gd-DTPA-BMEA | Linear | 4.7\n\n| |\n\n1.11\n\naOsmolarity values at 0.5 M concentration, except those in parentheses (1 M concentration)\n\nbRelaxivity at 0.5 T\n\nFig. ", "2.1.", "\n\nChemical structure of gadolinium-based extracellular fluid (ECF) agents\n\nNeutral chelates allow lower osmolarity in solution with respect to the ionic ones and can be formulated at high-concentration.", "\n\nLinear chelates have been reported to present a slightly lower thermodynamic stability with respect to cyclic complexes and they might theoretically facilitate the release of gadolinium ions because of biochemical competitions for the binding site (Wiginton et al. ", "2008). ", "However, no evidence of relevant effects in vivo has been reported.", "\n\nDespite different chemical structures, ECF agents are characterized by almost the same relaxation properties, biodistribution, and plasma half-life.", "\n\nECF agents are employed in contrast-enhanced MRA for bright blood imaging. ", "Their effect on T1 relaxation is ruled by (2.1) and thereafter, it linearly depends on the concentration of contrast agents. ", "While performing CEMRA examination, the concentration of contrast media within the vessel depends not only on contrast media formulation but also on physiological parameters as well as the injection rate and the contrast amount, as detailed in Chap. ", "7.", "\n\nContrast agents formulated at high concentration potentially allow higher relaxation effects. ", "However, they modify the bolus geometry by reducing the bolus length and are thus particularly suited for fast angio-graphic imaging.", "\n\n#### 2.4.1.2 Blood-Pool Agents\n\nWhile ECF agents rapidly leak out from the vascular compartment, the blood-pool agents (BPAs) are con-fined within vessels for a quite long time.", "\n\nIn order to keep gadolinium contrast complexes within the vascular compartment, two main approaches have been adopted. ", "The first approach consists in increasing the size of gadolinium ligands (large-size BPAs) and the second one in utilizing small gadolinium ligands reversibly bound to plasma proteins (small-size BPAs).", "\n\nLarge-size BPAs were initially obtained through covalent binding of gadolinium to macromolecules such as polylysine, dextran, or modified bovine serum albumin. ", "These compounds showed a negligible leakage in the extravascular compartment and provided optimal vascular imaging. ", "Moreover, they were associated with very high gadolinium relaxivity because large-size ligands lessen the gadolinium magnetic field fluctuation rate and favor energetic exchange between the protons and gadolinium. ", "Despite such promising features, large-size BPAs did not achieve clinical approval as they were limited by a very-slow blood clearance and by potentially dangerous immu-nologic effects.", "\n\nTo overcome these problems, a second generation of large-size BPAs has been developed. ", "This new class of BPAs agents (Table 2.2 and Fig. ", "2.2) is made of gadolinium complexes large enough to persist within vessels for long time but small enough to be excreted through glomerular filtration. ", "They are still characterized by high relaxivity. ", "An example is repre sented by Gd-DTPA-17 cascade polymer (Gadomer-17, B ay e r Schering), a macromolecular complex with a dentritic architecture which includes multiple gadolinium ions. ", "Gadomer-17 does not show significant affinity for plasma proteins and undergoes renal clearance.", "\n\nTable 2.2\n\nGadolinium-based blood pool agents approved for marketing or under clinical investigation\n\nType | Generic name | Trade name | Chemical abbreviation | Affi nity for albumin | Boundfraction (%) | R1 (0.5 T/37°C) (1/mM/s) | R2 (0.5 T/37°C) (1/mM/s)\n\n---|---|---|---|---|---|---|---\n\nLarge-size BPAs | Gadomer 17,24 | Gadomer-17 (Bayer Schering) | Gd-DTPA-17 cascade polymer | -- | -- | 11.9a | 16.5a\n\n|\n\nGadomelitol | Vistarem (Guerbet) | P792 | -- | -- | 45 | 50\n\nSmall-size | Gadobenate | Multihance | Gd-BOPTA | Weak | 10 | Buffer: 4.4 | 5.6\n\nBPAs\n\n| |\n\n(Bracco)\n\n| | | |\n\nPlasma: 9.7\n\n| \n|\n\nGadofosveset trisodium | Vasovistb (Bayer Schering) | MS-325 | Strong | 91 | Buffer: 6.6 Plasma: 50\n\n| \n|\n\nGadocoletic acid | B22956 (Bracco) | B22956 | Strong | 95 | Buffer: 39 Plasma: 44.5\n\n|\n\naRelaxivity at 1 T\n\nbApproved for marketing in Europe and USA\n\nFig. ", "2.2.", "\n\nChemical structure of some gadolinium-based blood-pool agents\n\nBiodegradable macromolecular complexes which decompose through disulfide-thiol exchange, facilitating the excretion of gadolinium chelates, are currently under development (Lu et al. ", "2004).", "\n\nSmall-size BPAs (Table 2.2) are designed to revers-ibly bind to plasma proteins, in particular to albumin which represents the protein with the highest concentration in plasma (about 0.67 mM). ", "The not-covalent binding to albumin is mediated by hydrophobic moieties attached to the chelating agents.", "\n\nThis class of contrast agents can be further subdivided on the basis of the level of affinity for plasma proteins. ", "Low-affinity BPAs (e.g., Gd-BOPTA, Multihance) are characterized by bound-fractions of about 10% while high-affinity BPAs (e.g., Gadofosveset trisodium, Vasovist or B22956) reach bound-fractions of 90-95%.", "\n\nSimilar to large-size BPAs, small-size BPAs have r1 relaxivity that is much higher than ECF agents, because of the lower fluctuation rate of gadolinium magnetic field secondary to the albumin binding.", "\n\nIt should be noted that neither large nor small-size BPAs can be considered pure blood-pool compounds, as they show a minimal diffusion into the interstitial space (Bremerich et al. ", "2007).", "\n\nContrast enhanced MR angiography may take advantage from BPAs. ", "Given the extended imaging window (concentration of BPAs in plasma remains stable for over 1 h), BPAs minimize the problem of sequence temporization and temporal resolution. ", "Furthermore, they potentially allow higher spatial resolution with acquisitions at the steady-state (Fig. ", "2.3) and extend the investigation from the arterial to the venous district. ", "All gadolinium-based BPAs, due to their high r1 relaxivities, provide potentially higher vessel-to-background signal ratio than ECF agents allowing the utilization of lower concentrations and doses. ", "Nevertheless, the effective signal gain on first pass magnetic resonance angiograms with BPAs, with respect to ECF agents, is controversial. ", "Indeed, according to both literature (Klessen et al. ", "2007) and personal data (Fig. ", "2.4), BPAs may show a reduced vessels-to-background relative contrast. ", "This finding could be explained by the nonlinear relationship between the T1 relaxation effect and the concentration of small-size BPAs. ", "Indeed, the relaxivity of small-size BPAs is strongly influenced by the albumin-bound fraction. ", "The reversible reaction between contrast complexes and albumin reaches equilibrium after a time interval, which depends on the reciprocal affinity constant. ", "During the contrast agent's first pass in the arterial district, the equilibrium between bound and unbound fractions may not be achieved yet. ", "Therefore, the first pass contrast relaxivity may be lower with respect to the steady-state one (Caravan and Randall 2006).", "\n\nFig. ", "2.3.", "\n\nContrast-enhanced MR angiography with a gadolinium blood-pool agent (Gadofosveset trisodium, Vasovist, Bayer Schering). ", "First pass contrast-enhanced angiograms (a) correctly classify the patient as having severe stenosis (#x003E;70%). ", "Nevertheless, the stenosis is overestimated with respect to the gold standard DSA (c) and the residual patent lumen is poorly defined. ", "The high spatial resolution MRA at steady state (b) increases the vessels' sharpness and allows a more clear depiction of the stenosis morphology (ulcerated plaque)\n\nFig. ", "2.4.", "\n\nVessels-to-background relative contrast on first pass CEMRA with gadolinium blood-pool and ECF agents. ", "The signal enhancement of a blood-pool agent (Gadofosveset trisodium, Vasovist, Bayer Schering) is compared with that of ECF agents on first-pass MRA. ", "Vessels' signal is measured by placing regions of interest in the aortic arch, in the subclavian and in the carotid arteries. ", "The relative vessels-to-background contrast (RC) is calculated by the ratio (SV − SF)/(SV + SF), where SV is the signal into the vessels and SF the signal of the background. ", "Gadofosveset shows a significantly lower signal enhancement in two regions\n\nTo date the only gadolinium blood-pool agent approved for marketing is Gadofosveset trisodium (Vasovist, Schering).", "\n\n### 2.4.2 Superparamagnetic Ultrasmall Iron Oxide Particles\n\nUSPIOs (Table 2.3) represent true BPAs, as they are too large to leak out from vessels. ", "While SPIOs (Table 2.3) are rapidly removed from the blood stream by endocytosis in liver, spleen, or lymp nodes through the reticulo-endothelial system (vascular half-life of about 10 min), USPIOs persist within vessels for quite a long time so that they can be exploited to obtain high-resolution steady-state angiograms. ", "Subsequent to RES clearance, iron oxide agents are incorporated in the body iron pool.", "\n\nTable 2.3.", "\n\nIron oxides-based contrast agents approved for marketing or under clinical investigation\n\nParticle type | Generic name | Trade name | Chemical abbreviation | Crystals diameter (nm) | Particle diameter (nm) | R1 (0.5 T, 37°C) (1/mM/s) | R2 (0.5 T, 37°C) (1/mM/s)\n\n---|---|---|---|---|---|---|---\n\nUSPIOs | Ferumoxtran | Sinerema (Guerbet) Combidex (AMAG Pharmaceuticals) | AMI-227 | 4.3-4.9 | 50 | 22.7 | 53.1\n\n|\n\nFeruglose | Clariscan (GE Healthcare) | NC 100150 | 4-7 | 20 | 21.8 | 35.3\n\n|\n\nFerucarbotran | Supravist (Bayer Schering) | SH U555 C | 3-5 | 20 | 22 | 45\n\nSPIOs | Ferumoxide | Endoremb (Guerbet) Feridexb (AMAG Pharmaceuticals) | AMI-25 | 4.3-4.8 | 200 | 24 | 107\n\n|\n\nFerucarbotran | Resovistb (Bayer Schering) | SH U555 A | 4.2 | 62 | 20 | 190\n\naWithdrawn from market\n\nbApproved for marketing in Europe and/or USA\n\nTo date, SH U555 C (Supravist, Bayer Schering) is the only USPIO agent which has completed the clinical trials, even though it has not achieved FDA approval. ", "It is a derivative of ferucarbutran with smaller dimensions with respect to Resovist, Bayer Schering (particle diameter of about 20 nm vs. 50 nm).", "\n\nWhile SPIO agents and some USPIOs (e.g., Sinerem, Guerbet) can be administered only by slow intravenous infusion, SH U555 C admits bolus injection, so it can be employed for both first pass and highresolution steady state angiography (up to 42 min postinjection) (Bremerich et al. ", "2007).", "\n\nGiven their superparamagnetic properties, USPIOs can be adopted as T1 agents to perform bright blood contrast-enhanced angiography. ", "To avoid signal loss due to rapid intravoxel dephasing (high r2 values and susceptibility effect), angiographic sequences with very low echo times are required (Bremerich et al. ", "2007).", "\n\n## 2.5 Safety\n\nECF gadolinium agents have been widely employed in clinical setting and their safety profiles have been deeply investigated. ", "For example, Gd-DTPA (Magnevist) has been used in more than 45 million magnetic resonance imaging procedures since 1988 and is currently used globally in more than 5 million applications annually. ", "The broadest category of spontaneously reported adverse events, that is subjective symptoms, occurs in less than 0.01% of procedures. ", "Within the total number of adverse events reported, the distribution of serious and non-serious reports was 9.3 and 90.7% respectively (Knopp et al. ", "2006).", "\n\nWith regard to blood-pool gadolinium agents, in particular Gadofosveset trisodium (Vasovist), phase II and phase III clinical trials report a safety profile comparable to that of conventional ECF gadolinium agents (Shamshi et al. ", "2006).", "\n\nAs gadolinium agents require very low doses to ensure adequate contrast enhancement compared to iodinate contrast agents, for many years they were considered safe compounds to be used in patients with renal function deficiency. ", "In the last years, an increasing alert on gadolinium-related nephrogenic systemic fibrosis (NFS) has arisen.", "\n\nNFS is a sclerosing disorder clinically characterized by indurated dermal plaques, mainly distributed in the lower extremities, and by fibrosis in other tissues such as striated muscles, myocardium, lungs, and dura mater (Wiginton et al. ", "2008).", "\n\nThe first case of NSF was reported by Cowper et al. ", "in 2000.The association between NSF and gadolinium contrast agents relies on the identification of gadolinium deposits in skin biopsies (Wiginton et al. ", "2008). ", "Up to now, the number of reported cases in the USA (about 130) is extremely small when compared with the millions of patients who have been exposed to gadolinium-based agents, which makes the overall risk of developing NSF very low (Geraldes and Laurent 2009). ", "NFS has been exclusively identified in patients with severely impaired renal function. ", "In these patients, the longer half-life of the contrast agents potentially increases the risk of trans- metallation with the release of free gadolinium ions in tissues (Bongartz 2007).", "\n\nAlthough there is currently evidence of a strong association between gadolinium exposure and the development of NSF in patients with severe renal failure, the causative role of gadolinium in the patho-genesis of the disease can not be stated with absolute certainty (Kurtkoty et al. ", "2008).", "\n\nOn 23 May 2007 the U.S Food and Drug Administration has asked manufacturers to include a new boxed warning on all gadolinium-based contrast agents, stating that patients with severe kidney insufficiency are at risk of developing NSF. ", "FDA has assessed that all gadolinium-based contrast agents marketed in the United States should be equally treated in this regard as it is not possible to know the extent of risk associated with each agent (Kanal et al. ", "2008).", "\n\nGiven the great concern on gadolinium-related NSF in patients with renal function impairment, an increasing interest has been addressed to iron oxide agents. ", "Indeed, USPIOs clearance is mediated by the reticulo-endothelial system and their safety profile is not altered in patients with kidney insufficiency (Neuwelt et al. ", "2009).", "\n\n## 2.6 Future Perspectives\n\n### 2.6.1 Contrast Agent Use at High Field\n\nEven though most contrast-enhanced MR angiogra-phy studies are currently performed with clinical 1.5 T scanners, higher magnetic fields (from 3 up to 7 T) are getting more and more widespread. ", "By increasing the external static magnetic field (B 0) both the relaxation properties of hydrogen protons and of contrast agents get modified.", "\n\nIndeed, as B 0 increases, water protons lessen their longitudinal relaxation and fasten their transversal relaxation. ", "The dependence of contrast agent relaxiv-ity from B 0 strength varies on the basis of the magnetic and chemical properties of the compounds.", "\n\nGadolinium ECF compounds manifest a minimal relaxivity field-dependence, while blood-pool gadolinium agents show relevant r1 variations at different B 0. ", "Such discrepancy between ECF and BPAs agents is mainly determined by the different fluctuation rates of gadolinium magnetic field (ωg). ", "Indeed, BPAs ligands (both large-size and small-size ligands) slow down molecule tumbling and reduce ωg. ", "This effect may strongly enhance r1 with a variable effectiveness depending on the external magnetic field B 0.", "\n\nIron oxide agents dramatically increase their transversal relaxivity (r2) together with their susceptibility effect at higher magnetic fields. ", "As a consequence, a confounding T2* shortening may affect the signal intensity on bright-blood angiograms so that the signal-to-noise ratio from blood is similar at 1.5 and 3 T (Bremerich et al. ", "2007).", "\n\n### 2.6.2 Other Contrast Agents\n\nA huge variety of new contrast agents are currently under development. ", "In some cases they represent a further evolution of traditional paramagnetic and superparamagnetic agents, while in other cases they exploit completely different principles.", "\n\n#### 2.6.2.1 Gadolinium-Based Particulate Agents\n\nGadolinium (III) can be employed in numerous particulate contrast agents in order to improve their relaxation efficiency (Geraldes and Laurent 2009). ", "For example, Gd3+ ions can be bound to amphiphylic chelates in micelles or liposomes, or to porous materials like zeolites. ", "Gadolinium oxide nanoparticles can also be formed. ", "Although promising, none of these agents has passed the preclinical status to date.", "\n\n#### 2.6.2.2 Hyperpolarized Contrast Agents\n\nThe signal intensity on magnetic resonance imaging is related to the number of protons which align to the external magnetic field. ", "At 1.5 T approximately 0.0006% of protons are polarized.", "\n\nIn order to increase signal intensity, contrast agents made of hyperpolarized nuclei have been designed. ", "Hyperpolarization is obtained by using a high-power laser on noble gases (3He, 129Xe) or 13C-enriched molecules. ", "In order to be exploited as contrast agents, these compounds require T1 relaxation times long enough to allow imaging before the recovery of the equili brium status. ", "13C-labeled water-soluble compounds have been employed for contrast-enhanced magnetic resonance angiograms in rats (Caravan and Randall 2006).", "\n\n#### 2.6.2.3 Chemical Exchange Saturation Transfer (CEST)\n\nChemical exchange saturation transfer (CEST) agents contain exchangeable hydrogen atoms (-NH, -OH, etc) which resonate at a Larmor frequency different from that of the bulk water. ", "CEST protons can be saturated by an off-set RF pulse and can transfer their magnetization to water molecules. ", "This effect results in water signal loss and negative image contrast. ", "By utilizing proper pulse sequences a positive-contrast effect can also be obtained (Caravan and Randall 2006; Geraldes and Laurent 2009). ", "CEST agents currently require a very high dose to obtain a relevant effect on signal intensity, so further development is needed for in vivo applications.", "\n\nReferences\n\nBongartz G (2007) Imaging in the time of NFD/NFS: Do we have to change our routines concerning renal insufficiency? ", "MAGMA 20:57-62PubMedCrossRef\n\nBremerich J, Bilecen D, Reimer P (2007) MR angiography with blood pool contrast agents. ", "Eur Radiol 17:3017-3024PubMedCrossRef\n\nCaravan P, Randall B (2006) Contrast agents: Basic principles. ", "In: Edelman RR, Zlatkin MB, Hesselink JR (eds) Clinical magnetic resonance imaging. ", "Saunders Elsevier, Philadelphia, PA, pp 361-366\n\nCowper SE, Robin HS, Steinberg SM, et al. (", "2000) Scleromyx-oedema-like cutaneous disease in renal-dialysis patients. ", "Lancet 356:1000-1001PubMedCrossRef02694-5)\n\nCreasy JL, Price RR, Presbrey T, et al. (", "1990) Gadolinium-enhanced MR angiography. ", "Radiology 175:280-283PubMed\n\nGeraldes CFGC, Laurent S (2009) Classification and basic properties of contrast agents for magnetic resonance imaging. ", "Contrast Media Mol Imaging 4:1-23PubMedCrossRef\n\nGueron M (1975) Nuclear relaxation in macromolecules by paramagnetic ions: A novel mechanism. ", "J Magn Reson 19:58-66\n\nKanal E, Broome DR, Martin DR, et al. (", "2008) Response to the FDA's May 23 2007, nephrogenic systemic fibrosis update. ", "Radiology 246:11-14PubMedCrossRef\n\nKlessen C, Hein PA, Huppertz A, et al. (", "2007) First-pass whole body magnetic resonance angiography (MRA) using the blood pool contrast medium gadofosveset trisodium. ", "Invest Radiol 42(9):659-664PubMedCrossRef\n\nKnopp M V, Balzer T, Esser M, et al. (", "2006) Assessment of utilization and pharmacovigilance based on spontaneous adverse event reporting of gadopentetate dimeglumine as a magnetic resonance contrast agent after 45 million administrations and 15 years of clinical use. ", "Invest Radiol 41(6): 491-499PubMedCrossRef\n\nKurtkoti J, Snow T, Hiremagalur B (2008) Gadolinium and nephrogenic systemic sclerosis: Association or causation. ", "Nephrology 13:235-241PubMedCrossRef\n\nLu ZR, Parker DL, Goodrich KC, et al. (", "2004) Extracellular biodegradable macromolecular gadolinium (III) complexes for MRI. ", "Magn Reson Med 51:27-34PubMedCrossRef\n\nMuller RN, Roch A, Colet JM, et al. (", "2001) Particulate magnetic contrast agents. ", "In: Merbach AE, Tçth E (eds) Chemistry of contrast agents in medical magetic resonance imaging. ", "Wiley, Chichester, UK, pp 417-435\n\nNeuwelt EA, Hamilton BE, Varallyay CG, et al. (", "2009) Ultrasmall superparamagnetic iron oxides (USPIOs): A future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?. ", "Kidney Int 75(5):465-474PubMedCrossRef\n\nRoch A, Muller RN, Gillis P (1999) Theory of proton relaxation induced by superparamagnetic particles. ", "J Chem Phys 110:5403-5411CrossRef\n\nShamshi K, Yucel EK, Chamberlin P (2006) A summary of safety of gadofosveset (MS-325) at 0.03 mmol/kg body weight dose: Phase II and phase III clinical trials data. ", "Invest Radiol 41(11):822-830CrossRef\n\nWiginton CD, Kelly B, Oto A, et al. (", "2008) Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. ", "AJR 190:1060-1068PubMedCrossRef\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_3(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 3. ", "Image Acquisition Technique and Sequences Contrast-Enhanced MRA\n\nMarco Francone1 , Michele Anzidei1, Ilaria Iacucci1, Francesco Vullo1 and Carlo Catalano1\n\n(1)\n\nDepartment of Radiology, University of Rome \"La Sapienza,\" Policlinico Umberto I, viale Regina Elena 324, Roma, 00161, Italy\n\n3.1 Introduction\n\n3.2 Basic Principle of CE-MRA\n\n3.3 Contrast Administration Strategy\n\n3.4 Imaging and Acquisition Technique\n\n3.4.1 Fast 3D Gradient Echo Sequences and Acquisition Technique\n\n3.4.2 Parallel Imaging\n\n3.4.3 Time-Resolved CE-MRA\n\n3.4.4 Steady-State Imaging\n\n3.5 k-Space Filling Strategies\n\n3.6 Conclusions\n\nReferences\n\nAbstract\n\nAlthough MR angiography (MRA) can be performed using either black-blood or bright blood, wich have the disvantage of high sensitive to flow related-artifacts, in-plane saturation, and field inhomogeneity, and are also limited by the long acquisition times. ", "Currently, the use of contrast medium for imaging of most vascular districts, agrees to obtain images of high diagnostic accuracy, that can be acquired in seconds rather than minutes with few flow-related artifacts. ", "Such introduction explains the reason, Currently, MR angiography has proven to be the best approach for imaging of most vascular districts is the use of contrast-enhanced (CE-MRA), offering the opportunity to detect vascular disease rapidly and early in the course of the disease.", "\n\nCE-MRA is based on the principle of shortening the T1 relaxation of blood by intravenously injecting Gd-chelate contrast agents, wich results in a significant difference in signal intensity between flowing blood and stationary tissue, in T1 arterial or venous phase. ", "Further advantage is shorter scan duration.", "\n\nContrast administration should be optimized in order to concentrate the highest amount of gadolinium in the acquisition temporal window within district of interest, and imaging should be ideally performed at the peak of vascular enhancement, when a maximum difference exists between signal intensity of the target vessel and the surrounding overlapping structures.", "\n\nThree different techniques are currently available for this purpose: the test bolus scan, the automated bolus detection, and the MR fluoroscopic trigger.", "\n\nObviously, to deliver the best contrast, k-space center-filling must correspond to the moment of peak intravascular contrast; for this purpose, the acquisition of central k-space data is timed to the contrast bolus arrival within the target vessels\n\nThe sequences best suited to CE-MRA imaging are:\n\n * Fast 3D-GRE sequences (e.g., spoiled gradient echo SPGR-General Electric Medical Systems, Waukesha, WI); fast low-angle shot FLASH-Siemens Medical), used to obtain high spatial resolution and a good signal-to-noise.", "\n\n * Parallel imaging that results in accelerated image acquisition while maintainingfull spatial resolution and image contrast.", "\n\n * Time-resolved CE-MRA acquisition techniques, providing dynamic information along with highresolution, extended anatomical coverage, and without contamination by the venous signal.", "\n\n * Steady-state imaging, which enables one to take advantage of the long temporal window during the equilibrium phase of the contrast material administration.", "\n\n## 3.1 Introduction\n\nAlthough MR angiography (MRA) can be performed using either black-blood (i.e., dark signal of blood-flowing spins) or bright blood sequences (time-of-flight, phase contrast and steady-state free precession), these techniques are highly sensitive to flow related-artifacts, in-plane saturation, and field inhomogeneity, and also limited by the long acquisition times (i.e., minutes).", "\n\nAs a result, unenhanced MRA have progressively shown limited clinical impact for the assessment of many vascular territories (Prince et al. ", "2003).", "\n\nCurrently, the best approach for imaging of most vascular districts is the use of contrast-enhanced MRA (CE-MRA) techniques, which have rapidly evolved over the past decade as a consequence of the continuous hardware development (i.e., scanners and gradients), and implementation of new sequences that brought significant improvements in contrast-to-noise-ratio, temporal resolution, and reliability of the examinations.", "\n\nCompared with unenhanced techniques, CE-MRA has proven to be highly accurate, robust, and reproducible, and can be performed in seconds rather than minutes with few flow-related artifacts (Zhang et al. ", "2007).", "\n\nThis chapter will specifically focus on the basic principles, and different techniques of CE-MRA with particular emphasis on three-dimensional gradient echo (3D-GRE) imaging, time-resolved MRA, and the role of parallel imaging. ", "Some practical aspects of contrast media administration optimization and k-space filling strategies will also be reviewed.", "\n\n## 3.2 Basic Principle of CE-MRA\n\nCE-MRA is based on the principle of shortening the T1 relaxation of blood by intravenously injecting Gd-chelate contrast agents. ", "This results in a significant difference in signal intensity between flowing blood and stationary tissue at heavily T1-weighted arterial-phase imaging, leading to the high signal intensity of blood on post-Gd T1-weighted sequences.", "\n\nSignal intensity (i.e., T1-weighted shortening) within the target vessel obviously depends on the amount of gadolinium concentrated within the vascular bed at the moment of acquisition; therefore, imaging should be ideally performed at the peak of vascular enhancement, when a maximum difference exists between signal intensity of the target vessel and the surrounding overlapping structures.", "\n\nUnlike time-of-flight (TOF) or phase contrast (PC) imaging, signal of vessels in CE-MRA is based on the intrinsic T 1 signal of blood, and rather less on flow effects; therefore, as already mentioned above, this technique is less flow sensitive, which means that vascular signal is not hampered by the numerous flow-related artefacts that may occur during acquisition such as signal loss from spin saturation, or slow-flow phenomena potentially mimicking a significant stenosis or vascular occlusion particularly in small vessels caliber-like carotid arteries (Prince et al. ", "2003).", "\n\nA further relevant advantage of CE-MRA is that the usual loss of signal-to-noise ratio (SNR) from faster scanning with most MR pulse sequences can be compensated for by injecting the same dose of contrast faster over a shorter scan duration. ", "In this way, faster scanning can attain higher-quality images with less motion artifacts (Prince et al. ", "2003; Zhang et al. ", "2007).", "\n\nWith CE-MRA, the pause between arterial enhancement and the onset of venous enhancement (i.e., arte-riovenous window) offers an opportunity for arterial phase imaging that shows only the arteries. ", "When this selective arterial phase is too short, simple additional maneuvers such as thigh compression with tourniquets inflated to a pressure intermediate between arterial and venous (e.g., 60 mmHg) delays onset of venous enhancement in the last station of a single-injection, multistation peripheral or whole-body MRA. ", "This can compensate for the fact that acquisition speed is still too slow to keep up with the bolus, and eliminates venous superimposition within the legs, one of the last remaining hurdles to routine implementation of peripheral and whole-body CE-MRA into clinical practice.", "\n\n## 3.3 Contrast Administration Strategy\n\nContrast administration should be optimized in order to concentrate the highest amount of gadolinium in the acquisition temporal window within district of interest. ", "This simple concept emphasizes the importance of contrast administration in CE-MRA as vascular visualization relies heavily on timing -- i.e., the moment in which imaging is actually performed.", "\n\nIt is obvious that delay between contrast administration and image acquisition is highly variable, and depends on various factors including patient's individual characteristics (i.e., cardiac output and vascular anatomy), injection parameters (i.e., flow rate, monophasic vs. biphasic injection, use of saline), and intrinsic characteristics of the Gd-chelate administered (i.e., concentration, relaxivity, viscosity).", "\n\nOptimal timing for image acquisition should be therefore individually determined, and three different techniques are currently available for this purpose, i.e., the test bolus scan, the automated bolus detection, and the MR fluoroscopic trigger; all these methods permit reliable and time-efficient CE-MRA acquisitions (Huston et al. ", "1999). ", "Briefly, optimal delay in test bolus scan is usually calculated by administering a 1-2 mL dose of Gd-chelate contrast agent prior to main MRA acquisition, using the same injection rate of the main bolus, and measuring its arrival time in the vessel of interest; the automated bolus detection is based on the concept that contrast bolus arrival and initiation of the MRA data acquisition are automated and integrated into a single pulse sequence (Ho and Foo 1998) whereas real time CE-MRA timing utilizes a fluoroscopic trigger (Riederer et al. ", "2000) in which monitoring is performed by the operator visually using a continuous fast 2D spoiled gradient echo pulse sequence in with imaging centered over the vascular bed.", "\n\nThe rate of injection influences the peak of Gd-concentration, and thus the achievable arterial SNR. ", "Generally, a faster injection rate will result in higher arterial SNR, but shorter bolus duration and earlier venous enhancement (Kopka et al. ", "1998). ", "Injection rates of 2 mL/s are ideal for most CE-MRA applications, with little benefit shown for higher rates. ", "Slower injection rates result in lower overall Gd concentrations, but extend the plateau phase of arterial enhancement and delay venous enhancement. ", "Slower injection rates (e.g., 0.8-1.0 mL/s) have generally been used for multistation CE-MRA in order to prolong the arterial phase, and delay venous enhancement, both of which are desirable to ensure adequate arterial signal for multistation coverage (Meaney et al. ", "1999).", "\n\n## 3.4 Imaging and Acquisition Technique\n\n### 3.4.1 Fast 3D Gradient Echo Sequences and Acquisition Technique\n\nThe sequences best suited to CE-MRA imaging are fast 3D-GRE sequences (e.g., spoiled gradient echo (SPGR), General Electric Medical Systems, Waukesha, WI; fast low-angle shot (FLASH), Siemens Medical Solutions, Erlangen, Germany; T1-fast field echo (T1-FFE), Philips Medical Systems, Best, The Netherlands), with short TR (≤5 ms) to maximize T1-weighting of images and short TE (1-2 ms) to minimize T2* effects (Table 3.1). ", "They are strongly T1-weighted sequences with destruction of residual transverse magnetization. ", "Given that echo time is very short, the gradients are not flow compensated.", "\n\nTable 3.1.", "\n\nSchematic representation of different manufacture's 3D GRE sequences with corresponding scanning parameters\n\nImaging parameters | General electric | Philips | Siemens\n\n---|---|---|---\n\nPulse sequence 3D FSPGR | 3D FSPGR (Fast, GX) | 3D FFE Contrast enhancment - T1 | 3D FLASH\n\nImaging options | − | Minimum | Minimum\n\nRepetition time (TR) | (e.g., 4-6 ms) | (e.g., 4-6 ms) | (e.g., 3-5 ms)\n\nEcho time (TE) | Minimum (e.g., 1-2 ms) | Minimum (e.g., 1-2 ms) | Minimum (e.g., 1-2 ms)\n\nFlip angle (FA) | 45° ±32.25 kHz | 40° WFS = 0.9 | 25° Variable\n\nBandwidth | (option: ±62.5 kHz) | (at 448 matrix = +57 kHz) | (± 590 Hz/pixel)\n\nField of view (FOV) | 30-40 cm (option: 0.8 FOV) | 400 mm, RFOV = 0.75 | 400 mm\n\nMatrix | 256 or 512 × 192-256 | 448 × 258 | 256-512 × 192-384\n\nNumber of partitions | 40-60 | 40-60 | 60-80\n\nPartition thickness | 1.0-2.5 mm | 1.0-2.5 mm | 1.0-2.5 mm\n\nk-space | Elliptical centric | CENTRA low_high linear half scan (=partial Fourier) | Elliptical centric ± partial Fourier\n\n|\n\nCentric | scan (=partial Fourier) | partial Fourier\n\n|\n\nReverse sequential (with partial Fourier or 0.5 NEX)\n\n| |\n\nNumber of excitations | 1 (option: 0.5) | 1 (option: 0.5) | 1 (option: 0.5)\n\n(NEX or NSA) Timing | SMARTPREP, Flouro trigger or test bolus | Bolus trak or test bolus | Care bolus or test bolus\n\nMisc. ", "options | ZIP × 2 | Overcontiguous slices | Reconstruct 256, 512, 1024\n\n|\n\nZIP 512 1024 | Reconstruct 256, 512, 1024 | SENSE, GRAPPA\n\n|\n\nASSET | SENSE\n\n|\n\nThree-dimensional acquisition is used to obtain high spatial resolution and a good signal-to-noise; a fat signal suppression method is also recommended to weaken the background signal.", "\n\nIt is important to note that flip angle significantly affects gradient echo signal intensity and should be of 30-45° when performing CE-MRA at 1.5 T. Also, flip angle influences the desired degree of contrast between vessels and background tissue; the higher the flip angle the greater the background suppression although signal from gadolinium contrast may also become attenuated.", "\n\nUsing state-of-the-art MRI scanners, high resolution images could be obtained using isotropic or almost isotropic voxels up to 0.8 mm3 with an image matrix of 384 × 384 mm; as already stated above, acquisition time should be ideally tailored according to patient's individual hemodynamic characteristic, contrast administration parameters adopted and obviously the length of the vascular district assessed.", "\n\nTo obtain high-quality images, it is important to have specialized coils overlying the patients to ensure a high signal to noise ratio. ", "Image acquisition should be ideally performed 3 times.", "\n\nA precontrast 3D MRA acquisition is recommended to determine proper anatomic coverage, positioning of the 3D volume, and also to potential unwanted aliasing artefacts. ", "It is also recommended that precontrast 3D MRA acquisition should be performed in an identical fashion to the actual CE-MRA acquisition, as this will familiarize the patient to both the breath holding procedure and the expected length for the breath hold. ", "In addition, the precontrast scan can serve as a mask for subsequent image subtraction; subtraction techniques allow to subtract background signal, and maximize the SNR of the images (Yuji Watanabe and Akira 2000).", "\n\nFor the CE-MRA, acquisitions are typically performed in both the arterial and delayed phases. ", "The addition of the second delayed phase acquisition will ensure proper visualization of vessels with slow flow or depiction of a late filling false channel in the case of an aortic dissection. ", "Additionally, the second acquisition can often distinguish artefacts from true vascular findings. ", "Finally, the inclusion of the second postcontrast 3D MRA acquisition may provide additional venous depiction that may be of clinical importance in certain specific clinical situations.", "\n\nImages can be further postprocessed with maximum and minimum intensity projections and volume rendering to generate more visually appealing images, but it should be noted that these images should not typically be used for image interpretation as manipulation of the original data can lead to over-or underestimation of critical dimensions (e.g., in the context of stenosis, extravascular pathology may also be obscured or overlooked).", "\n\n### 3.4.2 Parallel Imaging\n\nWith the gain in speed that it entails, parallel imaging is particularly well suited to CE-MRA. ", "Parallel imaging techniques (e.g., sensitivity encoding or SENSE (Van den Brink et al. ", "2003) and simultaneous acquisition of spatial harmonics or SMASH (Maki et al. ", "2002; Sodickson et al. ", "2000) ) use the spatial-encoding proprieties of multiphase array coils elements to reduce the number of spatial-encoding steps required to generate an image, thereby overcoming the gradient hardware performance limits imposed by on conventional MRA techniques. ", "In this way only a fraction of phase-encoding steps have to be acquired directly which result in accelerated image acquisition while maintaining full spatial resolution and image contrast.", "\n\nBesides increased temporal resolution at a given spatial resolution, the time savings due to parallel imaging can also be used to improve the spatial resolution in a given imaging time.", "\n\n### 3.4.3 Time-Resolved CE-MRA\n\nConventional static 3D GRE MRA techniques create high-spatial-resolution structural studies, but fail to provide physiological information inherent in the delivery of blood or contrast; as a consequence, dynamic assessment of contrast media bolus progression through a vascular territory, or vascular lesion has long been an essential, and exclusive feature of conventional X-ray angiography, especially X-ray digital subtraction angiography (DSA).", "\n\nHowever, the recent development of faster MR scanners with improved gradient performances and innovative software has enabled the performance of analogous dynamic viewing of Gd-chelate contrast media using fast 2D and/or 3D MRA acquisitions (Zou et al. ", "2008; Du et al. ", "2007; Brauck et al. ", "2007).", "\n\nThe clinical availability of temporally enhanced time-resolved acquisition techniques such as TRICKS (time-resolved imaging of contrast kinetics) revolutionizes the way that MRA is performed in the clinical setting, providing dynamic information along with high-resolution, extended anatomical coverage, and without contamination by the venous signal (Fig. ", "3.1) (Du and Bydder 2007).", "\n\nFig. ", "3.1.", "\n\nTime-resolved MRA of a large artero-venous malformation (AVM) of the pelvis in a 50-year-old male with abdominal discomfort and a palpable mass. ", "Dynamic MR imaging shows early and progressive filling of the AVM nidus, with evidence of an aneurismatic left internal iliac artery and dilated draining veins\n\nConversion of an MRA acquisition from singlephase high-resolution to time-resolved generally involves serial scan repetition as the contrast agent is delivered to the target object or organ. ", "Protocol modifications typically include reduction in spatial resolution and anatomical coverage (fewer and/or thicker slices) in the interest of faster cycling of the image capture. ", "The trade-off in quality inherent in this brute force approach with conventional imaging techniques is sufficiently severe to limit applicability in clinical practice.", "\n\nModern time-resolved techniques reduce these negative trade-off aspects by creatively altering the way in which image k-space is captured. ", "With TRICKS and its variants, the center of k-space is sampled more often than the periphery (see next paragraphs). ", "This produces multiple physiologic snapshots per each full pass through k-space, and typically delivers a four-fold increase in temporal resolution without a reduction in the SNR. ", "The addition of parallel imaging to a time-resolved protocol increases by twofold or more the temporal resolution, although with the typical reduction in SNR.", "\n\n### 3.4.4 Steady-State Imaging\n\nThe use of blood-pool contrast agents, in addition to conventional first-pass arterial phase imaging, also enables the use of steady-state acquisit ions (Parmelee et al. ", "1997; Caravan et al. ", "2002; Rohrer et al. ", "2005; Grist et al. ", "1998). ", "With use of this technique, which enables one to take advantage of the long temporal window during the equilibrium phase of the contrast material administration the imaging protocols are adjusted virtually without time limitations owing to the use of preparation pulses, smaller fields of view, an increased in-plane resolution, and extra-thin three-dimensional partitions (Anzidei et al. ", "2009). ", "The technique usually applied for steady state imaging is a modified three-dimensional high-spatial-resolution (up to 0.7 mm section thickness, 512 × 512 matrix, voxel size of 0.7 × 0.7 × 0.7 mm) spoiled gradient-echo sequence. ", "Using this technique, two approaches can be chosen in order to compensate for reduced SNR, which is associated with smaller voxel size: either the use of a short TR (4-7 ms), low flip angle, and multiple excitations or a longer TR (8-15 ms), higher flip angle, and using lower bandwidths (Figs. ", "3.2 and 3.3). ", "The initial observations suggest that the second strategy provides higher SNR.", "\n\nFig. ", "3.2.", "\n\nEighty percent stenosis (NASCET grade IV) of the left internal carotid artery (ICA) due to a long and slightly ir-regulae plaque. ", "Images show good correlation between DSA findings and thin-MIP (a) reconstruction from FP (b) and steady state (c) CE-MRA. ", "Multiple partition from coaxial reconstruction of steady state dataset offer a high resolution view of the plaque surface and residual lumen, confirming stenosis grading (d)\n\nFig. ", "3.3.", "\n\nDiscrepancy of grading ICA stenosis (arrow) between the different CE-MRA reading modalities. ", "DSA shows a 75% stenosis (NASCET grade IV) of the left ICA; on thin-MIP (a) reconstruction from first pass dataset (b) stenosis was underestimated at 66% (NASCET grade III), while on steady state images it was correctly measured as a NASCET grade IV (c)\n\n## 3.5 k-Space Filling Strategies\n\nTo deliver the best contrast, k-space center filling must correspond to the moment of peak intravas-cular contrast as the center of k-space contains the signal-to-noise, and contrast information for the image (also called low spatial frequency data), so it represents the major structures of the image, and thus most of the gross image form and contrast. ", "Also, a high rate of change of the contrast agent concentration during the acquisition of central k-space must be avoided to prevent ringing artifacts, arising in the Fourier transform (Zhang et al. ", "2007).", "\n\nk-Space filling should be therefore optimized (spiral or elliptical centrifugal trajectory, partial refilling, shared data on the k-space periphery) in CE-MRA to rapidly acquire its center (image contrast), and meet the constraints of the transient passage of the contrast agent.", "\n\nTraditional k-space acquisition schemes are linear in that k-space data is filled sequentially from top to bottom (sequential k-space filling), and the central portion of the k-space is filled in the middle of the acquisition period.", "\n\nContrast agent arrival and imaging however are best synchronized if the acquisition of central k-space data is timed to the contrast bolus arrival within the target vessels. ", "For this purpose, centric and more recently elliptical centric phase ordering schemes have been introduced for CE-MRA (Flamm and Muthupillai 2004). ", "In centric phase ordering, the central lines of k-space are filled in the first half of the acquisition period. ", "With elliptical centric phase ordering the most central points (i.e., radial distance from center) are acquired first, resulting in a shortened and more compact imaging period for the acquisition of central k-space data (Fig. ", "3.4).", "\n\nFig. ", "3.4.", "\n\nFigure shows alignment of preferential arterial-phase enhancement for different k-space filling schemes used for CE-MRA. ", "It is important to remark that central k-space data (i.e., low spatial frequency data) should be acquired during the plateau phase of arterial enhancement. ", "In the conventional sequential k-space scheme, the central k-space data is acquired during the middle of the data acquisition period whereas in both conventional centric and elliptical centric acquisition schemes, central k-space filling occurs at the beginning of imaging\n\n## 3.6 Conclusions\n\nMRA has evolved rapidly since the early studies by Prince et al. (", "1993), becoming a reference technique for noninvasive assessment of vascular anatomy, and hemodynamic significance of stenoses, particularly suited in pediatric patients.", "\n\nCurrently, the optimal quality for MRA image can only be achieved administering contrast agents, which allow to overcome many of the limitation of unenhanced MRA techniques; the recent development of blood-pool agent has further improved image quality enabling acquisition of high resolution submillimetric images during steady state imaging.", "\n\nFurthermore, faster imaging speed can also be used to improve the temporal resolution of CE MRA, and time-resolved MRA has emerged an interesting application in selected diagnostic situations allowing the possibility to dynamically assess progression of contrast bolus through the vascular bed.", "\n\nSafe, accurate mapping of vascular anatomy with MRA offers the opportunity to detect vascular disease rapidly and early in the course of the disease, while there is time to salvage end-organ function. ", "It gives both anatomical and functional information, and can image multiple fields of view for a more comprehensive assessment of systemic vascular disease.", "\n\nReferences\n\nAnzidei M, Napoli A, Marincola BC, et al. (", "2009) Gadofosveset-enhanced MR angiography of carotid arteries: does steady-state imaging improve accuracy of first-pass imaging? ", "Comparison with selective digital subtraction angiogra-phy. ", "Radiology 251:457-466CrossRefPubMed\n\nBrauck K, Maderwald S, Vogt FM, et al. (", "2007) Time-resolved contrast-enhanced magnetic resonance angiography of the hand with parallel imaging and view sharing: initial experience. ", "Eur Radiol 17:183-192CrossRefPubMed\n\nCaravan P, Cloutier NJ, Greenfield MT, et al. (", "2002) The interaction of MS-325 with human serum albumin and its effect on proton relaxation rates. ", "J Am Chem Soc 124:3152-3162CrossRefPubMed\n\nDu J, Bydder M (2007) High-resolution time-resolved contrast-enhanced MR abdominal and pulmonary angiography using a spiral-TRICKS sequence. ", "Magn Reson Med 58:631-635CrossRefPubMed\n\nDu J, Fain SB, Korosec FR, et al. (", "2007) Time-resolvedcontrast-enhanced carotid imaging using undersampled projection reconstruction acquisition. ", "J Magn Reson Imaging 25:1093-1099CrossRefPubMed\n\nFlamm SD, Muthupillai R (2004) Coronary artery magnetic resonance angiography. ", "J Magn Reson Imaging 19:686-709CrossRefPubMed\n\nGrist TM, Korosec FR, Peters DC, et al. (", "1998) Steady-state and dynamic MR angiography with MS-325: initial experience in humans. ", "Radiology 207:539-544PubMed\n\nHo VB, Foo TK (1998) Optimization of gadolinium-enhanced magnetic resonance angiography using an automated bolus-detection algorithm (MR SmartPrep). ", "Original investigation. ", "Invest Radiol 33:515-523\n\nHuston J 3rd, Fain SB, Riederer SJ, et al. (", "1999) Carotid arteries: maximizing arterial to venous contrast in fluoroscopically triggered contrast-enhanced MR angiography with elliptic centric view ordering. ", "Radiology 211:265-273PubMed\n\nKopka L, Vosshenrich R, Rodenwaldt J, et al. (", "1998) Differences in injection rates on contrast-enhanced breath-hold three-dimensional MR angiography. ", "AJR Am J Roentgenol 170:345-348PubMed\n\nMaki JH, Wilson GJ, Eubank WB, et al. (", "2002) Utilizing SENSE to achieve lower station sub-millimeter isotropic resolution and minimal venous enhancement in peripheral MR angiography. ", "J Magn Reson Imaging 15(4):484-491CrossRefPubMed\n\nMeaney JF, Ridgway JP, Chakraverty S, et al. (", "1999) Stepping-table gadolinium-enhanced digital subtraction MR angiog-raphy of the aorta and lower extremity arteries: preliminary experience. ", "Radiology 211:59-67PubMed\n\nParmelee DJ, Walovitch RC, Ouellet HS, et al. (", "1997) Preclinical evaluation of the pharmacokinetics, biodistribution, and elimination of MS-325, a blood pool agent for magnetic resonance imaging. ", "Invest Radiol 32:741-747CrossRefPubMed\n\nPrince MR, Grist TM, Debatin JF (2003) 3D contrast MR angiography, 3rd ed. ", "Springer, Berlin\n\nPrince MR, Yucel EK, Kaufman JA, et al. (", "1993) Dynamic gadolinium-enhanced three dimensional abdominal MR arte-riography. ", "J Magn Reson Imaging 3:877-881CrossRefPubMed\n\nRiederer SJ, Bernstein MA, Breen JF, et al. (", "2000) Three-dimensional contrast-enhanced MR angiography with real-time fluoroscopic triggering: design specifications and technical reliability in 330 patient studies. ", "Radiology 215:584-593PubMed\n\nRohrer M, Bauer H, Mintorovitch J, et al. (", "2005) Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. ", "Invest Radiol 40:715-724CrossRefPubMed\n\nSodickson DK, McKenzie CA, Li W, et al. (", "2000) Contrast-enhanced 3D MR angiography with simultaneous acquisition of spatial harmonics: A pilot study. ", "Radiology 217:284-289PubMed\n\nVan den Brink JS, Watanabe Y, Kuhl CK, et al. (", "2003) Implications of SENSE MR in routine clinical practice. ", "Eur J Radiol 46:3-27CrossRef00333-9)PubMed\n\nWatanabe Y, Dohke M, Okumura A, et al. (", "2000) Dynamic subtraction contrast-enhanced MR angiography: technique, clinical applications, and pitfalls. ", "Radiographics 20:135-152PubMed\n\nZhang H, Maki JH, Prince MR (2007) 3D contrast-enhanced MR angiography. ", "J Magn Reson Imaging 25:13-25CrossRefPubMed\n\nZou Z, Ma L, Cheng L, et al. (", "2008) Time-resolved contrast-enhanced MR angiography of intracranial lesions. ", "J Magn Reson Imaging 27(4):692-699CrossRefPubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_4(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 4. ", "Artifacts in MR-Angiography\n\nAndrea Laghi1 , Pasquale Paolantonio1, Marco Rengo1 and Paola Lucchesi1\n\n(1)\n\nDepartment of Radiological Sciences, \"Sapienza\", University of Rome, Polo Pontino, I.C.O.T. Hospital, Viale Franco Fagiana 34, Latina, 04100, Italy\n\n4.1 Introduction\n\n4.2 Classification\n\n4.3 Radiofrequency Artifacts\n\n4.4 Flow Artifacts\n\n4.4.1 Turbulence's Artifact\n\n4.4.2 The Artifact Due to Saturation\n\n4.5 Hinge Artifact\n\n4.6 Geometric Artifacts\n\n4.6.1 The Hypointensity Linear Horizontal Artifact\n\n4.6.2 The Artifact Due to Noninclusion of the Vase in the Excited Volume\n\n4.7 Magnetic Susceptibility Artifacts\n\n4.8 Maki Artifact\n\n4.9 Vascular Blurring\n\n4.10 Patient Artifacts\n\n4.11 Artifacts from Postprocessing\n\n4.11.1 The Artifact Due to Projection of Background Noise\n\n4.11.2 Step Artifact\n\nReferences\n\nAbstract\n\nArtifacts represent potential pitfalls in MR-angiography: radiologists should be aware of them to prevent their appearance. ", "They can be classified according to the mechanism responsible for their genesis. ", "Flow Artifacts are strictly related to modification of signal intensity induced by dephasing proton mechanism when the blood flow loses the characteristic laminar pattern; they are turbulence'artifact and artefact due to saturation. ", "Hinge artefact, typical of 3DTOF sequence, is characterized by alternating hyper-hypointense punctiform images. ", "Geometrical artefacts are caused by wrong geometric positioning of angiographic sequence or saturation bands; they are called hypointensity linear horizontal artefact and the artefact due to non-inclusion of the vase in the excited volume. ", "Artifacts related to wrong acquisition time with respect to contrast medium bolus arrival are maki artefact and vascular blurring. ", "Voluntary and involuntary movement are the primary cause of patient artifacts like the gost artifact. ", "The main artifacts from post-processing consist of the artifact from projection of the background noise and the step artifact. ", "Magnetic susceptibility artifacts are caused by paramagnetic external substances. ", "Finally we remember radiofrequency artifacts, due to the instability of radiofrequency or nonhomogeneity of magnetic field or instability of the the system receiver-trasmitter.", "\n\n## 4.1 Introduction\n\nArtifacts often corrupt MRI images and can be generated using basic MR sequences as well as more complex MR applications like MR-angiography (Arena 1995). ", "Artifacts represent false image without any rela tionship with the patient's anatomy. ", "They have many causes and consequences on image appearance due to complex technical reasons. ", "Artifacts may represent potential pitfalls in MR-angiography. ", "Radiologist and radiographers should be aware of them to prevent their appearance and recognize the diagnostic pitfalls they can mimic (Patton 1994; Carriero et al. ", "1994, 1995; Pusey et al. ", "1986; Glockner et al. ", "2005; Foo et al. ", "2005; Bradley and Stark 1992; Colagrande and Pazzaglini 2007). ", "The better the understanding of MR images built, the better the dealing with artifacts. ", "Some artifacts that usually affect basic MR acquisition such as aliasing, chemical shift, cross-talk, and ghost are less important in Angiographic application of MRI. ", "In this chapter we will focus our attention on artifacts in MR-Angiography.", "\n\n## 4.2 Classification\n\nArtifacts in MR-Angiography can be classified according to the mechanism responsible for their genesis in:\n\n * Radiofrequency artifacts (instability of radio-frequency, inhomogeneous magnetic field, instability of the system receiver-transmitter)\n\n * Flow artifacts\n\n * Hinge artifacts\n\n * Geometrical artifacts\n\n * Magnetic susceptibility artifacts\n\n * Artifacts related to wrong acquisition time with respect to contrast medium bolus arrival (Maki artifact, blurring)\n\n * Artifacts related to the patient (voluntary and involuntary movement)\n\n * Postprocessing artifacts\n\n## 4.3 Radiofrequency Artifacts\n\nInstability of radio frequency or nonhomogeneity of magnetic field, or instability of the system receiver-- transmitter may determine artifacts in basic MR sequences as well as in MR-angiography (Glockner et al. ", "2005; Foo et al. ", "2005). ", "Radiofrequency Artifacts may, however, be eliminated and prevented, thanks to strict and constant technical maintenance of the various components constituting the hardware since they are operator and patient independent. ", "The most common radiofrequency artifact is due to the contamination of magnetic bore by radiofrequency waves originating outside the faraday cage that lead to multiple lineary artifacts, each one of them involving very few number of pixels.", "\n\n## 4.4 Flow Artifacts\n\nSequence Artifacts are related to the adopted technique and the choice of angiographic sequence (Foo et al. ", "2005; Penman et al. ", "1986). ", "These artifacts especially affect non-contrast-enhanced-MRA sequence and are strictly related to modification of signal intensity induced by dephasing protons mechanism when the blood flow loses the characteristic laminar pattern.", "\n\n### 4.4.1 Turbulence's Artifact\n\nTurbulence's artifact generates an absence of signal of the spins of blood because of their whirling and turbulent motion (arterial flow), which is accentuated near physiological shrinkage or pathological stenosis (Penman et al. ", "1986).", "\n\nThe distribution speed of spins in the turbulent areas changes at every excitement, causing, in this way, dependence from the time of intravoxel coherence that leads to a further loss of signal. ", "The result is an overstatement of stenosis or a pronounced reduction in the caliber of the vessel.", "\n\nFor example, in MR-A of carotid arteries we can find diagnostic traps that lead to the diagnostic suspect of occlusion in patients with carotid stenosis >70% (overstatement) and the diagnostic suspect of stenosis of 50% in patients with stenosis of 70% (understatement) (Fig. ", "4.1).", "\n\nFig. ", "4.1.", "\n\nMIP reconstruction based on time of flight MR angiography of carotid artery showing an overestimation of degree of stenosis due to turbulence's artifact. ", "The artifact is generated by the turbulent motion of flowing blood at the level of the stenosis\n\nThe negative influence of this artifact can be reduced by the use of \"inflow-effect\"; for this reason MR-A of carotid is actually performed using a multislab technique acquired on the perpendicular plane of the vessel in relation to the pattern of blood flow. ", "In addition, the signal of turbulent spins can be fully recovered using a short TE variable between 4 and 6 ms.", "\n\nIn relation to MR-A of vertebral arterials, the same phenomenon of turbulence can determine the suspicion of an occlusion of one of the two arteries in patients with spinal stenosis of 70% (overstatement). ", "Also in this case, the modalities to avoid diagnostic pitfalls are similar to those already suggested for the carotid vessels and consist of applying multislab techniques with short TE acquired in a perpendicular plane in relation to the vessel's course that allow visualization of turbulent spin with high speed.", "\n\n### 4.4.2 The Artifact Due to Saturation\n\nThe artifact due to saturation is more common with the time of flight 3D technique and occurs with reduction and/or disappearance of the signal intensity from the mobile spins; this artifact is due to the accumulation of RF pulses by the spins that move with the excited volume (Foo et al. ", "2005). ", "It has been estimated that the total loss of signal of the mobile spins occurs in this sequence after about 10-20 pulses of radio frequency. ", "In relation to MR-A of vertebral arterials, this pitfall can determine mistaken diagnosis of occlusion of one of the two arteries. ", "Therefore the mis-visualization of a vertebral artery with acquisition of volume according to the coronal plane cannot lead to a diagnosis of occlusion but should suggest the presence of the \"theft of succla-via\" syndrome. ", "This suspicion can be confirmed by integrating 3D TOF sequence with 2D TOF acquisition: the visualization of vertebral vessel in 2D TOF and its absence in 3D TOF is suggestive of the diagnosis of \"theft.\"", "\n\nIn the study of renal arteries, the diagnostic trap that determines suspect occlusion in patients with normal renal arteries is the artifact due to saturation: there is loss of signal of mobile spins which accumulate 15-20 RF impulse during 3D TOF acquisition; this phenomenon is responsible for nonvisualization of the distal part of renal arteries (Carriero et al. ", "1994, 1995).", "\n\nTo optimize sequences, the reduction of flip angle with increase of TR, mount up the depth to which the mobile spins can penetrate the selected volume without being unduly affected by saturation artifact for accumulation of radio frequency.", "\n\n## 4.5 Hinge Artifact\n\nAnother artifact typical of 3D TOF sequences, is the \"hinge artifact\" that occurs along the direction of the coding frequency; It is characterized by alternating hyper-hypointense punctiform images. ", "The genesis of the \"hinge artifact\" is caused by the presence of \"stimulated echoes\" which occur when sequences with multiple impulses of radio frequency are used (Arena 1995; Glockner et al. ", "2005; Foo et al. ", "2005).", "\n\nFor example in the study of intracranial circle, this diagnostic trap could lead to a wrong diagnosis of venous angioma in patients with small intraparen-chymal spots of methemoglobin; the high signal of methemoglobin is not discriminated from the high signal of mobile spin by post processing algorithms. ", "Spin echo sequences and the careful analysis of MR-A during the acquisition process allow to correctly identify methemoglobin.", "\n\nThis kind of artifact is common when a head coil with linear polarization is used. ", "In this situation hyperintense pixels near the vessel can be incorrectly confused with small aneurysm of a cerebral artery; this is because of a sub-optimal signal noise to ratio.", "\n\nIn angio-thoracic-MR, this pitfall could cause wrong diagnosis like thoracic aneurysm of the aorta. ", "In cases of suspected diagnosis of aneurysm, it is possible to find structures that are already hyperin-tense before the acquisition (thrombus or chesty process with chronic bronchiectasis), which, being in contact with major thoracic vessels, may simulate an aneurysm.", "\n\nThese diagnostic traps can be avoided using Phase Contrast or Magnitude Contrast sequences; the subtraction allows canceling this hyperintensity in both moments of acquisition.", "\n\n## 4.6 Geometric Artifacts\n\nSometimes MRA may be affected by artifacts because of wrong geometric positioning of angiographic sequence or saturation bands. ", "These artifacts are the so called Hypointensity linear horizontal artifact and the artifact due to noninclusion of the vase in the excited volume (Glockner et al. ", "2005; Foo et al. ", "2005; Bradley and Stark 1992).", "\n\n### 4.6.1 The Hypointensity Linear Horizontal Artifact\n\nThe Hypointensity linear horizontal artifact consists of a linear signal void present in 2D or 3D acquisitions acquired using a presaturation impulse. ", "The genesis of this artifact is due to a wrong position of the saturation band positioned too close to the excited stratum. ", "The additional radiofrequency can saturate even the spins around the volume excited.", "\n\nThis diagnostic trap can lead to interpretation of a signal vacuum as thrombus especially during MR-A of peripheral vessels.", "\n\nOne or more dark longitudinal stripes can be seen within the aortic lumen simulating the presence of a dissection.", "\n\n### 4.6.2 The Artifact Due to Noninclusion of the Vase in the Excited Volume\n\nThe artifact due to noninclusion of the vase in the excited volume is frequent in anatomical districts where there is an abnormal course of the vessels (coiling, kinking); it is an exclusive prerogative of 3D technique and it is the result of wrong positioning of the acquisition volume compared to the course of the vessel.", "\n\nAll the sequence artifacts described can be removed by optimizing the use of MR-A sequences, and in particular their intrinsic parameters. ", "Echo times as short as possible (4-6 ms) and variable flip angle allow to recover artifacts from turbulence and saturation. ", "Elimination of the layer, which has the hinge artifact, before postprocessing allows to delete it completely without degrading the final quality of the image. ", "A proper positioning between presatura-tion impulse (FRODO technique) and the layer or volume excited and a wide safety margin in place acquisition volumes, help respectively to prevent linear and horizontal hypointensity artifact and the artifact owing to complete noninclusion of the vase in the excited volume.", "\n\n## 4.7 Magnetic Susceptibility Artifacts\n\nMagnetic susceptibility artifacts are not an absolute prerogative of MR-A sequences and can be caused by paramagnetic external substances (dental prosthe-ses, clips, etc..) which alter the geometry of the main magnetic field or by interfaces between different tissue sensitivity for the magnetic field (i.e., air-vessel) (Glockner et al. ", "2005; Foo et al. ", "2005; Bradley and Stark 1992).", "\n\nThe first ones determine a distortion of the image bounded by a small hyperintense edge, while interfaces artifacts are responsible for the presence of a hypointense board of a few millimetres thick. ", "These artifacts are minimized, but not completely eliminated using short TE sequences or 3D contrast MR-A. To get the shortest possible TE, it should be used as the widest band-width available on the imaging system used. ", "Intravascular stents can be particularly problematic depending on the stent composition. ", "The most MR compatible stents are nitinol or platinum, which are totally nonmagnetic. ", "Even nonmagnetic stents may obscure the artery lumen by attenuating the radiofrequency signal. ", "This can be at least partially overcome in platinum and nitinol stents using a higher flip angle.", "\n\nArtifacts caused by external paramagnetic substances may be partially removed by a thorough medical history of the patient.", "\n\n## 4.8 Maki Artifact\n\nMaki artifacts may occur using contrast-enhanced -- MR-angiography. ", "Maki artifact appears as a double contour of the vessel wall with low signal intensity of a central zone within the vessel.", "\n\nThis artifact depends on a too early acquisition of MR sequence with respect to the arrival of contrast medium bolus in the target vessel (Zhang et al. ", "2007; Maki et al. ", "1996).", "\n\nTherefore contrast medium reaches the ideal concentration into the target vessel during the later part of sequence acquisition. ", "In other terms, central lines of k-space are sampled before the arrival of contrast medium into the vascular district, while the good concentration of contrast medium is reached during peripheral k-space sampling where information of image contour is collected.", "\n\nThis mechanism explains the low grade of vascular enhancement as well as the effect on vessel wall contours (Fig. ", "4.2).", "\n\nFig. ", "4.2.", "\n\nMaki artifact: MIP reconstruction based on CE-MRA acquisition. ", "Image shows a good contrast enhancement of pulmonary arteries while abdominal aorta presents double contour with low signal intensity of the central vessel area. ", "This artifact is due to mis-registration of central k-space line with respect to contrast medium bolus arrival. (", "Reprint with permission by manuale di RM addominale, Poletto editore)\n\nTo prevent this artifact a strict monitoring of the contrast medium arrival into the target vessel using bolus-tracking system is essential. ", "Moreover it is essential to start image acquisition immediately when contrast medium has reached the entire vascular district, especially if a central sampling of the k-space is used to prevent the maki artifact in the distal portion of the vascular district while obtaining an excellent enhancement in the proximal portion.", "\n\n## 4.9 Vascular Blurring\n\nThis artifact may affect CE-MRA and is easily recognizable like a blurring of vessel wall (Carriero et al. ", "1994, 1995; Pusey et al. ", "1986; Glockner et al. ", "2005; Foo et al. ", "2005; Penman et al. ", "1986).", "\n\nSimilar to Maki artifact, the vascular blurring is also due to a suboptimal synchronization between acquisition of central k-space lines and the arrival of contrast medium bolus into the target vessel. ", "This artifact depends on the variation of signal intensity of target vessel during the central k-space sampling due to the usage of a too short bolus of contrast medium. ", "Usually this artifact may occur when a limited dose of contrast medium is used or when injection flow is high as well as when the acquisition of CE-MRE sequence starts before the vascular peak enhancement of the target vessel.", "\n\nIn other terms if the signal intensity of the vessel lumen shows relevant variation during the central k-space sampling with increasing signal intensity over time, the central portion of k-space will finally reflect inhomogeneity. ", "This k-space inhomogeneity will lead to signal blurring (Fig. ", "4.3).", "\n\nFig. ", "4.3.", "\n\nMIP reconstruction based on CE-MRA acquisition. ", "Note the blurring artifact at the level of abdominal aorta. ", "The artifact is due to the wrong synchronization between the contrast arrival and the k-space sampling. ", "During the central sampling of the k-space, the contrast medium reaches a good concentration into the vessel lumen while a poor concentration is achieved during peripheral sampling of the k-space leading to a loss of spatial resolution\n\nThe vascular blurring can be prevented by avoiding high flow rate injection for contrast medium and an underdosage of contrast medium as well by optimizing the image acquisition using bolus tracking system.", "\n\n## 4.10 Patient Artifacts\n\nPatient artifacts are common in Magnetic Resonance and particularly frequent in MR-A; the voluntary and involuntary movement (hyperperistalsis, throbbing of the arterial blood vessels) are the primary cause of the ghost artifact. ", "Ghost artifact manifests itself with the presence of hyper or hypointense bands with monotonous repetition of anatomical region considered along the phase encoding. ", "This causes a quality decay of the image both in the layer and volume acquisition. ", "Motion artifacts are particularly frequent in the study of thorax-abdominal vessels where it is not possible to maintain the apnoea (Arena 1995; Foo et al. ", "2005).", "\n\nThe change of position following a voluntary movement can lead completely to off-axis blood vessels so during the reconstruction for example, if it is a 2D acquisition, the image shows a typical segmented profile of vascular lumen especially evident in coronal reconstruction of axial acquisitions.", "\n\nIn 3D instead, you get an out-of-focus image in general because it establishes a causal dependence on the time between the various phases concerning the various repetitions of the sequence. ", "We must bear in mind that there is an interval time between the encoding phase and the frequency and also in recording of x and y positions which helps to prevent the artifact from moving, leading to an erroneous recording space.", "\n\nThe tortuosity inherent to the thoracic aorta and its branches may result in the inadvertent exclusion of important portions of the arterial anatomy from the 3D imaging volume. ", "To prevent this artifact, a 3D data set can be collected initially without contrast to assure that the relevant anatomy is encompassed within the imaging volume.", "\n\n## 4.11 Artifacts from Postprocessing\n\nThe main artifacts from postprocessing consist of the artifact from projection of the background noise and the step artifact (Foo et al. ", "2005; Bradley and Stark 1992; Maki et al. ", "1996).", "\n\n### 4.11.1 The Artifact Due to Projection of Background Noise\n\nThe artifact due to projection of background noise has its rational in a limited or wrong contrast to noise; spins in motion, which have a signal intensity equal to or even lower than that of stationary tissues are not in fact found by postprocessing algorithm and will not be represented in the angiogram after reconstruction.", "\n\nIn addition, MIP reduces the size of the vessel because of different phase precession of spins with different speed; spins at the centre of the vase have the same speed, so will have a homogeneously hyper-intense signal; spins that flow behind the wall have on the contrary, a different phase of precession that leads to a decay of the signal, when it approximates to 180.", "\n\nOn the other hand basic signal of hyperintense tissues such as methemoglobin is not differentiated from hyperintensity of mobile spins by postprocessing algorithm; it follows that tissues of nonvascular origin can be represented on definitive angiogram simultaneously to those of vascular.", "\n\n### 4.11.2 Step Artifact\n\nThis artifact is exclusive of 2D sequences acquired according to the axial plan it is characterized by an irregularity of vascular profile evident after postprocessing. ", "Its genesis is to be searched, especially, in nonperfect alignment of the profile of vases. ", "It is frequent in MR-A of peripheral arterial blood vessels in which the axial acquisition without cardiac synchronization can happen at any stage of the cardiac cycle, resulting in signal acquisition during the top of the sphygmic wave that conditions the axial diameter of vessel and the nonperfect alignment of their profile.", "\n\nIn order to prevent the artifact from postprocessing (MIP) which causes the disappearance of the vases with intensity signal like that of background noise, or the representation of stationary tissues with signal intensity overlap or greater than that of the vases, it is necessary in the first case to improve the contrast to noise, and in the second case, use MR-A techniques to subtract as the technical phase contrast. ", "Acquisitions synchronization with the cardiac circle for peripheral circle and correction factors in the development of postprocessing, permit finally, to prevent and correct the artifact by step.", "\n\nReferences\n\nArena L, et al. (", "1995) MR imaging artifacts that simulate disease: how to recognize and eliminate them. ", "Radiographics 15:1373-1394PubMed\n\nBradley WG, Jr, Stark DD (1992) Magnetic resonance imaging. ", "Mosby-Year Book, St Louis\n\nCarriero A, et al. (", "1994) Artifacts in magnetic resonance angiog-raphy. ", "Radiol Med 88:765-770PubMed\n\nCarriero A, et al. (", "1995) Diagnostic pitfalls in magnetic resonance angiography. ", "Radiol Med 90:719-725PubMed\n\nColagrande S, Pazzaglini S (2007) Manuale di RM addominale. ", "Poletto, Milano\n\nFoo TK, et al. (", "2005) MR angiography physics: an update. ", "Magn Reson Imaging Clin N Am 13:1-22CrossRefPubMed\n\nGlockner JF, et al. (", "2005) MR angiography interpretation: techniques and pitfalls. ", "Magn Reson Imaging Clin N Am 13: 23-40CrossRefPubMed\n\nMaki JH, et al. (", "1996) Three-dimensional contrast-enhanced MR angiography. ", "Top Magn Reson Imaging 8:322-344CrossRefPubMed\n\nPatton JA (1994) MR imaging instrumentation and image artifacts. ", "Radiographics 14:1083-1096PubMed\n\nPenman WH, et al. (", "1986) Artifacts from pulsatile flow in MR imaging. ", "J Comput Assist Tomogr 10:473-483\n\nPusey E, et al. (", "1986) Magnetic resonance imaging artifacts: Mechanism and clinical significance. ", "Radiographics 6:891-911PubMed\n\nZhang H, et al. (", "2007) 3D contrast-enhanced MR angiography. ", "J Magn Reson Imaging 25:13-25CrossRefPubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_5(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 5. ", "Image Processing\n\nLorenzo Faggioni1 and Emanuele Neri1\n\n(1)\n\nDiagnostic and Interventional Radiology Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Radiodiagnostica 1 Universitaria, Ospedale Cisanello. ", "Via Paradisa 2, Pisa, 56100, Italy\n\n5.1 Introduction\n\n5.2 Multiplanar Reformation (MPR)\n\n5.3 Maximum Intensity Projection (MIP)\n\n5.4 Shaded Surface Display (SSD)\n\n5.5 Volume Rendering (VR)\n\n5.6 Virtual Endoscopy (VE)\n\nReferences\n\nMagnetic resonance angiography (MRA) sequences generate an amount of data that represents the signal intensity of voxels from the image volume, distributed on consecutive slices and oriented on a user-defined plane. ", "In particular, the availability of wide anatomic coverage coils and high-field scanners, together with fast sequences and high relaxivity contrast media, allows to easily obtain MRA series formed by a high number of thin slices, usually partially overlapped on each other. ", "This poses the problem to achieve a synthetic view of such a large quantity of analytical information, as derived from each single partition, through either a panoramic or a targeted visualization of a given vascular territory. ", "The demonstration of a particular vascular anatomy may also raise the issue of separating or eliminating other structures contained in the same image volume (such as veins in an MR arteriogram, superimposed vessels or stationary tissues with contrast enhancement).", "\n\n## 5.1 Introduction\n\nMagnetic resonance angiography (MRA) sequences generate an amount of data that represents the signal intensity of voxels from the image volume, distributed on consecutive slices and oriented on a user-defined plane. ", "In particular, the availability of wide anatomic coverage coils and high-field scanners, together with fast sequences and high relaxivity contrast media, allows to easily obtain MRA series formed by a high number of thin slices, usually partially overlapped on each other. ", "This poses the problem to achieve a synthetic view of such a large quantity of analytical information, as derived from each single partition, through either a panoramic or a targeted visualization of a given vascular territory. ", "The demonstration of a particular vascular anatomy may also raise the issue of separating or eliminating other structures contained in the same image volume (such as veins in an MR arteriogram, superimposed vessels or stationary tissues with contrast enhancement).", "\n\nIn this chapter, the following main techniques for the postprocessing of MRA images will be illustrated:\n\n * Multiplanar reformation (MPR)\n\n * Maximum intensity projection (MIP)\n\n * Shaded surface display (SSD)\n\n * Volume rendering (VR)\n\n * Virtual endoscopy (VE)\n\n## 5.2 Multiplanar Reformation (MPR)\n\nThe MPR technique allows creating a bidimen-sional image on an arbitrary plane from a dataset of complanar images. ", "More precisely, the information about position and signal intensity of voxels belonging to a stack of images acquired on parallel planes with a given spatial orientation (for example, a series of axial images) is used to produce an output image where voxels are geometrically projected on a user-defi ned plane with a different inclination (e.g., a coronal, sagittal, or oblique plane), as a function of position and signal intensity of voxels from source images (Lell et al. ", "2006). ", "In this way, it is possible to obtain an integrated representation of structures located on planes different from the native one, which is usually chosen so to optimize technical parameters such as image acquisition time or to minimize artifacts.", "\n\nA typical vascular imaging application of the MPR algorithm is the continuous reconstruction of vessels which are not entirely included in single sections of the image volume, in particular of those with an anatomical inclination different from that of the acquisition plane. ", "In this sense, it is noteworthy that the majority of workstations and image processing software applications allow to automatically perform MPR on standard planes (axial, coronal, sagittal: orthogonal MPR) by generating additional stacks of reformatted images spanning from a given initial to a given final limit of the source dataset that can be saved in DICOM format as independent image series. ", "The thickness and spacing of reformatted images are user-definable; in particular, increasing slice thickness can be useful in order to increase signal-to-noise ratio (SNR) and/or to reduce total image number, and is a good practice if the dataset does not contain findings that do not require the highest available spatial resolution in order to be recognized. ", "More generally, the user is free to define oblique reconstruction planes arbitrarily by orienting and moving an electronic caliper on the three standard orthogonal planes, on which vessels are identified based on their anatomical course. ", "In this way, it is possible, for example, to create images on planes perpendicular to the longitudinal axis of the vessel in order to measure its diameter or section area, thereby avoiding the measurement error due to the geometric distortion that occurs whenever such measures are taken on native images from vessels coursing nonperpendicu-larly to the acquisition plane. ", "This is of particular importance, for example, for the evaluation of conditions associated with widening or narrowing of the vessel lumen, such as aneurysms or vascular stenoses, for which the exact measurement of dimensional parameters may affect treatment planning.", "\n\nIt is intuitive that the quality of MPR reconstructions is optimal when the dataset is composed of isotropic voxels. ", "Yet, this condition, which is easily fulfilled on modern MDCT scanners, is still seldom accomplished in MRA owing to limitations related to prolongation of imaging time and worsening of SNR and contrast-to-noise ratio (CNR). ", "In fact, the need for low section thickness in phase direction poses a penalty on acquisition time (proportional to the number of phase encoding steps and image averages), which forces the user to reduce matrix size in phase direction and use single averaging or k-space undersampling techniques in order to keep acquisition time down to a reasonable level, usually resulting in lower spatial resolution in phase direction and/or increased image noise (Prince et al. ", "2003). ", "A practical method for increasing spatial resolution in phase direction is represented by acquiring partially overlapped slices (typically, with 50% overlap), which also leads to reduction of partial volume effects with preserved SNR as compared with nonoverlapped sections.", "\n\nA variant of the MPR algorithm is CPR (curved planar reformation), that allows to project native images from a succession of planes lying on a user-defined polygonal trajectory. ", "CPR is particularly useful to display vessels with a tortuous course in the three spatial directions, such as coronary arteries or the arteries of the celiac district. ", "This operation can be carried out by selecting a series of points aligned along the center of the lumen (centerline) on one or more MPR projections, thus obtaining a continuous rectified representation of the vessel course (Fig. ", "5.1). ", "With CPR, it may also be easier to perform measurements of vessel size, as the selected vessel is visualized continuously without distortions of its lumen contour.", "\n\nFig. ", "5.1.", "\n\nCEMRA of normal renal arteries. (", "a, b) Single native images acquired on the coronal plane do not allow to evaluate the renal arteries over their entire course, nor to yield reliable information about the presence of stenosis. (", "c) Axial MPR image allows to exclude stenosis only within the proximal third of both renal arteries included in the reformat plane. (", "d, e) By tracing a curve (green line) that follows the course of the renal arteries as displayed on a coronal MIP image, it is possible to visualize the entire course of the vessels, which appear to be patent\n\nMPR and CPR have the advantage of preserving the whole spatial and contrast information of the dataset with relative computational simplicity, as well as being relatively operator-independent, because it is not necessary to perform any segmentation of source images prior to reconstruction. ", "On the other hand, the 2D nature of MPR and CPR images and their projective character do not allow to achieve a panoramic depiction of multiple vessels and, in particular, of branch vessels oriented on multiple planes. ", "For these reasons, as illustrated below, \"raw\" MPR and CPR tools are usually associated to the MIP algorithm, which can yield a simultaneous representation of multiple vessels located inside a user-defined spatially oriented slab.", "\n\n## 5.3 Maximum Intensity Projection (MIP)\n\nWith this algorithm, a slab with a defined thickness and a given spatial orientation is selected, and for each set of voxels aligned along the chosen direction, only that with the maximal intensity is represented on the resulting reconstructed image. ", "For better clarity, let us suppose to draw through the slab an array of parallel lines (ray casting), located at a distance from each other equal to the size of the voxel in the direction perpendicular to that of the oriented lines. ", "Among all the voxels crossed by each line, the MIP algorithm extracts that with the highest signal intensity and adds it to the output image, discarding the information relative to the other voxels. ", "As a consequence:\n\n * The MIP image is exclusively formed by the maximum intensity voxels included in each oriented slice in which the slab is subdivided.", "\n\n * Because a small fraction (about 10%) of the whole dataset information is used, the MIP algorithm requires little computational resources, resulting in fast postprocessing times even on low-power workstations.", "\n\n * Since the MIP algorithm requires only two parameters to be run (slab inclination and thickness), it is only moderately operator-dependent as well as conceptually simple, thus having the potential to reduce the time needed for reconstruction.", "\n\n * Eliminating nonmaximal intensity voxels leads to loss of information related to image depth and contrast resolution among structures with different signal intensity inside the slab (Calhoun et al. ", "1999; Fishman et al. ", "2006; Lell et al. ", "2006).", "\n\nThe MIP technique plays a fundamental role for the postprocessing of MRA data, as it allows displaying vessels (which have high signal intensity due to either flow phenomena in TOF and PC sequences, or T1 shortening of intravascular blood in CEMRA acquisitions) to their whole extent on user-defined planes, thereby achieving angiography-like reconstructions (Fig. ", "5.2). ", "Moreover, in contrast with pure MPR techniques, it is possible to visualize the course of multiple vessels inside the slab, such as branching or collateral vessels.", "\n\nFig. ", "5.2.", "\n\nCase of Fig. ", "5.1. (", "a) By selecting an oriented thin slab volume centered at a level corresponding to the origin of the renal arteries (left side), it is possible to display the course of the renal arteries on a para-axial plane (right side). ", "Notice the partial superimposition of the right renal vein on the ipsilateral renal artery at the hilum and the visualization of a pair of lumbar arteries arising from the abdominal aorta, that were not present on MPR and CPR reconstructions. (", "b) Thick-slab MIP on the coronal plane, allowing a paronamic view of the renal arteries and the aorto-iliac vessels. ", "The mid and distal third of the splenic artery, the proximal tract of the lumbar arteries and part of the cardiopulmonary circulation included in the field of view are also displayed\n\nA great advantage of MIP on MRA over CT angio-graphy images is that there is no need to remove bones, whose density is near that of contrast-enhanced vessels, resulting in vessel obscuration especially on thick-slab MIP reconstructions of CT angiograms (Kabul and Hagspeil 2006). ", "However, for a similar reason, it is necessary to ensure that source images do not contain structures with signal intensity similar to that of vessels (such as methemo-globin deposits or fat tissue). ", "This can be accomplished by using fat suppression techniques and/or by subtracting to CEMRA images a mask series acquired with the same imaging parameters before administration of contrast material.", "\n\nThe selection of slab thickness is relevant. ", "In fact, on one hand, the choice of a thick slab guarantees good panoramicity, but on the other hand it can lead to underestimate the diameter of small vessels or to overestimate stenoses because of partial volume averaging phenomena, especially on images with suboptimal stationary tissue suppression or low SNR (Lell et al. ", "2006, 2007). ", "This is due to the fact that the image contrast of a vessel parallel to the imaging plane varies as a Gaussian function with its maximum (proportional to the vessel diameter) corresponding to the vessel centerline, symmetrically tending to zero with increasing distance from this latter (Prokop et al. ", "1997; Sun and Parker 1999). ", "For this reason, CNR of vessels on MIP images decreases with increasing background signal intensity and reduced vessel size, and selection of the thinnest possible slab for MIP can be benefi cial, as it leads to minimize inclusion of background tissue into the slab. ", "Consequently, thin-slab MIP will be advisable if stenosis grading is to be performed, so as to include as few voxels as possible in the slab. ", "MIP with minimal slab thickness is required for representation of thrombi, as those are hypointense to blood on MRA images and would therefore be obscured on thicker slab MIP, as well as for depiction of aortic dissection (Glockner 2001; Lell et al. ", "2006; Prokop et al. ", "1997; Westenberg et al. ", "2000).", "\n\nFurthermore, the choice of a moderate slab thickness permits to avoid or reduce the problem of artero-venous overlap in territories (such as iliac, thoracic, and cervical vessels) where arteries and veins are close to each other with a parallel course. ", "In particular, MIP slab thickness should be kept to a minimum when concave vessels (such as the aortic arch) are to be displayed, as the use of excessively thick slabs might cause the surrounding contrast-enhanced structures or background noise to \"fill\" the concavity, resulting in impaired depiction of the vessel borders (Prokop et al. ", "1997).", "\n\nSuch limitations can usually be overcome, at some detriment for overall panoramicity, by performing multiple MIP reconstructions of the vessel anatomy under investigation: a practical method consists of producing several thin-slab MIP images of a vessel and its branches (or just some of them or even a single branching vessel) with different orientations. ", "In addition, the representation of vessel branching patterns can be facilitated by doing MIP over CPR reconstructions of the main vessels.", "\n\nAlternatively, it is possible to edit the dataset prior to MIP in order to remove undesired structures, either through intensity threshold- and/or region growing-based segmentation algorithms or by manual cutting on native and/or MPR images (Glockner 2001; Prokop et al. ", "1997). ", "For instance, the representation of hepatic arterial vessels can be signifi cantly improved by cropping away the retroperitoneal tissues, including the abdominal aorta and renal arteries (which would obscure the origin and course of the celiac trunk and the superior mesenteric artery), allowing to get an angiography-like MIP depiction of such vessels (Prokop et al. ", "1997). ", "However, the usage of editing techniques may be time-consuming and require high technical skills, especially if advanced editing is needed. ", "Despite this, the usage of MIP and MPR/CPR algorithms, eventually associated with image editing, is usually sufficient to achieve adequate results in vascular MRI, both in diagnostic and icono-graphic terms (Davis et al. ", "1997; Hany et al. ", "1998).", "\n\n## 5.4 Shaded Surface Display (SSD)\n\nWith this algorithm. ", "a threshold is fixed by the user defining the minimum intensity of the voxels to be imaged, while voxels with lower intensity will be discarded. ", "The reconstructed image will be composed by surfaces corresponding to the interface between voxels with intensity above the threshold and void voxels (i.e., with intensity below the threshold), obtained by simulating the illumination of surfaces from an external light source in a given user-defined direction. ", "The result of this process is a three-dimensional (3D) representation of the voxels with above-threshold intensity, in contrast with MIP and MPR techniques, which yield two-dimensional (2D) images because of their planar nature (Fig. ", "5.3) (Davis et al. ", "1997; Prokop et al. ", "1997).", "\n\nFig. ", "5.3.", "\n\nPatient with bilateral femoro-popliteal aneurysm (right thrombosed). (", "a, b) SSD reconstruction; (c, d) VR reconstruction; (e, f) MIP reconstruction. ", "This latter allows a more accurate assessment of infrapopliteal vessels, mainly due to elimination of nonmaximal intensity voxels associated with stationary tissues\n\nSSD has the advantage of relatively modest computational requirements, as only a part of the dataset voxels is used and their representation on the output image is binary. ", "However, its main weakness is represented by the difficulty to choose a threshold that allows to effectively separate parietal from extraparietal voxels, which is key to generating nondistorted 3D images. ", "In fact, setting too low a threshold leads to including voxels external to the vessel wall to the reconstructed image, reducing the apparent size of vascular ostia or causing \"floating objects\" to appear inside the vascular cavities under examination. ", "Choosing an excessively low threshold may also lead to superimposition of background tissues or noise, resulting in a more or less \"speckled\" appearance of the surface contours with potential loss of details. ", "Conversely, too high a threshold leads to surface erosion because of exclusion of parietal voxels, resulting in enlargement of vessel ostia or hole-shaped areas of signal void. ", "Setting a good threshold may be challenging, especially on images with low SNR or inho-mogenous intravascular signal, as often happens with aneurysms or cardiac cavities. ", "For these reasons, the SSD technique is inadequate for taking vascular measurements (which are usually performed on MPR reconstructions), as well as for depicting thin vessels, while it can be useful to get a 3D perspective representation of vascular anatomy. ", "SSD is seldom performed today, as it has been superseded by the more robust and powerful volume rendering (VR) algorithms.", "\n\n## 5.5 Volume Rendering (VR)\n\nWhile MIP is based on the extraction of maximum intensity voxels among those crossed by an array of parallel lines, VR techniques rely on the ray casting principle by using the whole spatial and intensity information of the dataset and representing on the reconstructed image a weighted average of the intensity of all voxels distributed on each slab section. ", "Each voxel is assigned a value of opacity, transparency, and color depending on its intensity, position, and the prospective direction in which the image volume is observed according to a predetermined transfer function that allows to generate the final image by weighing the intensity of the various voxels encountered by each ray. ", "The user contributes to the definition of the transfer function by choosing a color and a transparency value and setting at least two voxel intensity thresholds, corresponding to the minimum and maximum brightness of visualizable points on the reconstructed image. ", "It is possible to define linear transfer functions (implying that the ratio between the intensity of two voxels on native images and those of the corresponding voxels on the VR image is constant), as well as nonlinear (e.g., logarithmic) ones. ", "A user can also define his own transfer functions, such as complex ones with multiple thresholds, in order to enhance or attenuate the contribution to the VR image of voxels with intensities within a given range (Calhoun et al. ", "1999; Fishman et al. ", "2006; Lell et al. ", "2006, 2007).", "\n\nIn vascular imaging, the choice of suitable transfer functions allows to emphasize even modest contrast differences among different vessels (for example, between arteries and veins close to each other). ", "It is also evident, however, that the need for the user to defi ne the proper transfer function makes VR reconstructions more operator-dependent than MIP techniques, which do not have such requirement. ", "In addition, VR algorithms are quite computationally intensive (in terms of both processor and graphics hardware load), as they provide a 3D visualization of the whole dataset, although the continuous improvement of image-processing hardware makes this issue less important than in the past.", "\n\nIn comparison with MIP techniques, VR algorithms offer the advantage of greater panoramicity and anatomical fidelity, owing to the fact that the whole dataset information is maintained. ", "In particular, VR reconstructions tend to be superior to thick-slab MIP images for the evaluation of vascular stenoses, which are depicted without over-estimation due to flow dispersion phenomena (Fig. ", "5.4) (Baskaran et al. ", "2002; Mallouhi et al. ", "2002, 2003). ", "Moreover, unlike MIP images, VR reconstructions yield the geometric perception of depth, thus allowing to effectively separate contiguous or tortuous vessels that would appear superimposed on MIP images and making it easier to achieve a panoramic representation of aneu-rysms or cardiac cavities (Fishman et al. ", "2006; Lell et al. ", "2006). ", "Another advantage of VR over MIP is the possibility to simultaneously display vessels and stationary tissues within the same image volume, which can be useful, for example, for the depiction of hypervascular neoplasms together with their feeding vessels.", "\n\nFig. ", "5.4.", "\n\nPatient with renal transplant and ectasia of the arterial anastomosis associated with stenosis of post-anastomotic left external iliac artery. (", "a, b) On thick-slab MIP reconstructions the grade of the stenosis is overestimated and it is impossible to correctly evaluate patency of the venal rein due to the higher intensity of voxels of the overlying arterial graft. (", "c, d) VR image allows a more accurate grading of the left external iliac artery stenosis, as well as to assess patency of the renal vein, which can be separated from the renal artery owing to the usage of an appropriate transfer curve and to the possibility to generate perspective 3D views\n\nOn the other hand, the MIP technique (especially thin-slab MIP) should be preferred for the evaluation of small vessels (such as, for example, infrapopliteal arteries in patients with lower limb arteriopathy), because the selection of the sole maximum intensity voxels usually permits a more detailed and continuous vision of such structures, even on images with a low SNR and/or CNR (Fishman et al. ", "2006). ", "Thin-slab MIP also tends to be more widely used than VR for the evaluation of vascular stenoses and aneurysms because of its greater simplicity, speed, and reproducibility (Fink et al. ", "2003; Persson et al. ", "2004; Runck et al. ", "2008). ", "In practice, both VR and MIP techniques can be employed in an integrated manner in order to optimize the visualization of the various aspects of vascular pathology (Fishman et al. ", "2006).", "\n\n## 5.6 Virtual Endoscopy (VE)\n\nBy applying SSD or VR algorithms in order to visualize vessels from an intraluminal, rather than extraluminal light source, it is possible to achieve endoscopy-like views of the vascular lumen. ", "SSD-based VE techniques require the defi nition of an intensity threshold and generate surfaces formed by the interfaces between lower intensity voxels (which identify the non-contrast-enhanced extraluminal compartment) and higher intensity ones, corresponding to the intraluminal signal. ", "VR-based VE techniques are more robust and require, in analogy with the tools for adjustment of visualization window settings for digital images in general, the definition of a central intensity value (window level) together with an intensity range (window width) corresponding to the spectrum of signal intensities of voxels to be displayed with different opacities on the VE view.", "\n\nRegardless of whether an SSD- or VR-based VE algorithm is used, the correct choice of the above mentioned parameters is crucial to achieve a good separation between intra- and extraluminal signal, avoiding artifacts due to surface erosion or dilation (which occur when the lower threshold is too high or too low compared with the mean intensity of intra-vascular voxels, respectively).", "\n\nVE reconstructions play an important role for the evaluation of anatomic variants of the vascular tree such as early branching vessels, for which it may be diffi cult to decide between the presence of a short common trunk and direct origin of vessels from adjacent ostia. ", "Another similar vascular application of VE is the study of cardiac cavities or aneurysms, in which it is usually relevant to establish the number and position of vascular ostia (Cirillo et al. ", "2005; Davis et al. ", "1996). ", "On VE images, it is also possible to make intralu-minal geometric measurements (such as distance or section area) which cannot be performed by means of extraluminal postprocessing techniques (Fig. ", "5.5). ", "Once again, however, the reliability of such measurements depends significantly on the threshold chosen for endoscopic visualization, which reflects the quality of the MRA dataset. ", "In this sense, it is important that the signal of the territories under examination is homogenous and with a high contrast compared with stationary tissues, so to allow a faithful depiction of the details of the parietal structure.", "\n\nFig. ", "5.5.", "\n\n(a-c) VR images of the left atrium and pulmonary veins (PV) in patient scheduled for percuteneous radiofre-quency ablation of atrial fibrillation. ", "The right inferior PV has an early branching pattern (red arrow), confirmed by thin-slab MIP oriented along the course of the vessel (d). ", "VE views (e, f) allow optimal depiction of the PV ostia; in (f) the distance between the ostia of the superior and inferior PV is measured\n\nReferences\n\nBaskaran V, Pereles FS, Nemcek AA Jr, et al.(2002) Gadolinium-enhanced 3D MR angiography of renal artery stenosis: a pilot comparison of maximum intensity projection, multi-planar reformatting, and 3D volume-rendering postprocessing algorithms. ", "Acad Radiol 9(1):50-59CrossRef80296-9)PubMed\n\nCalhoun PS, Kuszyk BS, Heath DG, et al. (", "1999) Three-dimensional volume rendering of spiral CT data: theory and method. ", "Radiographics 19(3):745-764PubMed\n\nCirillo S, Tosetti I, Gaita F, et al. (", "2005) Magnetic resonance angiography of the pulmonary veins before and after radiofrequency ablation for atrial fibrillation. ", "Radiol Med 109(5-6):488-499PubMed\n\nDavis CP, Hany TF, Wildermuth S, et al. (", "1997) Postprocessing techniques for gadolinium-enhanced three-dimensional MR angiography. ", "Radiographics 17(5):1061-1077PubMed\n\nDavis CP, Ladd ME, Romanowski BJ, et al. (", "1996) Human aorta: preliminary results with virtual endoscopy based on three-dimensional MR imaging data sets. ", "Radiology 199(1):37-40PubMed\n\nFink C, Hallscheidt PJ, Hosch WP, et al. (", "2003) Preoperative evaluation of living renal donors: value of contrast-enhanced 3D magnetic resonance angiography and comparison of three rendering algorithms. ", "Eur Radiol 13(4):794-801PubMed\n\nFishman EK, Ney DR, Heath DG, et al. (", "2006) Volume rendering versus maximum intensity projection in CT angiogra-phy: what works best, when, and why. ", "Radiographics 26(3): 905-922CrossRefPubMed\n\nGlockner JF (2001) Three-dimensional gadolinium-enhanced MR angiography: applications for abdominal imaging. ", "Radiographics 21(2):357-370PubMed\n\nHany TF, Schmidt M, Davis CP, et al. (", "1998) Diagnostic impact of four postprocessing techniques in evaluating contrast-enhanced three-dimensional MR angiography. ", "AJR 170(4):907-912PubMed\n\nKabul HK, Hagspiel KD (2006) Cross-sectional vascular imaging with CT and MR angiography. ", "J Nucl Cardiol 13(3):385-401CrossRefPubMed\n\nLell MM, Anders K, Uder M, et al. (", "2006) New techniques in CT angiography. ", "Radiographics 26 (Suppl 1):S45-S62CrossRefPubMed\n\nLell M, Fellner C, Baum U, et al. (", "2007) Evaluation of carotid artery stenosis with multisection CT and MR imaging: infl uence of imaging modality and postprocessing. ", "AJNR 28(1):104-110PubMed\n\nMallouhi A, Felber S, Chemelli A, et al. (", "2003) Detection and characterization of intracranial aneurysms with MR angiography: comparison of volume-rendering and maximum-intensity-projection algorithms. ", "AJR 180(1):55-64PubMed\n\nMallouhi A, Schocke M, Judmaier W, et al. (", "2002) 3D MR angiography of renal arteries: comparison of volume rendering and maximum intensity projection algorithms. ", "Radiology 223(2):509-516CrossRefPubMed\n\nPersson A, Dahlstrom N, Engellau L, et al. (", "2004) Volume rendering compared with maximum intensity projection for magnetic resonance angiography measurements of the abdominal aorta. ", "Acta Radiol 45(4):453-459CrossRefPubMed\n\nPrince MR, Grist TM, Debatin JF (2003) 3D Contrast MR angiography. ", "Springer, Berlin\n\nProkop M, Shin HO, Schanz A, et al. (", "1997) Use of maximum intensity projections in CT angiography: a basic review. ", "Radiographics 17(2):433-451PubMed\n\nRunck F, Steiner R P, Bautz WA, et al. (", "2008) MR imaging: influ-ence of imaging technique and postprocessing on measurement of internal carotid artery stenosis. ", "AJNR 29(9): 1736-1742CrossRefPubMed\n\nSun Y, Parker DL (1999) Performance analysis of maximum intensity projection algorithm for display of MRA images. ", "IEEE Trans Med Imaging 18(12):1154-1169CrossRefPubMed\n\nWestenberg JJ, van der Geest RJ, Wasser MN, et al. (", "2000) Vessel diameter measurements in gadolinium contrast-enhanced three-dimensional MRA of peripheral arteries. ", "Magn Reson Imaging 18(1):13-22CrossRef00099-5)PubMed\n\n# Part 2 \nClinical Applications\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_6(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 6. ", "Radiologic Vascular Anatomy\n\nClaudio Vignali1 , Valentina Vallini1 and Francesca Bianchi1\n\n(1)\n\nDiagnostic and Interventional Radiology, University of Pisa, Via Roma 67, Pisa, 56100, Italy\n\n6.1 The Arteries\n\n6.1.1 The Arteries of the Head, Neck, and Thorax\n\n6.1.1.1 The Thoracic Aorta\n\n6.1.1.2 The Pulmonary Arteries\n\n6.1.2 The Abdominal Arteries\n\n6.1.2.1 Visceral Branches\n\n6.1.2.2 Parietal Branches\n\n6.1.2.3 Terminal Branches\n\n6.1.3 The Arteries of the Limb\n\n6.1.3.1 Upper Limb\n\n6.1.3.2 Lower Limb\n\n6.2 The Veins\n\n6.2.1 Veins of the Head, Neck, and Thorax\n\n6.2.1.1 The Superior Vena Cava\n\n6.2.1.2 The Pulmonary Veins\n\n6.2.1.3 The Veins of the Heart\n\n6.2.2 The Veins of the Abdomen and Pelvis\n\n6.2.2.1 The Portal System of Veins\n\n6.2.3 The Veins of the Limbs\n\n6.2.3.1 The Veins of the Upper Limb\n\n6.2.3.2 The Veins of the Lower Limb\n\nReferences\n\nAbstract\n\nThe distribution of the systematic arteries is like a highly ramified tree, the common trunk of which, formed by the aorta, commences at the left ventricle, while the smallest ramifications extend to the peripheral parts of the body and the contained organs.", "\n\nThe veins convey the blood from the capillaries of the different parts of the body to the heart. ", "They consist of two distinct sets of vessels, the pulmonary and systemic. ", "The Portal vein, an appendage to the systemic venous system, is confined to the abdominal cavity, and returns the venous blood from the spleen and the viscera of digestion to the liver.", "\n\n## 6.1 The Arteries\n\nThe distribution of the systematic arteries is like a highly ramified tree, the common trunk of which, formed by the aorta, commences at the left ventricle, while the smallest ramifications extend to the peripheral parts of the body and the contained organs.", "\n\nThe arteries, in their distribution, communicate with one another, forming what are called anastomoses, and these communications are very free between the large as well as between the smaller branches. ", "The anastomosis between trunks of equal size is found where great activity of the circulation is requisite, as in the brain and the intestinal arteries. ", "In the limbs the anastomoses are most numerous and of largest size around the joints. ", "The smaller branches of arteries anastomose more frequently than the larger and between the smallest twigs these anastomoses become so numerous as to constitute a close network that pervades nearly every tissue of the body.", "\n\nThroughout the body generally the larger arterial branches pursue a fairly straight course, but in certain situations they are tortuous. ", "Thus the external maxillary artery in its course over the face, and the arteries of the lips, are extremely tortuous to accommodate themselves to the movements of the parts. ", "The uterine arteries are also tortuous, to accommodate themselves to the increase of size which the uterus undergoes during pregnancy.", "\n\n### 6.1.1 The Arteries of the Head, Neck, and Thorax\n\n#### 6.1.1.1 The Thoracic Aorta\n\nThe thoracic aorta commences at the aortic orifice of the left ventricle, ascendes for a short distance, arches backward and to the left side, and then descends within the thorax on the left side of the vertebral column. ", "Through the aortic hiatus in the diaphragm, passes into the abdominal cavity becoming abdominal aorta.", "\n\nIt is divided in several portions: the ascending aorta, the arch of the aorta, and the descending aorta.", "\n\nThe ascending aorta is about 5 cm in length and 3 cm in diameter. ", "It commences at the upper part of the base of the left ventricle, on a level with the lower border of the third costal cartilage. ", "At its origin it presents a dilatation called the aortic bulb for the presence of three small dilatations, the aortic sinuses, opposite the segments of the aortic valve.", "\n\nThe only branches of the ascending aorta are the coronary arteries which supply the heart. ", "They arise near the commencement of the aorta immediately above the attached margins of the semilunar valves. ", "The right coronary artery arises from the right aortic sinus. ", "It passes at first between the conus arteriosus and the right auricula and then runs in the right portion of the coronary sulcus, until the diaphragmatic surface of the heart as far as the posterior longitudinal sulcus, down which it is continued to the apex of the heart as the posterior descending branch. ", "It gives off a large marginal branch which follows the acute margin of the heart and supplies branches to both surfaces of the right ventricle. ", "It also gives twigs to the right atrium and to the part of the left ventricle which adjoins the posterior longitudinal sulcus. ", "The left coronary artery, larger than the right, arises from the left aortic sinus and divides into two branches: (a) the anterior descending branch descends in the anterior longitudinal sulcus and it gives branches to both ventricles; (b) the circumflex branch follows the left part of the coronary sulcus, reaching nearly as far as the posterior longitudinal sulcus and anastomosing with branches of the right coronary artery. ", "It gives branches to the left atrium and ventricle.", "\n\nThe cursive script begins at the level of the upper border of the second sternocostal articulation of the right side, and runs at first upward, backward, and to the left in front of the trachea, then it passes downward on the left side of the body of the fourth thoracic vertebra, at the border of which it becomes continuous with the descending aorta. ", "Its upper border is usually about 2.5 cm below the superior border of the manubrium sterni.", "\n\nThe branches given off from the arch of the aorta are three, generally: the innominate artery, the left common carotid artery and the left subclavian artery (Fig. ", "6.1).", "\n\nFig. ", "6.1.", "\n\nMIP (maximum intensity projection). ", "The branches arising from the arch of the aorta are three: the innominate artery, the left common carotid artery and the left subcla-vian artery\n\nThe number of the primary branches may be reduced to one, or more commonly two because the left common carotid can arise with the innominate artery. ", "More rarely the carotid and subclavian arteries of the left side arising from a left innominate artery. ", "The number may be increased also to four, from the right carotid and subclavian arteries arising directly from the aorta, the innominate being absent. ", "In most of these latter cases the right subclavian has been found to arise from the left end of the arch; in other cases it is the second or third branch given off, instead of the first. ", "Another form in which there are four primary branches is when the left vertebral artery arises from the arch of the aorta between the left carotid and subclavian arteries. ", "In other cases, the two carotids may be joined in a common trunk, and the subclavi-ans arise separately from the arch, the right subcla-vian generally arising from the left end of the arch.", "\n\nIn some instances other arteries spring from the arch of the aorta. ", "Of these the most common are the bronchial, one or both; but the internal mammary and the inferior thyroid have been seen to arise from this vessel (Gray 1918).", "\n\nWhen the aorta arches over to the right side, the three branches have an arrangement the reverse of what is usual: the innominate artery is on the left and the right carotid and subclavian arise separately.", "\n\nThe innominate or brachiocephalic artery is the largest branch of the arch of the aorta, and is from 4 to 5 cm in length.", "\n\nIt arises, on a level with the upper border of the second right costal cartilage, on a plane anterior to the origin of the left carotid. ", "It ascends obliquely upward, backward, and to the right to the level of the upper border of the right sternoclavicular articulation, where it divides into the right common carotid and right subclavian arteries.", "\n\nThe innominate artery usually gives off no branches. ", "Occasionally a small branch, the thyreoidea ima, arises from it. ", "Sometimes it gives off a thymic or bronchial branch.", "\n\nThe common carotid arteries differ in their mode of origin.", "\n\nNormally the right begins at the bifurcation of the innominate artery behind the sternoclavicular joint while the left springs from the arch of the aorta.", "\n\nThe left common carotid varies in its origin more than the right. ", "In the majority of abnormal cases it arises with the innominate artery; if that artery is absent, the two carotids arise usually by a single trunk.", "\n\nAt the level of the upper border of the thyroid cartilage each artery divides into two branches, the external carotid, supplying the exterior part of the head, the face, and the greater part of the neck and the internal carotid, supplying the vast majority of the tissues within the cranial and orbital cavities (Fig. ", "6.2).", "\n\nFig. ", "6.2.", "\n\nMIP. ", "The common carotid arteries divide into two branches, the external carotid artery and the internal carotid artery\n\nIn the majority of abnormal cases the division occurs higher than usual, the artery dividing opposite or even above the hyoid bone.", "\n\nAt the bifurcation each common carotid has a dilatation which extent to the proximal tract of the internal carotid, the carotic bulb.", "\n\nThe common carotid usually gives off no branch previous to its bifurcation, but it occasionally gives origin to the superior thyroid or its laryngeal branch, the ascending pharyngeal, the inferior thyroid, or, more rarely, the vertebral artery.", "\n\nThe external carotid artery begins opposite the upper border of the thyroid cartilage, and, taking a slightly curved course, arrives behind the neck of the mandible, where it divides into the terminal branches, the superficial temporal and the internal maxillary arteries.", "\n\nThe external carotid artery is covered by the skin, superficial fascia, platysma, deep fascia, and anterior margin of the sternocleidomastoideus muscle.", "\n\nThe branches of the external carotid artery are: superior thyroid artery, ascending pharyngeal artery, lingual artery, occipital artery, posterior auricular artery, external maxillary artery.", "\n\nThe internal carotid artery considering its course and its relations may be divided into four portions: cervical, petrous, cavernous, and cerebral.", "\n\nThe cervical portion of the internal carotid begins at the bifurcation of the common carotid, opposite the upper border of the thyroid cartilage, and runs perpendicularly upward, in front of the transverse processes of the upper three cervical vertebre, to the carotid canal in the petrous portion of the temporal bone. ", "The cervical portion of the internal carotid gives off no branches.", "\n\nThe petrous portion of the artery is when the internal carotid artery enters the canal in the petrous portion of the temporal bone. ", "It first ascends a short distance, then curves forward and medialward, and again ascends as it leaves the canal to enter the cavity of the skull between the lingula and petrosal process of the sphenoid. ", "The artery is separated from the bony wall of the carotid canal by a prolongation of dura mater.", "\n\nIn the cavernous portion the artery is situated between the layers of the dura mater forming the cavernous sinus, but covered by the lining membrane of the sinus. ", "It at first ascends toward the posterior clinoid process, then passes forward by the side of the body of the sphenoid bone, and again curves upward on the medial side of the anterior clinoid process, and perforates the dura mater.", "\n\nIn the cerebral portion, The Artery, After having perforated the dura mater on the medial side of the anterior clinoid process passes to the anterior perforated substance at the medial extremity of the lateral cerebral fissure, where it gives off its terminal or cerebral branches.", "\n\nThe branches of the internal carotid artery are: caroticotympanic artery and artery of the pterygoid canal from the petrous portion, cavernous, hypophy-seal, anterior meningeal, ophthalmic arteries from the cavernous portion, anterior cerebral, middle cerebral, posterior communicating and choroidal artery from the cerebral portion.", "\n\n * The ophthalmic artery arises from the internal carotid, just as the vessel is emerging from the cavernous sinus, on the medial side of the anterior clinoid process, and enters the orbital cavity through the optic foramen. ", "It then reaches the medial wall of the orbit, and divides into two terminal branches, the frontal and dorsal nasal.", "\n\n * The anterior cerebral artery arises from the internal carotid, at the medial extremity of the lateral cerebral fissure. ", "It passes forward and medialward across the anterior perforated substance; here it comes into close relationship with the opposite artery, to which it is connected by a short trunk, the anterior communicating artery. ", "From this point the two vessels run side by side in the longitudinal fissure, curve around the genu of the corpus callosum, and turning backward continue along the upper surface of the corpus callosum to its posterior part, where they end by anastomosing with the posterior cerebral arteries.", "\n\nThe anterior communicating artery connects the two anterior cerebral arteries across the commencement of the longitudinal fissure. ", "Sometimes this vessel is wanting, the two arteries joining together to form a single trunk, which afterward divides or it may be wholly, or partially, divided into two.", "\n\n * The middle cerebral artery, the largest branch of the internal carotid, runs at first in the lateral cerebral or Sylvian fissure and then on the surface of the insula, where it divides into a number of branches which are distributed to the lateral surface of the cerebral hemisphere.", "\n\n * The posterior communicating artery runs backward from the internal carotid, and anastomoses with the posterior cerebral artery, a branch of the basilar. ", "It varies in size, being sometimes small, and occasionally so large that the posterior cerebral may be considered as arising from the internal carotid rather than from the basilar. ", "It is frequently larger on one side than on the other. ", "From its posterior half are given off a number of small branches for the medial surface of the thalami and the walls of the third ventricle.", "\n\nThe subclavian artery on the right side arises from the innominate artery behind the right sternoclavicular articulation; on the left side it springs from the arch of the aorta. ", "The two vessels, therefore, in the first part of their course, differ in length, direction, and relation with neighboring structures. ", "Each subclavian artery can be divided into three parts: (a) the first portion extends from the origin of the vessel to the medial border of the scalenus anterior; (b) the second lies behind this muscle; (c) the third extends from the lateral margin of the muscle to the outer border of the first rib, where it becomes the axillary artery.", "\n\nThe origin of the right subclavian from the innominate artery takes place, in some cases, above the ster-noclavicular articulation, and less frequently, below that joint. ", "The artery may arise as a separate trunk from the arch of the aorta, and in such cases it may be either the first, second, third, or even the last branch derived from that vessel; in the majority, however, it is the first or last, rarely the second or third. ", "When it is the first branch, it occupies the ordinary position of the innominate artery; when the second or third, it gains its usual position by passing behind the right carotid; and when the last branch, it arises from the left extremity of the arch, and passes obliquely toward the right side, usually behind the trachea, esophagus, and right carotid, sometimes between the esophagus and trachea, to the upper border of the first rib, whence it follows its ordinary course. ", "In very rare instances, this vessel arises from the thoracic aorta, as low down as the fourth thoracic vertebra.", "\n\nThe left subclavian is occasionally joined at its origin with the left carotid.", "\n\nThe branches of the subclavian artery are: vertebral artery, thyrocervical trunk, internal mammary artery, costocervical artery.", "\n\nThe vertebral artery is the first branch of the sub-clavian, and arises from the upper and back part of the first portion of the vessel and ascends through the foramina in the transverse processes of the upper six cervical vertebre. ", "It then winds behind the superior articular process of the atlas and, entering the skull through the foramen magnum, unites, at the lower border of the pons, with the vessel of the opposite side to form the basilar artery.", "\n\nThe branches of the vertebral artery may be divided into two sets: those given off in the neck (spinal and muscular arteries), and those within the cranium (meningeal, posterior spinal, anterior spinal, posterior inferior cerebellar, medullary arteries).", "\n\nThe basilar artery, is a single trunk formed by the junction of the two vertebral arteries. ", "It extends from the lower to the upper border of the pons, lying in its median groove, under cover of the arachnoid. ", "It ends by dividing into the two posterior cerebral arteries (Fig. ", "6.3).", "\n\nFig. ", "6.3.", "\n\nMIP. ", "The basilar artery ends by dividing into the two (left and right) posterior cerebral arteries\n\nIts Branches are pontine, anterior inferior cerebel-lar, internal auditory, superior cerebellar and posterior cerebral arteries.", "\n\nThe posterior cerebral artery is the largest branch. ", "Passing lateralward, parallel to the superior cerebellar artery, and receiving the posterior communicating from the internal carotid, it winds around the cerebral peduncle, and reaches the tentorial surface of the occipital lobe of the cerebrum, where it breaks up into branches for the supply of the temporal and occipital lobes.", "\n\nAt the base of the brain the internal carotid and the vertebral artery form a remarkable anastomosis known as the arterial circle of Willis (Fig. ", "6.4). ", "It is formed in front by the anterior cerebral arteries, branches of the internal carotid, which are connected together by the anterior communicating, behind by the two posterior cerebral arteries, branches of the basilar, which are connected on either side with the internal carotid by the posterior communicating.", "\n\nFig. ", "6.4.", "\n\nMIP. ", "Arterial circle of Willis\n\nThe thyrocervical trunk is a short thick trunk, which arises from the front of the first portion of the subclavian artery, close to the medial border of the scalenus anterior, and divides almost immediately into three branches, the inferior thyroid, transverse scapular, and transverse cervical.", "\n\nThe internal mammary artery arises from the under surface of the first portion of the subcla-vian, opposite the thyrocervical trunk. ", "It descends behind the cartilages of the upper six ribs at a distance of about 1 cm from the margin of the sternum, and at the level of the sixth intercostal space divides into the musculophrenic and superior epigastric arteries.", "\n\nThe thoracic descending aorta is contained in the posterior mediastinal cavity.", "\n\nIt begins at the fourth thoracic vertebra where it is continuous with the aortic arch, and ends in front of the twelfth at the aortic hiatus in the diaphragm.", "\n\nBranches of the thoracic aorta: (a) Visceral (peri-cardial arteries, bronchial arteries, esophageal arteries, mediastinal arteries); (b) Parietal (intercostal arteries, subcostal arteries, superior phrenic artery).", "\n\n##### Visceral Branches\n\nThe pericardial arteries consist of a few small vessels which are distributed to the posterior surface of the pericardium.", "\n\nThe bronchial arteries vary in number, size, and origin.", "\n\nGenerally there is one bronchial artery on the right and two bronchial arteries on the left. ", "The right bronchial artery can arises from the first aortic intercostal or from the upper left bronchial artery.", "\n\nEach vessel runs on the back part of its bronchus, dividing and subdividing along the bronchial tubes, supplying them, the lung's parenchyma, the bronchial lymph glands, and the visceral pleura.", "\n\nThe esophageal arteries are four or five in number. ", "They form a chain of anastomoses along the esophagus, anastomosing with the esophageal branches of the inferior thyroid arteries above, and with ascending branches from the left inferior phrenic and left gastric arteries below.", "\n\nThe mediastinal branches are numerous small vessels which supply the mediastinal lymph glands.", "\n\n##### Parietal Branches\n\nThe intercostal arteries are usually nine pairs.", "\n\nThey arise from the back of the aorta, and run to the lower nine intercostal spaces the first two spaces supplied by the highest intercostal artery, a branch of the costocervical trunk of the subclavian.", "\n\nEach artery divides into an anterior and a posterior branch.", "\n\nThe anterior branch crosses the corresponding intercostal space obliquely toward the angle of the upper rib, and thence is continued forward in the costal groove; it anastomoses in front with the intercostal branch of the internal mammary. ", "The first aortic intercostal artery anastomoses with the intercostal branch of the costocervical trunk. ", "The lower two intercostal arteries are continued anteriorly from the intercostal spaces into the abdominal wall, and anastomose with the subcostal, superior epigastric, and lumbar arteries. ", "The anterior rami give off the following branches: collateral intercostals, lateral cutaneous, muscular, mammary.", "\n\nThe posterior branch runs backward through a space which is bounded above and below by the necks of the ribs, medially by the body of a vertebra, and laterally by an anterior costotransverse ligament.", "\n\nIt gives off a spinal branch which enters the vertebral canal through the intervertebral foramen and is distributed to the medulla spinalis and its membranes and the vertebrae. ", "It then courses over the transverse process, supplies branches to the muscles of the back and cutaneous branches.", "\n\nThe Adamkiewicz or great anterior radiculomed-ullary artery is the largest anterior segmental medullary artery. ", "It typically arises from a left posterior intercostal artery and supplies the lower two-thirds of the spinal cord via the anterior spinal artery. ", "In some percentage of people, the artery of Adamkiewicz arises from a lumbar vessel.", "\n\nThe subcostal arteries, so named because they lie below the last ribs, constitute the lowest pair of branches derived from the thoracic aorta, and are in series with the intercostal arteries.", "\n\nEach passes along the lower border of the twelfth rib, and it anastomoses with the superior epigastric, lower intercostal, and lumbar arteries. ", "Each subcostal artery gives off a posterior branch which has a similar distribution to the posterior ramus of an intercostal artery.", "\n\nThe superior phrenic arteries are small and arise from the lower part of the thoracic aorta; they are distributed to the posterior part of the upper surface of the diaphragm.", "\n\n#### 6.1.1.2 The Pulmonary Arteries\n\nThe pulmonary arteries convey the venous blood from heart to the lungs.", "\n\nThe pulmonary trunk begins at the base of the right ventricle. ", "It is short and wide ~5 cm in length and 3 cm in diameter. ", "It then branches into two pulmonary arteries, left and right (Fig. ", "6.5), which accompany the bronchial tubes and end in a dense capillary network in the walls of the alveoli.", "\n\nFig. ", "6.5.", "\n\nVR (volume rendering). ", "The pulmonary arteries with the left atrium and the pulmonary veins\n\n### 6.1.2 The Abdominal Arteries\n\nThe abdominal aorta begins at the aortic hiatus of the diaphragm and, descending in front of the vertebral column, ends at the level of the fourth lumbar vertebra, by dividing into the two common iliac arteries.", "\n\nVariations in the abdominal aorta are not common. ", "The most common place for its bifurcation, is opposite the lower border of the body of the fourth lumbar vertebra 75% but it may divide opposite the disc between L4 and L5 or rarely opposite the body of the fifth lumbar vertebra. ", "A higher division is less common (9%) than a lower division (11%). ", "The following rare variations of the abdominal aorta have been described: (1) the aorta may pass through the esophageal hiatus (opening) of the diaphragm; (2) it may lie on the right side of the vena cava, the vein passing over the upper part of the aorta to gain access to the caval hiatus; (3) the aorta may have a vena cava on each side, the left vein passing across the upper part of the artery to open into the right vein just below the caval opening (Bergman et al. ", "1996).", "\n\nThe branches of the abdominal aorta may be divided into three sets: (a) Visceral (celiac trunk, superior mesenteric artery, inferior mesenteric artery, middle suprarenal artery, renal artery, internal spermatic or ovarian artery); (b) Parietal (inferior phrenic artery, middle sacral artery); (c) Terminal (common iliac artery).", "\n\n#### 6.1.2.1 Visceral Branches\n\nThe celiac trunk is a short thick trunk, which arise from the front of the aorta, just below the aortic hiatus of the diaphragm.", "\n\nThe celiac trunk conventionally divides after 1-2 cm into three large branches, the left gastric, the common hepatic, and the splenic (Fig. ", "6.6); this pattern is seen in 65-75% of individuals and it occasionally gives off one of the inferior phrenic arteries. ", "It may be absent and the branches usually arising from it then arise from the aorta. ", "The trunk may be shorter or longer than usual and in the latter case, the branches commonly arise separately from the trunk instead of radiating from a single point. ", "The celiac trunk may lack one or more of its main branches. ", "In such cases, the branch in question may arise from the aorta or the superior mesen-teric, either independently or in conjunction with another branch. ", "Variations have been reported to occur with the following frequencies (approximate): (1) hepatosplenogastric trunk, 90%; (2) hepatosplenic trunk (hepatic and splenic), 3.5%; (3) hepatosplenom-esenteric trunk (hepatic, splenic, and superior mesenteric), 0.5%; (4) hepatogastric trunk (hepatic and left gastric), 1.5%; (5) splenogastric trunk (splenic and left gastric), 5.5% (Bergman et al. ", "1996).", "\n\nFig. ", "6.6.", "\n\nMIP. ", "The celiac trunk and the superior mesenteric artery arise from the abdominal aorta\n\nThe left gastric artery is the smallest of the three branches of the celiac artery. ", "It runs from left to right, along the lesser curvature of the stomach to the pylorus, between the layers of the lesser omentum; It gives branches to both surfaces of the stomach and anastomoses with the right gastric artery. ", "The left gastric may arise directly from the abdominal aorta, and there may be two left gastric arteries instead of one.", "\n\nThe common hepatic artery in the adult is intermediate in size between the left gastric and lienal. ", "It crosses the portal vein anteriorly and ascends between the layers of the lesser omentum, and in front of the epiploic foramen, to the porta hepatis, where it divides into two branches, right and left, which supply the corresponding lobes of the liver. ", "Its branches are: right gastric, gastroduodenal, and cystic. ", "The common hepatic artery usually arises from the celiac trunk, but may also arise directly from the aorta or from the left gastric, gastroduodenal, right renal or splenic artery. ", "In ~30% of persons all or part of the hepatic arterial supply arises from the superior mesenteric artery. ", "The common hepatic artery may be doubled, tripled, or missing (12% of cases) and it is almost always located between the bile duct and the portal vein. ", "The left hepatic artery arises from the common hepatic in 89% of cases; in 11% of cases the vessel is may arise from the left gastric. ", "Accessory right or left hepatic arteries can be found approximately in 8% of subjects (Bergman et al. ", "1996).", "\n\nThe right gastric artery arises from the hepatic artery (~53%, the most frequent origin) above the pylorus, descends to the pyloric end of the stomach and anastomosing with the left gastric artery.", "\n\nThe gastroduodenal artery is a short but large branch, which descends, near the pylorus, between the superior part of the duodenum and the neck of the pancreas, and divides at the lower border of the duodenum into two branches, the right gastro-epiploic and the superior pancreaticoduodenal. ", "The gastroduodenal artery most commonly arises from the common hepatic artery almost always (75%) before the division of the hepatic artery into its right and left branches.", "\n\nThe right gastroepiploic artery runs from right to left along the greater curvature of the stomach, anastomosing with the left gastroepiploic branch of the lienal artery. ", "This vessel gives off numerous branches, some of which ascend to supply both surfaces of the stomach, while others descend to supply the greater omentum and anastomose with branches of the middle colic.", "\n\nThe superior pancreaticoduodenal artery descends between the contiguous margins of the duodenum and pancreas. ", "It supplies both these organs, and anastomoses with the inferior pancreaticoduodenal branch of the superior mesenteric artery, and with the pancreatic branches of the lienal artery.", "\n\nThe cystic artery, usually a branch of the right hepatic, divides into two branches, one of which ram-ifies on the free surface, the other on the attached surface of the gall-bladder. ", "There is only one cystic artery in 88% of individuals. ", "Of these individuals, the cystic artery arises from the right hepatic artery in 82%; from the proper hepatic artery in 3%; from the left hepatic artery, distal to the origin of the right hepatic artery, in 2%; and from the gastroduodenal in 1%.", "\n\nThe lienal or splenic artery, the largest branch of the celiac artery, is remarkable for the tortuosity of its course. ", "It passes along the upper border of the pancreas; it divides into branches, some of which enter the hilus of that organ to be distributed to the tissues of the spleen; some are given to the pancreas, while others pass to the greater curvature of the stomach. ", "The tortuous course of the splenic artery is considered so variable that no two arteries are alike, but the tortuosity of the artery is absent in infants and children. ", "In congenital absence of the spleen (very rare), the splenic artery terminates in the pancreas.", "\n\nThe superior mesenteric artery arises from the front of the aorta about 1.25 cm below the celiac artery (Fig. ", "6.6), and is crossed at its origin by the neck of the pancreas.", "\n\nIt is a large vessel which supplies the whole length of the small intestine, except the superior part of the duodenum; it also supplies the cecum and the ascending part of the colon and about one-half of the transverse part of the colon. ", "The variations in this artery are very common and numerous. ", "The artery may be doubled, arising from the aorta as two trunks; sometimes it arises from, or in common with the celiac trunk. ", "In some cases, it gives rise to the left colic and superior hemorrhoidal (superior rectal), thus wholly or partly replacing the inferior mesenteric artery.", "\n\nIts branches are: inferior pancreaticoduodenal, ileocolic, intestinal, right colic and middle colic.", "\n\nThe inferior mesenteric artery supplies the left half of the transverse part of the colon, the whole of the descending and iliac parts of the colon, the sig-moid colon, and the greater part of the rectum. ", "It is smaller than the superior mesenteric, and arises from the aorta, about 3 or 4 cm above its division into the common iliacs and close to the lower border of the inferior part of the duodenum. ", "It crosses the left common iliac artery and is continued into the lesser pelvis under the name of the superior hemorrhoidal artery, which descends between the two layers of the sigmoid mesocolon and ends on the upper part of the rectum.", "\n\nIts branches are: left colic, sigmoid, superior hemor-rhoidal.", "\n\nDuplication of this artery has been reported. ", "The inferior mesenteric artery may be absent entirely, its branches being given by the superior mesenteric artery or it may be just absent from its usual location. ", "This artery sometimes arises from the superior mesenteric by a common trunk with the middle colic or the left common iliac artery. ", "Usually, the origin of the artery from the aorta was at the level of L3, in a few cases at the level of the intervertebral disc between L3 and L4, or at the level of L4. ", "In a smaller number of cases, origin of the artery at the level of the intervertebral disc between L2 and L3 or L4 and L5 was observed.", "\n\nThe renal arteries are two large trunks, which arise from the side of the aorta, immediately below the superior mesenteric artery. ", "The right is longer than the left, on account of the position of the aorta; it passes behind the inferior vena cava and the right renal vein. ", "The left is somewhat higher than the right; it lies behind the left renal vein and is crossed by the inferior mesenteric vein.", "\n\nBoth renal arteries usually have two divisions which pass anterior and posterior to the renal pelvis (Fig. ", "6.7).", "\n\nFig. ", "6.7.", "\n\nMIP. ", "The renal arteries with the anterior and posterior divisions\n\nEach vessel gives off some small inferior suprarenal branches to the suprarenal gland, the ureter, and the surrounding cellular tissue and muscles.", "\n\nIn approximately two-thirds of individuals a single right and left renal artery is found. ", "Irregularites of the renal vessels are found in about 35% of the cases. ", "The most common is the presence of an additional vessel (~28%) and supernumerary vessels are more frequent on the left side than the right. ", "Multiple renal arteries occur unilaterally in 32% and bilaterally in 12%. ", "An independent superior renal pole artery observed in up to 7% and an inferior pole artery is ~5%. ", "Superior renal polar arteries are usually single. ", "They arise as separate branches from the aorta in 7% of cases, or as branches of the renal artery in 12% of cases. ", "There may be two or three unilaterally or bilaterally with different aortic or renal sources. ", "Superior renal polar arteries can also arise from the inferior phrenic or from the superior mesenteric artery. ", "Some superior renal polar arteries provide several branches to the suprarenal gland, dividing before entering the superior pole of the kidney. ", "Inferior renal polar arteries are usually single and arise from the aorta (95.5%), or the renal artery (1.4%). ", "The inferior polar arteries are sometimes doubled (Fig. ", "6.8), with one arising from the aorta and the other from the renal, or the pair from either source (Gray 1918).", "\n\nFig. ", "6.8.", "\n\nMIP. ", "Doubled inferior renal polar artery arising from the aorta\n\nAberrant renal arteries are common in fused kidneys (horseshoe- dumbbell- or disc-shaped): two to six such arteries are characteristically longer or shorter than usual. ", "The unusual vessels may originate from the aorta, gonadal, common iliac, middle sacral, external or internal iliac, or superior or inferior mes-enteric arteries. ", "There are reports in the literature of seven, eight, and ten arteries supplying horseshoe-shaped kidneys, but such findings, are very rare.", "\n\nThe internal spermatic arteries are distributed to the testes. ", "They are two slender vessels of considerable length, and arise from the front of the aorta a little below the renal arteries. ", "The right spermatic may run behind, instead of in front of the inferior vena cava. ", "Each crosses obliquely over the ureter and the lower part of the external iliac artery to reach the abdominal inguinal ring, through which it passes, along the inguinal canal to the scrotum, where it becomes tortuous, and divides into several branches. ", "The internal spermatic artery supplies one or two small branches to the ureter, and in the inguinal canal gives one or two twigs to the cremaster. ", "If one or both testicular arteries are missing, the testes are supplied by branches from the vesical or prostatic arteries passing under the arch of the pubis.", "\n\nThe ovarian arteries are the corresponding arteries in the female to the internal spermatic in the male. ", "They supply the ovaries, are shorter than the internal spermatics, and do not pass out of the abdominal cavity. ", "Small branches are given to the ureter and the uterine tube, and one passes on to the side of the uterus, and unites with the uterine artery. ", "Other offsets are continued on the round ligament of the uterus, through the inguinal canal, to the integument of the labium majus and groin. ", "The gonadal arteries usually arise from the anterior surface of the aorta below the renal vein, but in 15% of cases, the gonadal arteries arise from the renal artery, from one of the branches of the renal artery, or from a supernumerary or \"accessory\" renal artery. ", "More rarely, a gonadal artery can originate from a suprarenal, inferior phrenic, superior mesenteric, lumbar, common iliac, or internal iliac. ", "In some cases (17%), the gonadal arteries are doubled on one side; less commonly, they are doubled on both sides.", "\n\n#### 6.1.2.2 Parietal Branches\n\nThe inferior phrenic arteries are two small vessels (the left and the right phrenic), which supply the diaphragm and present much variety in their origin. ", "They may arise, by a common trunk from the aorta or the celiac trunk in 18-30% of cases, or as independent branches from these same sources in 62%. ", "Other sources may be the hepatic, left gastric, renal, suprarenal, or superior mesenteric arteries in about 8% of cases. ", "Variations in the origin of the phrenic arteries are numerous and supplementary phrenic vessels are common. ", "When independent, the right and left phrenics usually arise asymmetrically. ", "They run obliquely upward and lateralward under surface by the diaphragti. ", "Near the back part of the central tendon each vessel divides into a medial and a lateral branch. ", "Each vessel gives off superior suprarenal branches (in ~96%) to the suprarenal gland of its own side.", "\n\nThe middle suprarenal artery is usually a single vessel (85% of cases) and it often arises from the aorta, but may also originate from the inferior phrenic, renal, superior renal polar, or from the celiac trunk. ", "The artery may be absent, multiple, or may not even supply the suprarenal gland.", "\n\nThe lumbar arteries are in series with the intercos-tals. ", "They are usually four in number on either side, and arise from the back of the aorta, opposite the bodies of the upper four lumbar vertebrae.", "\n\nThe first lumbar may be joined at its origin with the lowest intercostal artery; the third and fourth lumbar, or less often the second and third lumbars, may arise from the aorta as a common stem. ", "One or both of the last pair of lumbar arteries may arise in common with the middle sacral.", "\n\nThe middle sacral artery is a small vessel, which arises from the back of the aorta, a little above its bifurcation. ", "It descends in the middle line in front of the fourth and fifth lumbar vertebrae, the sacrum and coccyx. ", "From it, minute branches pass to the posterior surface of the rectum.", "\n\n#### 6.1.2.3 Terminal Branches\n\nThe abdominal aorta divides, on the left side of the body of the fourth lumbar vertebra, into the two common iliac arteries. ", "Each artery is about 5 cm in length. ", "They diverge from the termination of the aorta, pass downward and lateralward, and divide, into two branches, the external iliac and hypogastric arteries, The former supplies the lower extremity the latter, the viscera and parietes of the pelvis. ", "The right common iliac artery is somewhat longer than the left. ", "The left common iliac artery, laterally, is in relation with the Psoas major and it is crossed at its point of bifurcation by the ureter.", "\n\nThe common iliac arteries give off small branches to the peritoneum, Psoas major, ureters, and the surrounding areolar tissue, and occasionally give origin to the iliolumbar, or accessory renal arteries. ", "The point of origin varies according to the bifurcation of the aorta.", "\n\nIn about 80% of the cases the aorta bifurcated within 1.25 cm above or below the level of the crest of the ilium; more frequently below than above. ", "The point of division is subject to great variety. ", "In 68% of individuals the division occurs between the last lumbar vertebra and the upper border of the sacrum; being above that point in one case out of eight, and below it in one case out of six. ", "The left common iliac artery divides lower down more frequently than the right.", "\n\nThe relative lengths, also, of the two common iliac arteries vary. ", "The length of the arteries varied, from 3.5 to 7.5 cm; in about half of the remaining cases the artery was longer, and in the other half, shorter; the minimum length being less than 1.25 cm, the maximum, 11 cm. ", "In rare instances, the right common iliac has been found wanting, the external iliac and hypo-gastric arising directly from the aorta (Gray 1918).", "\n\nThe hypogastric artery supplies the walls and viscera of the pelvis, the buttock, the generative organs, and the medial side of the thigh. ", "It is a short, thick vessel, smaller than the external iliac, and about 4 cm in length. ", "It arises at the bifurcation of the common iliac, opposite the lumbosacral articulation, and, passing downward to the upper margin of the greater sciatic foramen, divides into two large trunks, an anterior and a posterior. ", "The place of division of the hypogas-tric varies between the upper margin of the sacrum and the upper border of the greater sciatic foramen. ", "The right and left hypogastric arteries in a series of cases often differed in length, but neither seemed constantly to exceed the other. ", "The branches of the hypo-gastric artery are: (a) from the anterior trunk (superior, middle and inferior vesical, middle hemorrhoidal, obturator, internal pudendal, inferior gluteal, uterine and vaginal (in the female); (b) from the posterior trunk (iliolumbar, lateral sacral, superior gluteal).", "\n\nThe external iliac artery is larger than the hypogas-tric, and passes obliquely downward and lateralward along the medial border of the Psoas major, from the bifurcation of the common iliac to a point beneath the inguinal ligament, midway between the anterior superior spine of the ilium and the symphysis pubis, where it becomes the femoral artery. ", "Besides several small branches to the Psoas major and the neighboring lymph glands, the external iliac gives off two branches of considerable size: the inferior epigastric and the deep iliac circumflex.", "\n\nThe inferior epigastric artery arises from the external iliac, immediately above the inguinal ligament. ", "It curves forward in the subperitoneal tissue, and ascends between the Rectus abdominis and the posterior lamella of its sheath. ", "It finally divides into numerous branches. ", "The origin of the inferior epigastric may take place from any part of the external iliac between the inguinal ligament and a point 6 cm above it; or it may arise below this ligament, from the femoral. ", "It frequently springs from the external iliac, by a common trunk with the obturator. ", "Sometimes it arises from the obturator, the latter vessel being furnished by the hypogastric, or it may be formed of two branches, one derived from the external iliac, the other from the hypogastric.", "\n\nThe deep iliac circumflex artery arises from the lateral aspect of the external iliac nearly opposite the inferior epigastric artery. ", "It ascends between the Obliquus internus and Transversus muscles, supplying them, and anastomosing with the lumbar and inferior epigastric arteries.", "\n\n### 6.1.3 The Arteries of the Limb\n\n#### 6.1.3.1 Upper Limb\n\nThe artery which supplies the upper extremity continues as a single trunk from its commencement down to the elbow; but different portions of it have received different names, according to the regions through which they pass. ", "That part of the vessel which extends from its origin to the outer border of the first rib is termed the subclavian; beyond this point to the lower border of the axilla it is named the axillary; and from the lower margin of the axillary space to the bend of the elbow it is termed brachial; here the trunk ends by dividing into two branches the radial and ulnar.", "\n\nThe axillary artery is the continuation of the sub-clavian, commences at the outer border of the first rib, and ends at the lower border of the tendon of the Teres major, where it takes the name of brachial. ", "Its direction varies with the position of the limb; thus the vessel is nearly straight when the arm is directed at right angles with the trunk, concave upward when the arm is elevated above this, and convex upward and lateralward when the arm lies by the side. ", "At its origin the artery is very deeply situated, but near its termination is superficial, being covered only by the skin and fascia. ", "The branches of the axillary are: highest thoracic artery, thoracoacromial artery, lateral thoracic artery, subscapular artery, posterior humeral circumflex artery, anterior humeral circum-flex artery.", "\n\nSometimes the axillary artery divides into the radial and ulnar arteries, and occasionally it gives origin to the volar interosseous artery of the forearm. ", "Occasionally the subscapular, humeral circumflex, and profunda Brach arteries arise from a common trunk, and when this occurs the branches of the brachial plexus surround this trunk instead of the main vessel.", "\n\nThe brachial artery commences at the lower margin of the tendon of the Teres major, and, passing down the arm, ends about 1 cm below the bend of the elbow, where it divides into the radial and ulnar arteries. ", "At first the brachial artery lies medial to the humerus; but as it runs down the arm it gradually gets in front of the bone, and at the bend of the elbow it lies midway between its two epicondyles. ", "The brachial artery may leave the medial border of the Biceps brachii, and descend toward the medial epicondyle of the humerus; in such cases it usually passes behind the supracondylar process of the humerus, from which a fibrous arch is in most cases thrown over the artery; it then runs beneath or through the substance of the Pronator teres, to the bend of the elbow. ", "Occasionally, the artery is divided for a short distance at its upper part into two trunks, which are united below. ", "Frequently the artery divides at a higher level than usual, and the vessels concerned in this high division are three: radial, ulnar, and interosseous. ", "Most frequently the radial is given off high up, the other limb of the bifurcation consisting of the ulnar and interosseous; in some instances the ulnar arises above the ordinary level, and the radial and interosseous form the other limb of the division; occasionally the interosseous arises high up. ", "Sometimes, long slender vessels, connect the brachial or the axillary artery with one of the arteries of the forearm, or branches from them. ", "The branches of the brachial artery are, arteria profunda brachii, nutrient artery, superior ulnar collateral artery, inferior ulnar collateral artery, muscular branches.", "\n\nThe vessels engaged in the anastomoses may be conveniently divided into those situated in front of and those behind the medial and lateral epicondyles of the humerus. ", "The branches anastomosing in front of the medial epicondyle are: the anterior branch of the inferior ulnar collateral, the anterior ulnar recurrent, and the anterior branch of the superior ulnar collateral. ", "Those behind the medial epicondyle are: posterior branch of the inferior ulnar collateral, the posterior ulnar recurrent, and the posterior branch of the superior ulnar collateral. ", "The branches anastomosing in front of the lateral epicondyle are: the radial recurrent and the terminal part of the profunda brachii. ", "Those behind the lateral epicondyle are: the inferior ulnar collateral, the interosseous recurrent, and the radial collateral branch of the profunda brachii. ", "There is also an arch of anastomosis above the olecranon, formed by the interosseous recurrent joining with the inferior ulnar collateral and posterior ulnar recurrent.", "\n\nThe radial artery appears, from its direction, to be the continuation of the brachial, but it is smaller in caliber than the ulnar. ", "It commences at the bifurcation of the brachial, just below the bend of the elbow, and passes along the radial side of the forearm to the wrist. ", "It then winds backward, around the lateral side of the carpus, beneath the tendons of the Abductor pollicis longus and Extensores pollicis longus and brevis to the upper end of the space between the metacarpal bones of the thumb and index finger. ", "Finally it passes forward between the two heads of the first Interosseous dorsalis, into the palm of the hand, where it crosses the metacarpal bones and at the ulnar side of the hand unites with the deep volar branch of the ulnar artery to form the deep volar arch.", "\n\nThe origin of the radial artery is, in nearly one case in eight, higher than usual; more often it arises from the axillary or upper part of the brachial than from the lower part of the latter vessel. ", "In the forearm it deviates less frequently from its normal position than the ulnar. ", "It has been found lying on the deep fascia instead of beneath it.", "\n\nThe branches of the radial artery may be divided into three groups, corresponding with the three regions in which the vessel is situated: (a) in the forearm (radial recurrent, muscular, volar carpal, superficial volar); (b) at the wrist (dorsal carpal, first dorsal meta-carpal); (c) in the hand (princeps pollicis, volaris indi-cis radialis, volar metacarpal, perforating, recurrent).", "\n\nThe ulnar artery the larger of the two terminal branches of the brachial, begins a little below the bend of the elbow, and, passing obliquely downward, reaches the ulnar side of the forearm at a point about midway between the elbow and the wrist. ", "It then runs along the ulnar border to the wrist, crosses the transverse carpal ligament on the radial side of the pisiform bone, and immediately beyond this bone divides into two branches, which enter into the formation of the superficial and deep volar arches.", "\n\nThe ulnar artery may arise about 5-7 cm below the elbow, but more frequently higher, the brachial being more often the source of origin than the axillary. ", "Variations in the position of this vessel are more common than in the radial. ", "When its origin is normal, the course of the vessel is rarely changed. ", "When it arises high up, it is almost invariably superficial to the Flexor muscles in the forearm, lying commonly beneath the fascia, more rarely between the fascia and integument. ", "In a few cases, its position is subcutaneous in the upper part of the forearm, and subaponeurotic in the lower part.", "\n\nThe branches of the ulnar artery may be arranged in the following groups: (a) in the forearm (anterior recurrent, posterior recurrent, common interosseous, muscular); (b) at the wrist (volar carpal, dorsal carpal); (c) in the hand (deep volar, superficial volar arch).", "\n\n#### 6.1.3.2 Lower Limb\n\nThe artery which supplies the greater part of the lower extremity is the direct continuation of the external iliac. ", "It runs as a single trunk from the inguinal ligament to the lower border of the Popliteus, where it divides into two branches, the anterior and posterior tibial. ", "The upper part of the main trunk is named the femoral, the lower part the popliteal.", "\n\n##### The Femoral Artery\n\nThe femoral artery begins immediately behind the inguinal ligament, midway between the anterior superior spine of the ilium and the symphysis pubis, and passes down the front and medial side of the thigh. ", "It ends at the junction of the middle with the lower third of the thigh, where it passes through an opening in the Adductor magnus to become the popliteal artery. ", "The vessel, at the upper part of the thigh, lies in front of the hip-joint; in the lower part of its course it lies to the medial side of the body of the femur, and between these two parts, where it crosses the angle between the head and body, the vessel is some distance from the bone. ", "The first 4 cm of the vessel is enclosed in a fibrous sheath, the femoral sheath. ", "In the upper third of the thigh the femoral artery is contained in the femoral triangle (Scarpa's triangle), and in the middle third of the thigh, in the adductor canal (Hunter's canal).", "\n\nSeveral cases are recorded in which the femoral artery divided into two trunks below the origin of the profunda, and became reunited near the opening in the Adductor magnus, so as to form a single popliteal artery. ", "A few cases have been recorded in which the femoral artery is absent, its place being supplied by the inferior gluteal artery which accompanied the sciatic nerve to the popliteal fossa. ", "The external iliac in these cases is small, and terminate in the profunda.", "\n\nThe branches of the femoral artery are: superficial epigastric, deep external pudendal, superficial iliac circumflex, muscular, superficial external pudendal, profunda femoris, highest genicular.", "\n\nThe superficial epigastric artery arises from the front of the femoral artery about 1 cm below the inguinal ligament. ", "It distributes branches to the superfi-cial subinguinal lymph glands, the superficial fascia, and the integument; it anastomoses with branches of the inferior epigastric, and with its fellow of the opposite side.", "\n\nThe superficial iliac circumflex artery, the smallest of the cutaneous branches, arises close to the preceding, and it distributes branches to integument of the groin, the superficial fascia, and the superficial subinguinal lymph glands, anastomosing with the deep iliac circumflex, the superior gluteal and lateral femoral circumflex arteries.", "\n\nThe superficial external pudendal artery arises from the medial side of the femoral artery and it distributes to he integument on the lower part of the abdomen, the penis and scrotum in the male, and the labium majus in the female, anastomosing with branches of the internal pudendal.", "\n\nThe deep external pudendal artery, more deeply seated than the preceding, is distributed, in the male, to the integument of the scrotum and perineum, in the female to the labium majus; its branches anastomose with the scrotal (or labial) branches of the perineal artery.", "\n\nMuscular branches are supplied by the femoral artery to the Sartorius, Vastus medialis, and Adductores.", "\n\n##### The Profunda Femoris Artery\n\nThe profunda femoris artery is a large vessel arising from the lateral and back part of the femoral artery, from 2 to 5 cm below the inguinal ligament. ", "At first it lies lateral to the femoral artery; it then runs behind it to the medial side of the femur, and, passing downward behind the Adductor longus, ends at the lower third of the thigh in a small branch, which pierces the Adductor magnus, and is distributed on the back of the thigh to the hamstring muscles. ", "The terminal part of the profunda is sometimes named the \"fourth perforating artery.\"", "\n\nThis vessel sometimes arises from the medial side, and, more rarely, from the back of the femoral artery. ", "In three-fourths of a large number of cases it arises from 2.25 to 5 cm below the inguinal ligament; in a few cases the distance is less than 2.25 cm; more rarely, opposite the ligament, or above the inguinal ligament, from the external iliac. ", "Occasionally the distance between the origin of the vessel and the inguinal ligament exceeds 5 cm (Gray 1918).", "\n\nThe profunda gives off the following branches: lateral femoral circumflex, perforating, medial femoral circumflex, muscular.", "\n\nThe lateral femoral circumflex artery arises from the lateral side of the profunda, passes horizontally behind the Sartorius and Rectus femoris, and divides into ascending, transverse, and descending branches.", "\n\nThe medial femoral circumflex artery arises from the medial and posterior aspect of the profunda, and winds around the medial side of the femur, passing first between the Pectineus and Psoas major, and then between the Obturator externus and the Adductor brevis.", "\n\nNumerous muscular branches arise from the profunda; some of these end in the Adductores, others pierce the Adductor magnus, give branches to the hamstrings, and anastomose with the medial femoral circumflex artery and with the superior muscular branches of the popliteal.", "\n\n##### The Popliteal Artery\n\nThe popliteal artery is the continuation of the femoral, and courses through the popliteal fossa (Fig. ", "6.9). ", "It extends from the opening in the Adductor magnus, at the junction of the middle and lower thirds of the thigh, downward and lateralward to the intercondyloid fossa of the femur, and then vertically downward to the lower border of the Popliteus, where it divides into anterior and posterior tibial arteries (Fig. ", "6.10). ", "Occasionally the popliteal artery divides into its terminal branches opposite the knee-joint. ", "The anterior tibial under these circumstances usually passes in front of the Popliteus. ", "The artery sometimes divides into the anterior tibial and peroneal, the posterior tibial being wanting, or very small. ", "Occasionally it divides into three branches, the anterior and posterior tibial, and peroneal. ", "Around and above the patella, and on the contiguous ends of the femur and tibia, There is a network of vessels forming a superficial and a deep plexus.", "\n\nFig. ", "6.9.", "\n\nMIP. ", "The popliteal arteries: popliteal aneurysm (on the right of the picture), an arterial obstruction (on the left of the picture)\n\nFig. ", "6.10.", "\n\nMIP. ", "The popliteal artery divides into anterior and posterior tibial arteries\n\n##### The Anterior Tibial Artery\n\nThe anterior tibial artery commences at the bifurcation of the popliteal, at the lower border of the Popliteus, passes forward between the two heads of the Tibialis posterior, and through the aperture above the upper border of the interosseous membrane, to the deep part of the front of the leg. ", "It then descends on the anterior surface of the interosseous membrane, gradually approaching the tibia. ", "At the lower part of the leg it lies on this bone, and then on the front of the ankle-joint, where it is more superficial, becomes the dorsalis pedis.", "\n\nThe arteries around the ankle-joint anastomose freely with one another and form networks below the corresponding malleoli.", "\n\nThe arteria dorsalis pedis, the continuation of the anterior tibial, passes forward from the ankle-joint along the tibial side of the dorsum of the foot to the proximal part of the first intermetatarsal space, where it divides into two branches, the first dorsal metatarsal and the deep plantar.", "\n\n##### The Posterior Tibial Artery\n\nThe posterior tibial artery begins at the lower border of the Popliteus, opposite the interval between the tibia and fibula; it extends obliquely downward, and, as it descends, it approaches the tibial side of the leg, lying behind the tibia, and in the lower part of its course is situated midway between the medial malle-olus and the medial process of the calcaneal tuberos-ity. ", "Here it divides, beneath the origin of the Adductor hallucis, into the medial plantar arteries and the lateral plantar arteries.", "\n\nThe branches of the posterior tibial artery are: peroneal, posterior medial malleolar, nutrient, communicating, muscular, medial calcaneal.", "\n\n##### The Peroneal Artery\n\nThe peroneal artery is deeply seated on the back of the fibular side of the leg. ", "It arises from the posterior tibial, about 2.5 cm below the lower border of the popli-teus, passes obliquely toward the fibula, and then descends along the medial side of that bone, contained in a fibrous canal between the Tibialis posterior and the Flexor hallucis longus, or in the substance of the latter muscle (Fig. ", "6.11). ", "It then runs behind the tibio-fibular syndesmosis and divides into lateral calcaneal branches which ramify on the lateral and posterior surfaces of the calcaneus. ", "The peroneal artery may arise 7 or 8 cm below the Popliteus, or from the posterior tibial high up, or even from the popliteal. ", "Its size is more frequently increased than diminished; and then it either reinforces the posterior tibial by its junction with it, or altogether takes the place of the posterior tibial in the lower part of the leg and foot, the latter vessel only existing as a short muscular branch. ", "The branches of the peroneal are: muscular, perforating, nutrient, communicating, lateral calcaneal.", "\n\nFig. ", "6.11.", "\n\nMIP. ", "The peroneal artery arises from the posterior tibial artery\n\n## 6.2 The Veins\n\nThe veins convey the blood from the capillaries of the different parts of the body to the heart. ", "They consist of two distinct sets of vessels, the pulmonary and systemic.", "\n\nThe pulmonary veins, unlike other veins, contain arterial blood, which they return from the lungs to the left atrium of the heart.", "\n\nThe systemic veins return the venous blood from the body generally to the right atrium of the heart.", "\n\nThe portal vein, an appendage to the systemic venous system, is confined to the abdominal cavity, and returns the venous blood from the spleen and the viscera of digestion to the liver. ", "This vessel rami-fies in the substance of the liver and there breaks up into a minute network of capillary-like vessels, from which the blood is conveyed by the hepatic veins to the inferior vena cava.", "\n\nThe veins commence by minute plexuses which receive the blood from the capillaries. ", "The branches arising from these plexuses unite together into trunks, and these, in their passage toward the heart, constantly increase in size as they receive tributaries, or join other veins. ", "The veins are larger and altogether more numerous than the arteries; hence, the entire capacity of the venous system is much greater than that of the arterial. ", "The capacity of the pulmonary veins, however, only slightly exceeds that of the pulmonary arteries. ", "The veins are cylindrical like the arteries; their walls, however, are thin and they collapse when the vessels are empty, and the uniformity of their surfaces is interrupted at intervals by slight constrictions, which indicate the existence of valves in their interior. ", "They communicate very freely with one another, especially in certain regions of the body and these communications exist between the larger trunks as well as between the smaller branches. ", "Thus, between the venous sinuses of the cranium, and between the veins of the neck, where obstruction would be attended with imminent danger to the cerebral venous system, large and frequent anastomoses are found. ", "The same free communication exists between the veins throughout the whole extent of the vertebral canal, and between the veins composing the various venous plexuses in the abdomen and pelvis, e.g., the spermatic, uterine, vesical, and pudendal.", "\n\nThe systemic venous channels are subdivided into three sets, superficial and deep veins, and venous sinuses.", "\n\nThe superficial veins are found between the layers of the superficial fascia immediately beneath the skin; they return the blood from these structures, and communicate with the deep veins by perforating the deep fascia.", "\n\nThe deep veins accompany the arteries, and are usually enclosed in the same sheaths with those vessels. ", "With the smaller arteries -- as the radial, ulnar, brachial, tibial, peroneal -- they exist generally in pairs, one lying on each side of the vessel, and are called venae comitantes. ", "The larger arteries -- such as the axillary, subclavian, popliteal, and femoral -- have usually only one accompanying vein. ", "In certain organs of the body, however, the deep veins do not accompany the arteries; for instance, the veins in the skull and vertebral canal, the hepatic veins in the liver, and the larger veins returning blood from the bones.", "\n\nVenous sinuses are found only in the interior of the skull, and consist of canals formed by a separation of the two layers of the dura mater. ", "Their outer coat consists of fibrous tissue, their inner of an endothelial layer continuous with the lining membrane of the veins.", "\n\n### 6.2.1 Veins of the Head, Neck, and Thorax\n\n#### 6.2.1.1 The Superior Vena Cava\n\nThe superior vena cava forms in the thorax by the confluence of innominate veins or venous brachioce-falic trunks right and left; these are formed from the union of the internal jugular vein and the subclavian vein of each side (Fig. ", "6.12).", "\n\nFig. ", "6.12.", "\n\nMIP. ", "The superior vena cava and the confluence of the right brachiocefalic trunk\n\nThe only tributary of the superior vena cava is the azygos vein.", "\n\nThe azygos vein begins opposite the first or second lumbar vertebra, by a branch called the ascending lumbar vein. ", "It enters the thorax through the aortic hiatus in the diaphragm, and passes along the right side of the vertebral column to the fourth thoracic vertebra, where it arches forward and ends in the superior vena cava. ", "Its tributaries: Are the right subcostal and intercostal veins, the upper three or four of these latter opening by a common stem, the highest superior intercostal vein. ", "It receives the hemi-azygos veins, several esophageal, mediastinal, and pericardial veins, and, near its termination, the right bronchial vein.", "\n\nThe hemiazygos vein begins in the left ascending lumbar or renal vein. ", "It enters the thorax, through the left crus of the diaphragm, and, ascending on the left side of the vertebral column, as high as the ninth thoracic vertebra, passes across the column, behind the aorta, esophagus, and thoracic duct, to end in the azygos vein. ", "It receives the lower four or five intercostal veins and the subcostal vein of the left side, and some esophageal and mediastinal veins.", "\n\nThe accessory hemiazygos vein descends on the left side of the vertebral column, and varies inversely in size with the highest left intercostal vein. ", "It receives veins from the three or four intercostal spaces between the highest left intercostal vein and highest tributary of the hemiazygos; the left bronchial vein sometimes opens into it. ", "It either crosses the body of the eighth thoracic vertebra to join the azygos vein or ends in the hemiazygos.", "\n\nIn the obstruction of the superior vena cava, the azygos and hemiazygos veins are one of the principal means by which the venous circulation is carried on, connecting the superior and inferior vena cava, and communicating with the common iliac veins by the ascending lumbar veins and with many of the tributaries of the inferior vena cava.", "\n\nThe venous brachiocefalic trunk has the following tributaries: inferior thyroid veins, internal mammary vein, superior phrenic veins, vertebral vein, posterior jugular vein, timic, pericardic, anterior mediastinal veins.", "\n\nThe inferior thyroid veins two or frequently three or four in number, arise in the venous plexus on the thyroid gland, communicating with the middle and superior thyroid veins. ", "They form a plexus in front of the trachea, behind the sternothyreoidei muscles. ", "From this plexus, a left vein descends and joins the left innominate trunk, and a right vein passes obliquely downward to open into the right innominate vein, just at its junction with the superior vena cava; sometimes the right and left veins open by a common trunk in the latter situation. ", "These veins receive esophageal, tracheal and inferior laryngeal veins, and are provided with valves at their terminations in the innominate veins.", "\n\nThe internal mammary vein is a trunk which runs up on the medial side of the artery and ends in the corresponding innominate vein.", "\n\nThe vertebral vein is formed in the suboccipital triangle, from numerous small tributaries which spring from the internal vertebral venous plexuses and issue from the vertebral canal above the posterior arch of the atlas. ", "They unite with small veins from the deep muscles at the upper part of the back of the neck, and form a vessel which enters the foramen in the transverse process of the atlas, and descends, forming a dense plexus around the vertebral artery, in the canal formed by the foramina transversaria of the cervical vertebrae. ", "This plexus ends in a single trunk, which emerges from the foramen transversarium of the sixth cervical vertebra, and opens at the root of the neck into the back part of the innominate vein near its origin.", "\n\nThe internal jugular vein collects the blood from the brain, from the superficial parts of the face, and from the neck. ", "It is directly continuous with the transverse sinus, and begins in the posterior compartment of the jugular foramen, at the base of the skull. ", "It runs down the side of the neck in a vertical direction, lying at first lateral to the internal carotid artery, and then lateral to the common carotid, and at the root of the neck unites with the subclavian vein to form the innominate vein. ", "The left vein is generally smaller than the right, and each contains a pair of valves, which are placed about 2.5 cm above the termination of the vessel.", "\n\nThis vein receives in its course the inferior petro-sal sinus, the common facial, lingual, pharyngeal, superior and middle thyroid veins, and sometimes the occipital.", "\n\nThe subclavian vein is the continuation of the axillary vein. ", "It extends from the outer border of the first rib to the sternal end of the clavicle, where it unites with the internal jugular to form the innominate vein. ", "It is in relation, in front, with the clavicle and the subclavius muscle; behind and above, with the subclavian artery, from which it is separated medially by the scalenus anterior muscle and the phrenic nerve; below, it rests in a depression on the first rib and upon the pleura. ", "Its tributary is the external jugular vein.", "\n\nThe external jugular vein receives the greater part of the blood from the exterior of the cranium and the deep parts of the face, being formed by the junction of the posterior division of the posterior facial with the posterior auricular vein. ", "It commences in the substance of the parotid gland, on a level with the angle of the mandible, and runs perpendicularly down the neck at the posterior border of the sternocleidomas-toideus. ", "It ends in the subclavian vein, lateral to or in front of the scalenus anterior muscle. ", "The external jugular vein varies in size, bearing an inverse proportion to the other veins of the neck. ", "This vein receives the occipital vein and, near its termination, the transverse cervical, transverse scapular and anterior jugular veins. ", "In the substance of the parotid, a large branch of communication from the internal jugular joins it.", "\n\nThe anterior jugular vein begins near the hyoid bone by the confluence of several superficial veins from the submaxillary region. ", "It descends between the median line and the anterior border of the sternocleidomastoi-deus, and, at the lower part of the neck, open into the termination of the external jugular, or, in some instances, into the subclavian vein. ", "Most frequently there are two anterior jugulars, a right and a left; but sometimes only one. ", "Its tributaries are some laryngeal veins, and occasionally a small thyroid vein. ", "Just above the sternum the two anterior jugular veins communicate by a transverse trunk, the venous jugular arch, which receive tributaries from the inferior thyroid veins.", "\n\nThe veins of the brain possess no valves, and their walls, owing to the absence of muscular tissue, are extremely thin. ", "They pierce the arachnoid membrane and the inner or meningeal layer of the dura mater, and open into the cranial venous sinuses. ", "They may be divided into two sets, cerebral and cerebellar.", "\n\nThe cerebral veins are divisible into external and internal groups according as they drain the outer surfaces or the inner parts of the hemispheres. ", "The external veins are the superior, inferior, and middle cerebral. ", "The internal cerebral veins drain the deep parts of the hemisphere and are two in number; each is formed near the interventricular foramen by the union of the terminal and choroid veins. ", "They run backward parallel with one another, between the layers of the tela chorioidea of the third ventricle, and beneath the splenium of the corpus callosum, where they unite to form a short trunk, the great cerebral vein; just before their union each receives the corresponding basal vein.", "\n\nThe cerebellar veins are placed on the surface of the cerebellum, and are disposed in two sets, superior and inferior.", "\n\nThe sinuses of the dura mater are venous channels which drain the blood from the brain. ", "They are devoid of valves, and are situated between the two layers of the dura mater and lined by endothelium continuous with that which lines the veins.", "\n\nThey may be divided into two groups: a postero-superior group, at the upper and back part of the skull, and an antero-inferior group, at the base of the skull. ", "The postero-superior group comprises: the superior sagittal, the straight, the inferior sagittal, the two transverse, the occipital. ", "The antero-inferior group of sinuses comprises: the two cavernous, the two superior petrosal, the two intercavernous, the two inferior petrosal, the basilar plexus.", "\n\n#### 6.2.1.2 The Pulmonary Veins\n\nThe pulmonary veins return the arterialized blood from the lungs to the left atrium of the heart. ", "They are four in number, two from each lung (Fig. ", "6.13). ", "They commence in a capillary network upon the walls of the air sacs, where they are continuous with the capillary ramifications of the pulmonary artery. ", "These vessels uniting successively form a single trunk for each lobe, three for the right, and two for the left lung. ", "The vein from the middle lobe of the right lung generally unites with that from the upper lobe, so that ultimately two trunks from each lung are formed; they open separately into the upper and back part of the left atrium. ", "Occasionally the three veins on the right side remain separate. ", "Not infrequently the two left pulmonary veins end by a common opening. ", "At the root of the lung, the superior pulmonary vein lies in front of and a little below the pulmonary artery; the inferior is situated at the lowest part of the hilus of the lung and on a plane posterior to the upper vein.", "\n\nFig. ", "6.13.", "\n\nVR. ", "The pulmonary veins: four in number, two from each lung\n\n#### 6.2.1.3 The Veins of the Heart\n\nMost of the veins of the heart open into the coronary sinus. ", "This is a wide venous channel situated in the posterior part of the coronary sulcus, and covered by muscular fibers from the left atrium. ", "It ends in the right atrium between the opening of the inferior vena cava and the atrioventricular orifice, where there is a semilunar valve, the valve of the coronary sinus (valve of Thebesius).", "\n\nIts tributaries are the great, small, and middle cardiac veins, the posterior vein of the left ventricle, and the oblique vein of the left atrium.", "\n\nThe great cardiac or left coronary vein begins at the apex of the heart and ascends along the anterior longitudinal sulcus to the base of the ventricles. ", "It then curves to the left in the coronary sulcus, and reaching the back of the heart, opens into the left extremity of the coronary sinus. ", "It receives tributaries from the left atrium and from both ventricles: one, the left marginal vein, is of considerable size, and ascends along the left margin of the heart.", "\n\nThe small cardiac or right coronary vein runs in the coronary sulcus between the right atrium and ventricle, and opens into the right extremity of the coronary sinus. ", "It receives blood from the back of the right atrium and ventricle. ", "The right marginal vein ascends along the right margin of the heart and joins it in the coronary sulcus, or opens directly into the right atrium.", "\n\nThe middle cardiac vein commences at the apex of the heart, ascends in the posterior longitudinal sul-cus, and ends in the coronary sinus near its right extremity.", "\n\nThe following cardiac veins do not end in the coronary sinus:\n\n * The anterior cardiac veins, comprising three or four small vessels which collect blood from the front of the right ventricle and open into the right atrium.", "\n\n * The right marginal vein frequently opens into the right atrium, and is therefore sometimes regarded as belonging to this group.", "\n\n * The veins of Thebesius, consisting of a number of minute veins which arise in the muscular wall of the heart; the majority open into the atria, but a few end in the ventricles (Gray 1918).", "\n\n### 6.2.2 The Veins of the Abdomen and Pelvis\n\nThe external iliac vein, the upward continuation of the femoral vein, begins behind the inguinal ligament, and, passing upward along the brim of the lesser pelvis, ends opposite the sacroiliac articulation, by uniting with the hypogastric vein to form the common iliac vein. ", "It frequently contains one, sometimes two, valves and it may be doubled or lie lateral to the external iliac artery.", "\n\nThe external iliac vein receives the inferior epigastric, deep iliac circumflex, and pubic veins.", "\n\nThe hypogastric vein begins near the upper part of the greater sciatic foramen, passes upward behind and slightly medial to the hypogastric artery and, at the brim of the pelvis, joins with the external iliac to form the common iliac vein. ", "The tributaries of the hypogastric vein correspond with the branches of the hypogastric artery. ", "It receives: (a) the gluteal, internal pudendal, and obturator veins, which have their origins outside the pelvis; (b) the lateral sacral veins, which lie in front of the sacrum; and (c) the middle hemorrhoidal, vesical, uterine, and vaginal veins, which originate in venous plexuses connected with the pelvic viscera. ", "The internal iliac vein may receive an unusual vessel representing a confluence of the internal pudendal, obturator, gluteal, and sciatic veins and occasionally both internal iliac veins unite and open as a common trunk at the confluence of the right and left external iliac veins to form the vena cava.", "\n\nThe common iliac veins are formed by the union of the external iliac and hypogastric veins, in front of the sacroiliac articulation; passing obliquely upward toward the right side, they end upon the fifth lumbar vertebra, by uniting with each other at an acute angle to form the inferior vena cava. ", "The right common iliac is shorter than the left, nearly vertical in its direction, and ascends behind and then lateral to its corresponding artery. ", "The left common iliac, longer than the right and more oblique in its course, is at first situated on the medial side of the corresponding artery, and then behind the right common iliac. ", "Each common iliac receives the iliolumbar, and sometimes the lateral sacral veins. ", "The left receives, in addition, the middle sacral vein. ", "No valves are found in these veins. ", "One of the veins may be absent, in which case the external and internal veins join the opposite common iliac to form the vena cava and a connection between the portal and right common iliac has been reported. ", "The left common iliac vein, instead of joining with the right in its usual position, occasionally ascends on the left side of the aorta as high as the kidney, where, after receiving the left renal vein, it crosses over the aorta, and then joins with the right vein to form the vena cava. ", "In these cases, the two common iliacs are connected by a small communicating branch at the spot where they are usually united.", "\n\nThe inferior vena cava returns to the heart the blood from the parts below the diaphragm. ", "It is formed by the junction of the two common iliac veins (Fig. ", "6.14), on the right side of the fifth lumbar vertebra. ", "It ascends along the front of the vertebral column, on the right side of the aorta and, having reached the liver, is continued in a groove on its posterior surface. ", "It then perforates the diaphragm between the median and right portions of its central tendon and subsequently inclines forward and medialward for about 2.5 cm, and, piercing the fibrous pericardium, passes behind the serous pericardium to open into the lower and back part of the right atrium. ", "In front of its atrial orifice is a semilunar valve, termed the \"valve of the inferior vena cava\": this is rudimentary in the adult, but is of large size and exercises an important function in the fetus.", "\n\nFig. ", "6.14.", "\n\nMIP. ", "The inferior vena cava\n\nThis vessel is sometimes placed on the left side of the aorta, as high as the left renal vein, and, after receiving this vein, crosses over to its usual position on the right side. ", "It may be placed altogether on the left side of the aorta, and in such a case the abdominal and thoracic viscera, together with the great vessels, are all transposed. ", "The inferior vena cava may be doubled (2.2-3.0% of cases) or it may be absent. ", "If the inferior vena cava is absent, the blood from the lower limbs may pass through the diaphram into the superior vena cava by way of a large vein in the location of the ascending lumbar and azygos veins. ", "As a result, the hepatic veins drain directly into the right atrium through the normal caval opening in the diaphragm. ", "Occasionally the inferior vena cava joins the azygos vein, which is then of large size (Gray 1918).", "\n\nThe inferior vena cava receives the following veins: Lumbar, Right Spermatic or Ovarian, Renal, Suprarenal, Inferior Phrenic and Hepatic.", "\n\nThe lumbar veins four in number on each side, collect the blood by dorsal tributaries from the muscles and integument of the loins, and by abdominal tributaries from the walls of the abdomen, where they communicate with the epigastric veins. ", "At the vertebral column, they receive veins from the vertebral plexuses, and then pass forward, around the sides of the bodies of the vertebra, beneath the Psoas major, and end in the back part of the inferior vena-cava. ", "The left lumbar veins are longer than the right, and pass behind the aorta. ", "The lumbar veins are connected together by a longitudinal vein which passes in front of the transverse processes of the lumbar vertebrae, and is called the; it forms the most frequent origin of the corresponding vein ascending lumbar azygos or hemiazygos vein, and serves to connect the common iliac, iliolumbar, and azygos or hemiazygos veins of its own side of the body.", "\n\nThe spermatic veins emerge from the back of the testis, and receive tributaries from the epididymis; they unite and form a convoluted plexus, called the \"pampiniform plexus,\" which constitutes the greater mass of the spermatic cord; the vessels composing this plexus are very numerous, and ascend along the cord, in front of the ductus deferens. ", "Below the subcutaneous inguinal ring they unite to form three or four veins, which pass along the inguinal canal, and, entering the abdomen through the abdominal inguinal ring, coalesce to form two veins, which ascend on the Psoas major, behind the peritoneum, lying one on either side of the internal spermatic artery. ", "These unite to form a single vein, which opens on the right side into the inferior vena cava, at an acute angle; on the left side into the left renal vein, at a right angle. ", "The spermatic veins are provided with valves. ", "The left spermatic vein passes behind the iliac colon, and is thus exposed to pressure from the contents of that part of the bowel.", "\n\nThe ovarian veins correspond with the spermatic in the male. ", "They form a plexus in the broad ligament near the ovary and uterine tube, and communicate with the uterine plexus. ", "They end in the same way as the spermatic veins in the male. ", "Valves are occasionally found in these veins. ", "Like the uterine veins, they become much enlarged during pregnancy.", "\n\nThe renal veins are of large size, and placed in front of the renal arteries. ", "The left is longer than the right, and passes in front of the aorta, just below the origin of the superior mesenteric artery. ", "It receives the left spermatic and left inferior phrenic veins, and, generally, the left suprarenal vein. ", "It opens into the inferior vena cava at a slightly higher level than the right. ", "The renal veins may be multiple in about 28% of cases but they show less variation than do the renal arteries. ", "The left renal vein may be retroaortic (3%) or circumaortic (17%). ", "The right renal vein may be doubled, even though the left renal vein is usually single(Bergman et. ", "al. ", "1996).", "\n\nThe vsuprarenal veins are two in number: the right ends in the inferior vena cava; the left, in the left renal or left inferior phrenic vein.", "\n\nThe inferior phrenic veins follow the course of the inferior phrenic arteries; the right ends in the inferior vena cava; the left is often represented by two branches, one of which ends in the left renal or suprarenal vein, while the other passes in front of the esophageal hiatus in the diaphragm and opens into the inferior vena cava.", "\n\nThe hepatic veins commence in the substance of the liver, in the terminations of the portal vein and hepatic artery, and are arranged in two groups, upper and lower. ", "The upper group usually consists of three large veins, which converge toward the posterior surface of the liver, and open into the inferior vena cava, while that vessel is situated in the groove on the back part of the liver. ", "The veins of the lower group vary in number, and are of small size; they come from the right and caudate lobes. ", "They are destitute of valves. ", "A common variant of the hepatic veins is the presence of a varying number of accessory hepatic veins draining blood from the lateral and posterior segments of right hepatic lobe directly into the inferior vena cava. ", "This occurs in ~6% of subjects.", "\n\n#### 6.2.2.1 The Portal System of Veins\n\nThe portal system includes all the veins which drain the blood from the abdominal part of the digestive tube (with the exception of the lower part of the rectum) and from the spleen, pancreas, and gall-bladder. ", "From these viscera the blood is conveyed to the liver by the portal vein. ", "In the liver this vein ramifies like an artery and ends in capillary-like vessels termed sinusoids, from which the blood is conveyed to the inferior vena cava by the hepatic veins. ", "In the adult the portal vein and its tributaries are destitute of valves.", "\n\nThe portal vein is about 8 cm in length, and is formed at the level of the second lumbar vertebra by the junction of the superior mesenteric and lienal veins (Fig. ", "6.15), the union of these veins taking place in front of the inferior vena cava and behind the neck of the pancreas.", "\n\nFig. ", "6.15.", "\n\nMIP. ", "The confluence of the lienal and the superior mesenteric veins into the portal vein\n\nAt the porta hepatis, the portal vein divides into a right and a left branch, which accompany the corresponding branches of the hepatic artery into the substance of the liver. ", "The right branch of the portal vein enters the right lobe of the liver, but before doing so generally receives the cystic vein. ", "The left branch, longer but of smaller caliber than the right, gives branches to the caudate lobe, and then enters the left lobe of the liver. ", "The portal vein is rarely variable; it is among the most constant blood vessels (including arteries and veins). ", "It has also been reported to be doubled. ", "Branches forming the portal vein are also variable. ", "Accessory splenic veins have been reported by several investigators. ", "The splenic vein may anastomose with the renal or with the superior mesenteric vein. ", "The superior mesenteric vein has been reported opening into the renal vein.", "\n\nThe tributaries of the portal vein are: Lienal, Superior Mesenteric, Coronary, Pyloric, Cystic, and Paraumbilical veins.", "\n\nThe vlienal vein commences by five or six large branches which return the blood from the spleen. ", "These unite to form a single vessel, which passes from left to right, grooving the upper and back part of the pancreas, below the lineal artery, and ends behind the neck of the pancreas by uniting at a right angle with the superior mesenteric to form the portal vein. ", "The lienal vein is of large size, but is not tortuous like the artery.", "\n\nThe lineal vein receives the short gastric veins, the left gastroepiploic vein, the pancreatic veins, and the inferior mesenteric veins.", "\n\nThe inferior mesenteric vein returns blood from the rectum and the sigmoid, and descending parts of the colon. ", "It begins in the rectum as the superior hemorrhoidal vein, which has its origin in the hem-orrhoidal plexus, and through this plexus communicates with the middle and inferior hemorrhoidal veins. ", "The inferior mesenteric vein receives the sig-moid veins from the sigmoid colon and iliac colon, and the left colic vein from the descending colon and left colic flexure.", "\n\nThe superior mesenteric vein returns the blood from the small intestine, from the cecum, and from the ascending and transverse portions of the colon. ", "It begins in the right iliac fossa and ascends between the two layers of the mesentery on the right side of the superior mesenteric artery. ", "Behind the neck of the pancreas it unites with the lienal vein to form the portal vein. ", "Besides the tributaries which correspond with the branches of the superior mesenteric artery, the intestinal, ileocolic, right colic, and middle colic veins, the superior mesenteric vein is joined by the right gastroepiploic and pancreaticoduodenal veins. ", "Collateral venous circulation to relieve portal obstruction in the liver may be effected by communications between: (a) the gastric veins and the esophageal veins which often project as a varicose bunch into the stomach, emptying themselves into the hemiazygos vein; (b) the veins of the colon and duodenum and the left renal vein; (c) the accessory portal system of Sappey, branches of which pass in the round and falciform ligaments (particularly the latter) to unite with the epigastric and internal mammary veins, and through the diaphragmatic veins with the azygos; a single large vein, shown to be a parumbilical vein, may pass from the hilus of the liver by the round ligament to the umbilicus, producing there a bunch of prominent varicose veins known as the caput medusae; (d) the veins of Retzius, which connect the intestinal veins with the inferior vena cava and its retroperitoneal branches; (e) the inferior mesenteric veins, and the hemorrhoidal veins that open into the hypogastrics; (f) very rarely the ductus venosus remains patent, affording a direct connection between the portal vein and the inferior vena cava (Gray 1918).", "\n\n### 6.2.3 The Veins of the Limbs\n\nThe veins of the extremities are divided into two sets, superficial and deep with diffuse anastomoses. ", "The superficial veins are placed immediately beneath the integument between the two layers of superficial fascia. ", "The deep veins accompany the arteries. ", "Both sets are provided with valves, which are more numerous in the deep than in the superficial veins.", "\n\n#### 6.2.3.1 The Veins of the Upper Limb\n\nThe superficial veins of the upper extremity are the digital, metacarpal, cephalic, basilic, median.", "\n\nThe dorsal digital veins pass along the sides of the fingers and are joined to one another by oblique communicating branches. ", "Those from the adjacent sides of the fingers unite to form three dorsal meta-carpal veins, which end in a dorsal venous network opposite the middle of the metacarpus. ", "The radial part of the network is joined by the dorsal digital vein from the radial side of the index finger and by the dorsal digital veins of the thumb, and is prolonged upward as the cephalic vein. ", "The ulnar part of the network receives the dorsal digital vein of the ulnar side of the little finger and is continued upward as the basilic vein. ", "A communicating branch frequently connects the dorsal venous network with the cephalic vein about the middle of the forearm.", "\n\nThe volar digital veins on each finger are connected to the dorsal digital veins by oblique intercapitular veins. ", "They drain into a venous plexus which is situated over the thenar and hypothenar eminences and across the front of the wrist.", "\n\nThe cephalic vein begins in the radial part of the dorsal venous network and winds upward around the radial border of the forearm, receiving tributaries from both surfaces. ", "Below the front of the elbow it gives off the vena mediana cubiti, which receives a communicating branch from the deep veins of the forearm and passes across to join the basilic vein. ", "The cephalic vein then ascends in front of the elbow in the groove between the brachioradialis and the biceps brachii. ", "It crosses superficial to the musculo-cutaneous nerve and ascends in the groove along the lateral border of the biceps brachii. ", "In the upper third of the arm it passes between the pectoralis major and deltoideus, where it is accompanied by the deltoid branch of the thoracoacromial artery. ", "It pierces the coracoclavicular fascia and, crossing the axillary artery, ends in the axillary vein just below the clavicle. ", "Sometimes it communicates with the external jugular vein by a branch which ascends in front of the clavicle.", "\n\nThe accessory cephalic vein arises either from a small tributory plexus on the back of the forearm or from the ulnar side of the dorsal venous network; it joins the cephalic below the elbow. ", "In some cases the accessory cephalic springs from the cephalic above the wrist and joins it again higher up. ", "A large oblique branch frequently connects the basilic and cephalic veins on the back of the forearm.", "\n\nThe basilic vein begins in the ulnar part of the dorsal venous network. ", "It runs up the posterior surface of the ulnar side of the forearm and inclines forward to the anterior surface below the elbow, where it is joined by the vena mediana cubiti. ", "It ascends obliquely in the groove between the biceps brachii and pronator teres and crosses the brachial artery, from which it is separated by the lacertus fibrosus. ", "It then runs upward along the medial border of the biceps brachii, perforates the deep fascia and ends in the medial brachial vein.", "\n\nThe median antibrachial vein drains the venous plexus on the volar surface of the hand. ", "It ascends on the ulnar side of the front of the forearm and ends in the basilic vein or in the vena mediana cubiti; in a small proportion of cases it divides into two branches, one of which joins the basilic, the other the cephalic, below the elbow.", "\n\nThe deep veins follow the course of the arteries. ", "They are generally arranged in pairs, and are situated one on either side of the corresponding artery, and connected at intervals by short transverse branches.", "\n\nThe superficial and deep volar arterial arches are each accompanied by a pair of venae comitantes which constitute respectively the superficial and deep volar venous arches, and receive the veins corresponding to the branches of the arterial arches; thus the common volar digital veins, formed by the union of the proper volar digital veins, open into the super-ficial, and the volar metacarpal veins into the deep volar venous arches. ", "The dorsal metacarpal veins receive perforating branches from the volar metacar-pal veins and end in the radial veins and in the super-ficial veins on the dorsum of the wrist.", "\n\nThe deep veins of the forearm are the venae comi-tantes of the radial and ulnar veins and constitute respectively the upward continuations of the deep and superficial volar venous arches; they unite in front of the elbow to form the brachial veins. ", "The radial veins are smaller than the ulnar and receive the dorsal metacarpal veins. ", "The ulnar veins receive tributaries from the deep volar venous arches and communicate with the superficial veins at the wrist; near the elbow they receive the volar and dorsal interosseous veins and send a large communicating branch (profunda vein) to the vena mediana cubiti.", "\n\nThe brachial veins are placed one on either side of the brachial artery, receiving tributaries corresponding with the branches given off from that vessel. ", "Near the lower margin of the subscapularis, they join the axillary vein; the medial one frequently joins the basilic vein.", "\n\nThese deep veins have numerous anastomoses, not only with each other, but also with the superficial veins.", "\n\nThe axillary vein begins at the lower border of the teres major, by the confluence of the two brachial veins and ends at the outer border of the first rib as the subclavian vein. ", "Close to its termination, It receives the cephalic vein its other tributaries correspond with the branches of the axillary artery. ", "It lies on the medial side of the artery, which it partly overlaps; between the two vessels are the medial cord of the brachial plexus, the median, the ulnar, and the medial anterior thoracic nerves. ", "It is provided with a pair of valves opposite the lower border of the sub-scapularis; valves are also found at the ends of the cephalic and subscapular veins.", "\n\n#### 6.2.3.2 The Veins of the Lower Limb\n\nThe superficial veins of the lower extremity are the great and small saphenous veins and their tributaries.", "\n\nOn the dorsum of the foot the dorsal digital veins receive, in the clefts between the toes, the intercapitular veins from the plantar cutaneous venous arch and join to form short common digital veins which unite across the distal ends of the metatarsal bones in a dorsal venous arch. ", "Proximal to this arch is an irregular venous network which receives tributaries from the deep veins and is joined at the sides of the foot by a medial and a lateral marginal vein, formed mainly by the union of branches from the superficial parts of the sole of the foot. ", "On the sole of the foot the super-ficial veins form a plantar cutaneous venous arch which extends across the roots of the toes and opens at the sides of the foot into the medial and lateral marginal veins. ", "Proximal to this arch is a plantar cutaneous venous network which is especially dense in the fat beneath the heel; this network communicates with the cutaneous venous arch and with the deep veins, but is chiefly drained into the medial and lateral marginal veins.", "\n\nThe great saphenous vein the longest vein in the body, begins in the medial marginal vein of the dor-sum of the foot and ends in the femoral vein about 3 cm below the inguinal ligament. ", "It ascends in front of the tibial malleolus and along the medial side of the leg in relation with the saphenous nerve. ", "It runs upward behind the medial condyles of the tibia and femur and along the medial side of the thigh and, passing through the fossa ovalis, ends in the femoral vein. ", "At the ankle it receives branches from the sole of the foot through the medial marginal vein; in the leg it anastomoses freely with the small saphenous vein, communicates with the anterior and posterior tibial veins and receives many cutaneous veins; in the thigh it communicates with the femoral vein and receives numerous tributaries; those from the medial and posterior parts of the thigh frequently unite to form a large accessory saphenous vein which joins the main vein at a variable level. ", "Near the fossa ovalis it is joined by the superficial epigastric, superficial iliac circumflex, and superficial external pudendal veins. ", "A vein, named the thoracoepigastric, runs along the lateral aspect of the trunk between the superficial epigastric vein below and the lateral thoracic vein above and establishes an important communication between the femoral and axillary veins.", "\n\nThe valves in the great saphenous vein vary from ten to twenty in number; they are more numerous in the leg than in the thigh.", "\n\nThe small saphenous vein begins behind the lateral malleolus as a continuation of the lateral marginal vein; it first ascends along the lateral margin of the tendocalcaneus, and then crosses it to reach the middle of the back of the leg. ", "Running directly upward, it perforates the deep fascia in the lower part of the popliteal fossa, and ends in the popliteal vein, between the heads of the gastrocnemius. ", "It communicates with the deep veins on the dorsum of the foot, and receives numerous large tributaries from the back of the leg. ", "Before it pierces the deep fascia, it gives off a branch which runs upward and forward to join the great saphenous vein. ", "The small saphenous vein possesses from nine to twelve valves, one of which is always found near its termination in the popliteal vein. ", "In the lower third of the leg the small saphenous vein is in close relation with the sural nerve, in the upper two-thirds with the medial sural cutaneous nerve.", "\n\nThe deep veins of the lower extremity accompany the arteries and their branches. ", "The plantar digital veins arise from plexuses on the plantarsurfaces of the digits, and, after sending intercapitular veins to join the dorsal digital veins, unite to form four meta-tarsal veins; these run backward in the metatarsal spaces, communicate, by means of perforating veins, with the veins on the dorsum of the foot, and unite to form the deep plantar venous arch which lies alongside the plantar arterial arch. ", "From the deep plantar venous arch the medial and lateral plantar veins run backward close to the corresponding arteries and, after communicating with the great and small saphenous veins, unite behind the medial malleolus to form the posterior tibial veins.", "\n\nThe posterior tibial veins accompany the posterior tibial artery, and are joined by the peroneal veins.", "\n\nThe anterior tibial veins are the upward continuation of the venae comitantes of the dorsalis pedis artery. ", "They leave the front of the leg by passing between the tibia and fibula, over the interosseous membrane, and unite with the posterior tibial, to form the popliteal vein.", "\n\nThe popliteal vein is formed by the junction of the anterior and posterior tibial veins at the lower border of the Popliteus; it ascends through the popliteal fossa to the aperture in the Adductor magnus, where it becomes the femoral vein. ", "It receives tributaries corresponding to the branches of the popliteal artery, and it also receives the small saphenous vein.", "\n\nThe femoral vein accompanies the femoral artery through the upper two-thirds of the thigh. ", "In the lower part of its course it lies lateral to the artery, higher up, it is behind it, and at the inguinal ligament, it lies on its medial side. ", "It receives numerous muscular tributaries, and about 4 cm below the inguinal ligament is joined by the deep femoral vein. ", "Near its termination it is joined by the great saphen-ous vein.", "\n\nThe deep femoral vein receives tributaries corresponding to the perforating branches of the profunda artery, and through these establishes communications with the popliteal vein below and the inferior gluteal vein above. ", "It also receives the medial and lateral femoral circumflex veins.", "\n\nReferences\n\nBergman RA, AfifiAK, Miyauchi R (1996). ", "Illustrated encyclopedia of human anatomic variation: opus II: cardiovascular system. ", "Available at www.anatomyatlases.org\n\nGray H (1918) Anatomy of the human body. ", "Philadelphia, Lea & Febiger. ", "Available at Bartleby.com, 2000. ", "www.bartleby.com/107/\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_7(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 7. ", "Neck Vessels\n\nMirco Cosottini1 and Ilaria Pesaresi2\n\n(1)\n\nUnit of Neuroradiology Department of Neurosciences, University of Pisa, Via Roma 67, Pisa, 56126, Italy\n\n(2)\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, Pisa, 56100, Italy\n\n7.1 Technical Considerations\n\n7.2 Subclaflian Arteries\n\n7.3 Carotid Arteries\n\n7.3.1 Atherosclerotic Disease\n\n7.3.2 Dissection\n\n7.4 Vertebral Arteries\n\n7.4.1 Atherosclerosis\n\n7.4.2 Dissection\n\nReferences\n\nAbstract\n\nThe technology advancement including high performance gradients, parallel imaging, more efficient methods in sampling k-space, intravascular contrast agents, and higher magnetic field strengths, allows to improve time and spatial resolution of contrast-enhanced MRA. ", "Moreover, technical refine-ments contribute to a renaissance of nonenhanced MRA techniques.", "\n\nClinical applications of MRA in studying neck vessels benefit of both faster acquisitions and sharpened images. ", "Arterial steno-occlusive disease of supra-aortic vessels may lead to cerebral infarction that is one of the main worldwide problem of public health. ", "Therefore, the principal MRA application concerns the atherosclerosis of carotid bifurcation. ", "In this field, MRA is a competitor of CTA as a confirmatory noninvasive diagnostic test, aiming to replace DSA in the diagnostic workup of patients with carotid stenosis. ", "In this chapter, we discuss the role and limitations of MRA in grading carotid stenosis before revascularization. ", "Indication to surgical or endovascular revascularization could be set with MRA with a low misclassification rate in case of high-grade carotid stenosis while inconclusive data are available for moderate stenosis.", "\n\nBecause of its short acquisition time, neck vessels MRA can be easily implemented in an MRI protocol of patients with cerebrovascular pathology also in the acute phase of the disease. ", "Typical examples are carotid or vertebral dissections as the main cause of juvenile stroke. ", "In these cases, MRA in conjunction with conventional MR images allows a prompt diagnosis avoiding invasive procedures both at the onset and in the follow-up for monitoring recanalization or eventual pseudoaneurismatic dilation.", "\n\nSince the introduction of dedicated coils coflering the upper thorax, MRA constitutes a robust tool for the panoramic eflaluation of the origin of epiaortic flessel, a flascular district traditionally difficult to be explored noninflasiflely. ", "Stenosis of flertebral origin, subclaflian steal, or thoracic outlet syndrome can now be detected with an objectifle noninflasifle technique.", "\n\n## 7.1 Technical Considerations\n\nIn this paragraph we report some technical considerations to focus on some proper aspects of the neck vessels examination that are extensively reported in Chap. ", "3.", "\n\nThe introduction of CE-MRA technique in the evaluation of neck vessels provided diagnostic gain in several pathologies. ", "Although some investigators insist that TOF MR angiography remains the most accurate technique in evaluating carotid stenosis (Townsend et al. ", "2003), the main advantage of CEMRA was the limitation of artifacts with respect to flow-based MRA techniques. ", "The basic principle of CE-MRA is the T1 shortening effect of a paramagnetic contrast media passing as a bolus through the vasculature (Prince et al. ", "1993). ", "The contrast between stationary tissues and vessels depend on shortening the T1 time of blood. ", "As a consequence CEMRA is less sensitive to intra-voxel dephasing from turbulent flow and does not suffer from loss of signal due to saturation effects. ", "Moreover the short acquisition time limits the motion artifacts that causes degradation of images.", "\n\nThe crucial point in obtaining an adequate CEMRA examination is the timing of acquisition with respect to the contrast bolus injection. ", "The main goal of CEMRA acquisition is the sampling of the center of k-space during the peak arterial concentration of contrast media. ", "CEMRA of neck vessels is actually acquired with elliptical centric encoding that helps to fill the centre of k-space in a short period of time at the beginning of the scan. ", "Elliptical centric encoding permits sampling the low spatial frequencies (image contrast) quickly during the arterial phase of bolus passage and reducing the venous contamination of the image. ", "By using a centric or elliptical encoding that fills the k-space at the beginning of the acquisition, the scan delay corresponds to the circulation time. ", "The calculation of the acqui sition time may be obtained with a bolus test. ", "Nevertheless for acquisitions with an elliptical centric encoding an automatic or semiautomatic method to detect the bolus arrival may be preferable; indeed a fast k-space center filling determines a narrow temporal window to collect the arterial passage of contrast bolus.", "\n\nThe bolus geometry is the other important factor in executing CEMRA besides the acquisition timing (Wetzel and Bongartz 2000). ", "The bolus geometry in the vasculature depends not only on physiological parameters of the patient but also on the contrast amount and injection rate. ", "The main parameters characterizing the bolus geometry (Fig. ", "7.1) are the maximum peak (as the maximal contrast media concentration in the vessel of interest), the bolus arrival time (as the time from injection to reach the 80% of the maximum peak of concentration), and the bolus length (as the time during which the intravascular concentration of contrast media remains over 80% of maximum). ", "Generally a fixed dose of contrast media is administered for CEMRA acquisition of the neck vessels. ", "A standard injection dose of 20 mL of gadolinium chelate facilitates the exam conduction. ", "Adopting an injection rate of 2.5 mL/s we can obtain bolus geometry with a constant bolus length in the arterial phase of 5-7 s. With the actually permitted acquisition time, a bolus length of this order achieves at least the filling of the central part of the k-space, guaranteeing a sufficient contrast resolution of the angiogram. ", "Lower amount of contrast media or higher injection rates determine a shorter bolus length, while higher contrast doses or lower injection rates cause a longer bolus length. ", "An important consequence of this consideration is that bolus length can be optimized on the bases of the scan duration. ", "A faster acquisition time (shorter duration of k-space center filling) needs a lower contrast dose to fill the entire center of k-space; on the other hand a longer acquisition time needs a higher amount of contrast media. ", "Summarizing faster is cheaper.", "\n\nFig. ", "7.1.", "\n\nBolus geometry in arteries (red line) and fleins (blue line). ", "Bolus arriflal time (BAT) is the time from injection to the time 80% of the maximum peak of concentration is reached. ", "Bolus length (BL) is the time during which the intraflascular concentration of contrast media remains ofler 80% of maximum. ", "Examples of mistimed acquisition of CEMRA. ", "Each image represent the acquisition time of CEMRA. ", "The green box is the time during which the center of k-space is collected while the remain portion of the image is the time during which the periphery of k-space is collected. (", "a, ringing artefact): the central k-space is collected before reaching BL while the periphery of k-space is sampled during the arterial phase. (", "c, blurring artefact): the center of k-space is correctly sampled during BL while the periphery of k-space is sampled when the contrast concentration falls down within the arteries. (", "d, flenous superimposition): the entire k-space is collected during the maximum of flenous enhancement. (", "b, optimal acquisition time): a good quality angiogram is obtained if the centre and periphery of k-space are collected during bolus length\n\nAn inadequate timing in CEMRA acquisition determines artifacts that deteriorate the image quality (Fig. ", "7.1). ", "A precocious acquisition, before the bolus reach the maximum in the vessel of interest, causes the sampling of the central k-space before the arterial phase of contrast distribution, while the periphery of k-space (high spatial frequencies) is sampled during the arterial phase. ", "The obtained angiogram will be affected by ringing artifact (Maki's effect) (Maki et al. ", "1996) and will have poor contrast but high resolution (Fig. ", "7.1a). ", "A delayed acquisition, after the bolus reach the maximum in the vessel of interest, causes the collection of the central k-space after the arterial phase and during the flenous phase of contrast distribution. ", "The obtained angiogram will be a good quality flenogram with superimposition of arterial and flenous structures (Fig. ", "7.1d). ", "A third error occurs if the center of k-space is correctly sampled when the bolus reach the maximum in the flessel of interest but the bolus length is too short and solely low spatial frequencies are sampled during the arterial phase. ", "Since the periphery of k-space is sampled when the contrast concentration falls down within the arteries, the obtained angiogram will be affected by a blurring artifact and will hafle good contrast but a low spatial resolution (Fig. ", "7.1c).", "\n\nAutomatic or semiautomatic methods for bolus detection, facilitates the exam conduction reducing the artifacts linked to the incorrect acquisition timing. ", "A further technique that frees CEMRA from circulation time calculation and afloids mistimed examinations is the time resolfled CEMRA. ", "This technique has the distinct adflantage of improfling the temporal resolution of CEMRA, which is one of its main limitations. ", "In circles with high circulation rate such as cerebral or renal arteries, the temporal resolution may be a limitation in clinical application of CEMRA. ", "Time resolfled MRA was introduced to often improfle the temporal resolution in spite of spatial resolution. ", "Smaller matrixes and flolumes of acquisition, higher bandwidth, rectangular field of fliew, and partial Fourier and zero filling techniques were implemented. ", "The technology adflancement implementing gradients with faster slew rates permits lower TE (less than 2 ms) and TR (less that 4 ms) improfling time resolution. ", "Moreofler time resolution of CEMRA is improfled by more efficient methods in sampling k-space. ", "Three dimension acquisitions reconstructed with a noflel oflersampling of the center of k-space are aflailable for clinical use. ", "An example is the TRICKS technique (time-resolfled intraflascular contrast kinetics) that samples the center of k-space eflery 2 s profliding well enhanced serial images of which at least one captured the arterial phase of contrast distribution.", "\n\nTo reduce acquisition time, parallel imaging techniques partially substitute gradient-encoded steps with coil-encoding. ", "An array of multiple receifling coils with specific spatial sensitiflity is employed to detect the electromagnetic signal. ", "In order to shorten the acquisition time, some portion of the gradient-encoding steps are omitted and the lacking spatial information is obtained by combining the signals from each receifling coils on the basis of their specific spatial sensitiflity functions (coil-encoded steps). ", "Depending on the parallel reconstruction algorithm, the coil-encoded spatial information can be utilized in the k-space domain (SMASH, GRAPPA algorithms) or in the image domain (SENSE algorithm). ", "The acceleration factor defines the acquisition time gain due to parallel acquisition, calculated by the ratio between the numbers of gradient steps in the unaccelerated acquisition with respect to the accelerated one. ", "The drawback of parallel acquisition is a degradation in SNR (signal-to-noise ratio), mainly based on the degree of k-space undersampling and the coil array geometry known as the g factor. ", "In CEMRA acquisition of high number of receifler channels, optimized coil geometry, and an adequate acceleration factor (four) proflide better sensitiflity profiles resulting in g factors closer to one.", "\n\nMoreofler the introduction in the clinical practice of high field magnet (3 T) permits improfled SNRs which is adflantageous when highly accelerated parallel imaging is applied, obtaining high resolution images with a lower in plane resolution to CTA or DSA with a comparable diagnostic flalue (Nael et al. ", "2007).", "\n\nAmong the technical improflements in CEMRA of carotid arteries, deflelopment in the field of contrast media deserfle mention. ", "Standard extracellular contrast media are currently used for almost all CE-MRA applications; howefler the rapid extraflasation of the contrast medium limits acquisition time and therefore spatial resolution as well as contrast-to-noise ratio. ", "To improfle spatial resolution of CEMRA, it is necessary to prolong imaging time and extend the arterial phase of contrast distribution. ", "Intraflascular contrast media allows both a first-pass contrast-enhanced MRA and high-resolution T1-weighted imaging approach in the equilibrium phase extending acquisition windows.", "\n\nSefleral preclinical studies tested paramagnetic or superparamagnetic compounds synthesized to obtain a blood pool agent with a selectifle intraflascu-lar distribution (Bremerich et al. ", "2007). ", "To date only the Gadolinium chelates with a protein binding are clinically tested and approfled for humans. ", "Gd-BOPTA had weak and transient interaction with serum proteins -- particularly albumin; its greater intraflas-cular T1 relaxiflity has been shown to produce a higher flascular peak enhancement of longer duration than that achiefled with other Gadolinium che-lates at the same dose (Knopp et al. ", "2002). ", "Higher signal to noise ratio between flessel and signal background may improfle the eflaluation of carotid arteries (Anzalone et al. ", "2006). ", "Gadofosfleset trisodium is an intraflascular contrast agent approfled for clinical application in MRA. ", "Due to strong hydrophilic profile which allows a reflersible noncoflalent binding with albumin, this contrast agent increases its intra-flascular half life permitting ultra-high resolution in the equilibrium phase with promising results on the eflaluation of neck flessels (Bluemke et al. ", "2001).", "\n\nIn eflaluating carotid arteries, CEMRA replaced nonenhanced MRA. ", "Actually solely PC sequences can be implemented in a clinical MR protocol to obtain information about flow direction or quantification. ", "Besides considerations regarding the leflel of diagnostic accuracy, long acquisition time and image artifacts limited the use of classical flow-based techniques in faflor of CEMRA. ", "Neflertheless, recent improflement in MR hardware and software permitting faster acquisition and concerns about gadolinium based contrast agents contribute to the renaissance of non-enhanced MRA techniques (Fig. ", "7.2). ", "Two new families of nonenhanced MRA techniques are becoming commercially aflailable: EEG gated partial-Fourier fast spin echo technique and balanced steady-state free precession imaging with or without arterial spin labeling. ", "While EEG gated partial-Fourier fast spin echo method and balanced steady-state free precession imaging without arterial spin labeling are implemented in studying different flascular districts, nonenhanced MRA with arterial spin labeling may also be used for carotid imaging. ", "The ALS-based MRA can be obtained by subtracting tag-on and tag-off images (Nishimura et al. ", "1987) by placing an inflersion pulse to the upstream slab. ", "The tagged blood flows to the flessels of interest after a time delay (depending on blood flelocity and distance between tagged and imaged area) and can be imaged with partial-Fourier fast spin echo or balanced steady-state free precession sequence. ", "A bright blood angio-gram can also be obtained with a single acquisition by using spatially nonselectifle and selectifle tagged pulses. ", "If images are acquired after a proper delay time after nonselectifle pulse, stationary tissue can be selectiflely suppressed at their null point while selectiflely tagged protons of blood reached the imaged area (Miyazaki and Lee 2008).", "\n\nFig. ", "7.2.", "\n\nNonenhanced MRA obtained with SSFP sequence. ", "Courtesy Ghedin GE Medical systems\n\n## 7.2 Subclaflian Arteries\n\nAtherosclerotic stenosis is the most frequent pathology in the subclaflian arteries. ", "With the adflent of endoflascular treatment, the correct grading of the stenosis has assumed an important clinical impact. ", "In order to determine the success of endoflascular treatment it is fundamental to know the site, the length, and the morphology of the lesion.", "\n\nCEMRA reflealed an optimal agreement with DSA findings in different types of subclaflian diseases constituting a robust tool in the noninflasifle eflaluation of epiaortic flessels. ", "The method identifies correctly the presence of stenoses, with a slight tendency to oflerestimation. ", "For the steno-occlusifle disease of the sublaflian arteries, agreement with conflentional angiography, is excellent (k= 0.85), with a sensitiflity of 90%, specificity of 95%, and diagnostic accuracy of 93% (Cosottini et al. ", "2000).", "\n\nSubclaflian artery stenosis may cause arm claudication, paresthesias, weakness, and pain and also a subclaflian steal. ", "Subclaflian steal is due to reflersal flow in a flertebral artery associated with a preflerte-bral tract obstruction or stenosis of the subclaflian artery. ", "Subclaflian steal may result in flertebrobasilar insufficiency. ", "In diagnosing subclaflian steal, CE-MRA is often associated with flow-based MRA techniques such as phase contrast or time of flight. ", "In the first case, a phased display axial 2D PC sequence sensitized to flow in slice direction is helpful to depict the reflerse flow direction in the flertebral artery homolateral to the obstructed/stenosed subclaflian artery. ", "In the second case, a 2D TOF sequence implemented with spatial band saturation can be repeated, alternatiflely placing the saturation band abofle and below the slices to obtain selectifle spin saturation that flow downward or upward.", "\n\nReperfusion of the subclaflian artery in the post-flertebral tract by the inflerted flertebral flow may be due to subclaflian obstruction or seflere stenosis. ", "Because endoflascular treatment yields poor results with occlusions especially for occluded tracts longer than 5 cm, a preoperatifle diagnosis of subcla-flian occlusion is important. ", "Differential diagnosis between high grade stenosis and occlusion may be problematic with CEMRA. ", "Due to the tendency of oflerestimation of CEMRA, it is possible to misinterpret the occluded arteries that are reperfused by inflerted flow in the flertebral artery as an oflergraded seflere stenosis (Fig. ", "7.3).", "\n\nFig. ", "7.3.", "\n\nCEMRA (a) refleals a proximal obstruction of the left subclaflian artery with postflertebral enhancement. ", "Distal reperfusion by reflersal blood flow in left flertebral artery is demonstrated with 2D PC sequence with phase display (b). ", "Subclaflian obstruction can be erroneously interpreted as an oflerestimated seflere stenosis. ", "DSA confirms the left subcla-flian obstruction (c)\n\nDiagnostic gain in solfling the dilemma between occlusion and oflergraded seflere stenosis comes from technical deflelopment in the fields of dedicated multichannel coils and parallel imaging, which improfles the spatial resolution. ", "A further possibility may source from increasing temporal resolution. ", "The main limit of CEMRA compared to DSA, is the scarce temporal resolution that does not permit appreciation of the progressifle flowing of the contrast medium into the arterial tree enough to see the reperfusion of the occluded subclaflian artery directly through the flertebral artery. ", "Time resolfled MRA, especially with implementation of more efficient methods in sampling k-space, allows sampling of eflery few seconds the contrast media passes through flertebral and subclaflian flessels. ", "It permits adoption of the same radiological semiology in CEMRA examinations as that in DSA.", "\n\nThoracic outlet syndrome (TOS) refers to clinical manifestations due to impingement of the brachial plexus and subclaflian flessels as they pass from the thoracic caflity to the axilla. ", "Approximately 98% of patients with TOS hafle compression of the brachial plexus, while a minority referred symptoms due to arterial or flenous impingement.", "\n\nThe flascular or neuroflascular compression is profloked by anatomical abnormalities and/or eliciting maneufler and is characterized by a functional subclaflian stenosis causing transient paresthesias, weakness, and pain of the upper limb. ", "Repetitifle arterial trauma results in focal stenosis, subsequent poststenotic dilatation, and ultimately micro-embolization with tissue loss.", "\n\nThere is no generally accepted diagnostic protocol for the inflestigation of TOS although DSA is considered the mainstain technique. ", "CT or MRI can be used to determine the functional anatomy of the thoracic outlet and can be implemented with angiographic acquisition to demonstrate the effect of flascular compression. ", "MRI eflentually acquired during proflocatifle maneufler into the scanner showed the cause of impingement by reformatting the 3D data set and other conflentional sequences (Charon et al. ", "2004).", "\n\nPresently, CE MRA offers extensifle flessel coflerage, is less prone to artifact, and frequently demonstrates the underlying cause of compression as compared to flow-based MRA sequences. ", "CT angiography can be preferred to MRA for its ability to depict bony thorax, scalene muscles insertion expecially in case of aberrant cerflical ribs.", "\n\n## 7.3 Carotid Arteries\n\n### 7.3.1 Atherosclerotic Disease\n\nStroke and transient ischemic attack exceed coronary heart disease (Rothwell et al. ", "2005) constituting one of the main problems of public health and social assistance for surfliflals. ", "Arterial steno-occlusifle disease of supra-aortic flessels is frequent in the general population with a potential risk of thrombo-embolic and hemodynamic cerebral infarctions.", "\n\nBased upon data of multicenter trials, carotid endarterectomy (CEA) is a proflen treatment in carotid artery stenosis and is considered the most effectifle method of preflenting stroke occurrence in patients with symptomatic and asymptomatic high-g rade carotid artery disease (NASCET 1991; Barnett et al. ", "1998). ", "CEA may preflent stroke in symptomatic patients with >70% stenosis, or eflen with stances of 50-69%, and in asymptomatic patients with at least 60% stenosis (ACAS 1995). ", "For high risk surgical patients, percutaneous carotid transluminal angio-plasty and stenting (CAS) are emerging with encouraging results as alternatifle method to CEA (Roubin et al. ", "2001).", "\n\nFor effectifle surgical treatment, correct classification of atherothrombotic lesions is essential and an accurate carotid imaging is important for secondary stroke preflention.", "\n\nCurrently, digital subtraction angiography (DSA) is considered the standard of reference in detecting and grading carotid stenosis due to the excellent spatial (matrix size 1,024 × 1,024) and temporal resolution (3-6 frames/s). ", "Neflertheless the procedural risk of stroke for this method is not negligible and reported ranging between 0.7 and 1% (Kuntz et al. ", "1995).", "\n\nA recent refliew of 19,826 consecutifle patients who underwent cerebral catheter angiography (Kaufmann et al. ", "2007) showed an oflerall neurologic complication rate of 2.63%.", "\n\nIn order to reduce the risks and discomfort of inflasifle procedures, new and noninflasifle diagnostic tools such as spiral CT, enhanced magnetic resonance angiography (MRA), and color Doppler ultrasound were defleloped.", "\n\nNoninflasifle techniques are changing the diagnostic algorithm in patients with arterial occlusifle disease. ", "There is a distinct trend towards surgery without DSA, adopting ultrasound as a screening tool in combination with a confirmatory test (CTA or MRA). ", "DSA is increasingly reserfled for endoflascular interflention or for cases in which noninflasifle test results are equiflocal.", "\n\nCEMRA was eflaluated as a highly safe, feasible tool for assessing patients with suspected carotid atherosclerosis, showing high accuracy and agreement with DSA in detecting and grading ICA stenosis. ", "CEMRA has the adflantages of being noninflasifle, more tolerated (U-King Im et al. ", "2004c), less expensifle(U-King Im et al. ", "2004a), less time-consuming as compared with DSA. ", "With respect to conflentional flow-based MRA techniques, CEMRA proflides better image quality, higher leflel of diagnostic confidence, and more interobserfler agreement (Mitra et al. ", "2006).", "\n\nFor clinical application, the main problem in replacing an inflasifle tool with a noninflasifle one is the diagnostic accuracy of the new method. ", "Sefleral works stated the high leflel of diagnostic accuracy of CEMRA in grading carotid stenosis (Le Clerc et al. ", "1999; Remonda et al. ", "1998; Nederkoorn et al. ", "2002). ", "A meta-analysis study (Wardlaw et al. ", "2006a) reflised 2,541 patients with carotid stenosis eflaluated with CEMRA and digital subtraction angiography reporting high sensitiflity (0.94) and specificity (0.93) solely for high grade stenosis (70-99%), while inconclusifle data are aflailable for moderate stenosis (50-69%). ", "They cautiously suggest a possible replacing of DSA by using CEMRA for high grade stenosis. ", "A more recent meta-analysis (Debrey et al. ", "2008) confirms the preflious high leflels of diagnostic accuracy for seflere stenosis (sensitiflity 94.6% and specificity of 91.9%) and also for carotid occlusion (sensitiflity 99.4% and specificity 99.6%) but assesses a fair sensitiflity for moderate stenosis (sensitiflity 65.9% and specificity 93.5%).", "\n\nResults on the diagnostic accuracy that source from sefleral dedicated studies may be biased by selection of patient population. ", "In the majority of cases CEMRA is flalidated with respect to DSA after these patients are screened with CD-US for carotid stenosis (flerification bias). ", "The number of true positifle as well as sensitiflity is thus inflariably increased. ", "This bias has a limited role if CEMRA is considered as a screening tool. ", "Neflertheless CEMRA is proposed to scientific community as a confirmatory test after a screening with CD-US. ", "In this case a counteract effect on the diagnostic accuracy may source from the spectrum bias. ", "In calculating diagnostic accuracy, the inclusion of normal or nearly normal flessels (true-negatifle cases) can be expected to falsely eleflate the specificity of CE-MRA as a confirmatory test because calculation of specificity is heaflily dependent on the number of true-negatifle cases. ", "In the clinical setting CEMRA should be a tool for identifi-cation of true negatifle patients erroneously screened as stenotic. ", "In the literature the specificity of MRA has likely been oflerstated for the inclusion of true negatifle patients in the statistical analysis (Layton et al. ", "2007).", "\n\nA further problem is due to operators who publish diagnostic accuracy results. ", "In sefleral works, specialized radiologists dedicated to the carotid artery stenosis, eflaluate the stenosis grade, while in clinical practice, the wide spread of noninflasifle imaging modalities is aflailable for nonspecialized radiologists. ", "In this regard studies showing excellent concordance between MRA and DSA are most often performed in academic radiology departments while lower leflels of CEMRA diagnostic accuracy are reported if the grading of stenosis is retrospectiflely eflaluated by the radiological report in daily actiflity of general hospitals (Johnston et al. ", "2002).", "\n\nCEMRA has gained increasing importance as a noninflasifle test in the preoperatifle work-up of carotid artery stenosis (Borisch et al. ", "2003) The acceptance of this MRA technique by surgeons is due to the reported high diagnostic accuracy, panoramic potential of the eflaluation, and to the better representation of the morphology of the stenosis as compared to the angiographic flow-based methods.", "\n\nNefletheless many clinicians require (Westwood et al. ", "2002) further clinical eflidence to establish the effectifleness of MRA in diagnosing ICA stenosis and in making decisions about reflascularization.", "\n\nFor the preoperatifle eflaluation of atherosclerotic pathology of carotid arteries a low leflel (3.1%) of misclassification rate has been reported when adopting CEMRA (Cosottini et al. ", "2005b). ", "Less encouraging results show that 24% of patients would hafle been misclassified for CEA on the basis of CEMRA results alone (sensitiflity, 92%; specificity, 62%) When both duplex ultrasonography and CEMRA were performed and results were concordant, the misclassifi-cation rate decreased to 17%. ", "More data is also needed on the accuracy of less inflasifle tests in combination. ", "No studies reported on the accuracy of less inflasifle tests in the same patients or gafle an account with any reliability on how the accuracy of two less inflasifle tests used in combination compares with each indiflidual test used alone (Wardlawet al. ", "2006b).", "\n\nThe classification error of CEMRA in planning endarterectomy afloids a necessary surgical interflention and deprifles patients of the surgical benefit of reflascularization; it mainly exposes patients with nonsignificant stenosis to unnecessary surgical risk. ", "Indeed the greater errors in stenosis grading source from the tendency of CEMRA to oflerestimate the stenosis.", "\n\nThe phenomenon of stenosis oflerestimation is well known (Leclerc et al. ", "1998) and CE-MRA tended to oflerestimate stenosis compared with DSA by a mean bias of 2.4-3.8% (U-King-Im et al. ", "2004b). ", "Sefleral factors may contribute to oflerestimation. ", "The first one is the low spatial resolution of CEMRA with respect to the digital angiography as a stan dard of reference. ", "Larger floxels causes a blurring of the flessels profiles especially in narrowed tracts (Cosottini et al. ", "2003). ", "It has been estimated (Hoogefleen et al. ", "1998) that at least three pixels need to be included into the patent residual lumen at leflel of stenosis to obtain a correct grading. ", "For seflere stenosis with extremely narrowed residual patent lumen, small floxel size is necessary to maintain image sharpness.", "\n\nIn clinical practice the floxel size suggested for CEMRA examination of carotid arteries is about 1 mm3. ", "Based upon the published data about first-pass CEMRA, it is reasonable to exploit parallel imaging capabilities in order to increase spatial resolution instead of temporal resolution.", "\n\nTo improfle spatial resolution of CEMRA, it is necessary to prolong imaging time. ", "Due to the prolongation of intraflascular distribution, blood pools contrast agents allow extending the imaging windows, opening up the possibility of high resolution imaging in the equilibrium phase. ", "A noflel strategy in the conduct of CEMRA examination includes the possibility of obtaining angiograms in the first pass acquisition and at the equilibrium phase using high resolution sequence. ", "In our experience, first pass CEMRA is useful for a panoramic eflaluation of cere-bropethal flessels while high resolution CEMRA at steady state reduces the number of ofler graded stenosis flisualizing a more sharpened stenosis (Fig. ", "7.4). ", "Oflerall accuracy for carotid high resolfled CE-MRA performed during steady state, approximately 5 min after blood pool agent injection has been reported to be high (88-100%). ", "Interestingly, the image quality seems to be best at relatiflely larger floxel size (0.8 mm) with faster acquisition (acquisition time = 40 s) than with respect to smaller floxel size (0.5 mm) with longer acquisition time (acquisition time = 1 min 40 s) because images are degraded by pulsation and motion artifacts.", "\n\nFig. ", "7.4.", "\n\nFirst pass CE-MRA obtained with blood pool agent Gadofosfleset trisodium (a). ", "The intraflascular contrast media allows the acquisition of high resolution CE-MRA at steady state (b) that improfles the sharpness of carotid bifurcation. ", "CE-MRA at steady state shows a more accurate grading of the stenosis reducing the tendency of first pass CE-MRA to oflerestimation with respect to DSA (c)\n\nFurther causes of oflerestimation may be related to the mistimed examinations during arterial bolus passage or to spin intrafloxel dephasing in CEMRA (Scheffler et al. ", "1998).", "\n\nThe postprocessing technique (MPR tended to show lower degrees of stenoses than MIP) adopted to display the carotid bifurcation has been reported (Lell et al. ", "2007) as a cause of stenosis oflerestimation as well as the method adopted from the radiologist to measure the stenosis. ", "With respect to an objectifle measurement with a calliper, the subjectifle flisual impression determines a misclassification in 11.3-15.1% of the stenosis ranging between 70 and 99% (U-King-Im et al. ", "2007). ", "An automated approach to the measurement of the stenosis seems to allow accurate assessment of stenosed flessel diameter according to the North American Symptomatic Carotid Endarterectomy Trial criteria (Habibi et al. ", "2009).", "\n\nFinally the stenosis oflerestimation adopting CEMRA may be related to the DSA as the standard of reference. ", "The limited number of projections obtained with DSA may be a limitation in the eflaluation of high-grade stenosis leading to underestimation of seflerity (Elgersma et al. ", "1999).", "\n\nA comparison between bidimensional techniques used as gold standard with respect to a 3D method may generate a false oflerestimation due to an underestimation of stenosis by conflentional DSA (Fellner et al. ", "2001). ", "A better correlation was obserfled between rotational DSA and CE MRA than between rotational DSA and conflentional DSA suggesting that the multiplanar capability of MRA makes it superior to conflentional DSA in two or three planes in grading carotid stenosis (Anzalone et al. ", "2005). ", "Although 3D imaging modalities could achiefle a more accurate measurement of the stenosis, without repeating the endarterectomy trials, conflentional DSA must remain the reference standard as the link between the percentage of stenosis and risk of stroke. ", "As a consequence, noninflasifle imaging modalities hafle to mimic and not oflercome conflentional DSA in grading stenosis to correctly locate the single patient in a precise risk category.", "\n\nIn assessing carotid artery stenosis, CT angiog-raphy is an alternatifle to CEMRA as a confirmatory test. ", "The wider diffusion of CT angiography in the eflaluation of the carotid arteries results from its simplicity and high spatial resolution. ", "The axial images obtained hafle the adflantage of being utilized in the measurement of the crosssection area reduction of the flessel or in the measurement of the plaque densities to establish fatty, calcified, or fibrous components. ", "The main drawbacks of CT angiography are radiation exposure, nephrotoxic-ity, and sensitiflity to artifacts from dental amalgam and flascular calcifications.", "\n\nWith the introduction of multisection technology, CT angiography increases its performance and can be proposed as a substitute for CEMRA due to excellent correlation with conflentional angiography and the best spatial resolution among all noninflasifle techniques. ", "Accuracy of CTA has been shown to hafle a sensitiflity in the range of 85-95% and specificity of 93-98% for detecting carotid stenoses >70% (Koelemay et al. ", "2004) comparable to that of CEMRA (Alflarez-Linera et al. ", "2003) (Fig. ", "7.5).", "\n\nFig. ", "7.5.", "\n\nMultiplanar and flolume reconstructions of a left internal carotid stenosis obtained with CTA (a, b) and CE-MRA (c, d) with respect to the gold standard DSA (e). ", "Diagnostic accuracy of CTA and MRA are comparable in detecting and grading carotid stenosis\n\n### 7.3.2 Dissection\n\nCerflical artery dissection (CAD) is a major cause of cerebral infarction in young people, and accounts for 10% of strokes under the age of 20 and 20% under the age of 30. ", "The major cause of internal carotid dissection is trauma; the remaining cases are spon taneous. ", "The pathogenesis of CAD remains unclear and an underlying arteriopathy responsible for the weakness of the arterial wall is postulated. ", "Predisposing factors for spontaneous dissection include fibromuscular dyspla-sia (up to 15%), Marfan's syndrome, Ehlers Danlos type IV syndrome, osteogenesis imperfecta, pseudox-antoma elasticum, cystic medial necrosis, and other collagen flascular diseases (Cosottini et al. ", "2005a).", "\n\nUltra structural connectifle tissue aberrations in skin biopsies of patients without manifestations of a connectifle tissue disease are shown to correlate with CAD suggesting that it represents a manifestation of a genetic predisposition with a flascular phenotype (Brandt et al. ", "2001).", "\n\nIn conflentional MRI, hematoma in carotid dissection appears as a crescent-shaped area around the eccentric signal floid of the patent lumen. ", "The signal intensity of the hematoma flaries according to the timing of the bleeding. ", "On T1-weighted images it is classically hypointense in the acute phase for the presence of deoxiemoglobin and in the chronic stage for the presence of methemoglobin. ", "On the other hand hematoma is hyperintense due to the methemoglobin deposit between 7 days and 2 months. ", "Subintimal dissection is responsible for stenotic pattern of dissection characterized by progressifle luminal narrowing detectable with angiographic techniques including CEMRA. ", "The intramural hematoma in conflentional MRI can often be seen to spiral along the length of the dissected segment.", "\n\nInstead the subadflentitial dissection causes an aneurismal dilation when the arterial lumen communicates with the dissection caflity (Anson and Crowell 1991). ", "This type of angiographic pattern suggests a more seflere underlying arteriopathy with respect to dissection without aneurysm and is reported in 49.3% of spontaneous CADs (Touze et al. ", "2001). ", "Although classical flow-based MRA techniques are reported as an useful noninflasifle method in the detection, follow-up, and response to treatment of CAD, their main limit remain the eflaluation of flessel wall morphology such as in the case of fibromuscular dysplasia and aneurismal pattern of carotid dissection (Zuber et al. ", "1994). ", "CEMRA as a luminography has a better resolution in eflaluating flessel wall irregularities and is reported as a robust method to also eflaluate dissections with pseudoaneurysm (Phan et al. ", "2001). ", "To eflaluate patients with recurrent asymptomatic dissection, DSA follow-up is generally accepted. ", "A noninflasifle method of detection that can be carried out repeatedly ofler many years like CEMRA may constitute a reliable method in inflestigating the recurrent dissection (Fig. ", "7.6).", "\n\nFig. ", "7.6.", "\n\nSpontaneous left internal carotid artery dissection. ", "CE-MRA refleals a progressifle luminal narrowing in the middle portion of cerflical tract (a) while conflentional T1-weighted images with fat saturation pulse obtained in the axial plane at leflel of dissection shows a hyperintense ring of metahemoglobin (b) referred to mural haema-toma. ", "The angiogram of the right internal carotid artery (c) depicts a narrowed middle cerflical tract and an irregular dilation referred to an aneuris-mal pattern of a preflious asymptomatic carotid dissection. ", "One month later DSA statesd recanalization of left internal carotid artery (d) and confirmed a stable pseudo aneurismal pattern of a preflious dissection (e)\n\n## 7.4 Vertebral Arteries\n\n### 7.4.1 Atherosclerosis\n\nPathologies inflolfling the flertebral circulation hafle deflastating consequences compared to that of carotid arteries (Fig. ", "7.7). ", "Vertebral arteries atherosclerotic stenosis is associated with carotid stenosis but is generally less seflere. ", "The most frequent site of flertebral artery inflolflement is at the origin of the subclaflian artery. ", "CE-MRA allows imaging of the flertebral arteries from their origins to the basilar artery and has taken the place of TOF techniques, which are notoriously unreliable in the study of the flertebral ostium because of breath-motion artifacts, and in the study of the superior cerflical tract, where the tortuous coursing of the flertebral artery is burdened by on-plane saturation artefacts. ", "The sensitiflity and specificity of CE-MRA for the eflaluation of flerte bral ostial stenosis was 100 and 85%, respectiflely (Randoux et al. ", "2003). ", "Suboptimal results in this flascular segment are due to a more pronounced tendency to oflerestimate the degree of stenosis when the flessels hafle small dimensions and the floxel size is excessifle. ", "Oflerestimation may also be explained by the possible reduced concentration of the con trast medium in the poststenotic arterial lumen as a result of altered flow by the stenosis. ", "Now after CD-US screening, a preferable second leflel of diagnosis is made with CEMRA. ", "Indeed, notwithstanding adflanced algorithms for bone remoflal, CTA application was limited by the close relationship of the flertebral arteries to the bone in the transflerse foramina and at the skull base.", "\n\nFig. ", "7.7.", "\n\nClaude Bernard Horner syndrome with acute onset due to a posterior-lateral infarction of the medulla oblongata (a). ", "Note the high signal intensity of the intracranial tract of the left flertebral artery. ", "CE-MRA angiogram obtained in the same session (b) reflealed an obstruction of the V4 tract and atherosclerotic parietal irregularities of the controlateral artery\n\n### 7.4.2 Dissection\n\nVertebral dissection is the penetration of blood into the flessel wall splitting the tunica media. ", "It may occur spontaneously or following seflere or blunt trauma. ", "Complications of flertebral dissection include embolic infarct of the posterior circulation or suba-rachnoid hemorrhage. ", "Conflentional angiography is still considered the gold standard in the diagnosis of flertebral dissection but is gradually being replaced by MRI and MRA. ", "As well as occur in carotid arteries, MRI can show intramural hematoma. ", "One of the main pitfalls of conflentional MRI to diagnose flertebral dissection is that the flow-related enhancement of the flertebral flenous plexus can mimic the high signal of intramural hematoma (Miaux et al. ", "1996). ", "Moreofler conflentional MRI also cannot differentiate between intramural hematoma and intraluminal thrombus.", "With CE-MRA it is possible to detect the leflel of stenosis/obstruction.", "CE-MRA also has the adflantage of differentiating residual flow from mural hematoma. ", "Encouraging results of combined CEMRA and MRI for the follow-up of flertebral dissection are reported especially in dissecting aneurysms type.", "\n\nReferences\n\nAlflarez-Linera J, Benito-Leon J, Escribano J, et al. (", "2003) Prospectifle eflaluation of carotid artery stenosis: Elliptic centric contrastenhanced MR angiography and spiral CT angiography compared with digital subtraction angiogra-phy. ", "AJNR Am J Neuroradiol 24:1012-1019\n\nAnson J, Crowell RM (1991) Cerflicocranial arterial dissection. ", "Neurosurgery 29(1):89-96CrossRefPubMed\n\nAnzalone N, Scomazzoni F, Castellano R, et al. 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", "Thoracic Aorta and Pulmonary Vessels\n\nMarco Di Terlizzi1 , Ambrosini Roberta1, Rita Fossaceca1 and Alessandro Carriero2\n\n(1)\n\nDiagnostic and Interventional Radiology Department, Corso Mazzini 18, Novara, 28100, Italy\n\n(2)\n\nDiagnostic and Interventional Radiology Department, University del Piemonte Orientale \"A. AVOGADRO,\", Corso Mazzini 18, Novara, 28100, Italy\n\n8.1 Introduction\n\n8.2 Thoracic Aorta\n\n8.2.1 Spectrum and Prevalence of Disease\n\n8.2.2 Normal Aortic Anatomy\n\n8.3 MR Technique\n\n8.3.1 Contrast-Enhanced Magnetic Resonance Angiography (CE-MRA)\n\n8.3.2 Contrast Injection Synchronization\n\n8.3.3 Contrast Dose and Administration\n\n8.3.4 Image Processing\n\n8.3.5 Black Blood Techniques\n\n8.3.6 Bright Blood Techniques\n\n8.3.7 Fundamental Sequences\n\n8.4 Normal MR Aortic Anatomy\n\n8.5 Aortic Diseases\n\n8.5.1 Aortic Aneurysm\n\n8.5.1.1 Clinical Findings\n\n8.5.1.2 Histopathology\n\n8.5.1.3 MR Features\n\n8.5.1.4 Differential Diagnosis\n\n8.5.2 Aortic Dissection and Intramural Hematoma\n\n8.5.2.1 Clinical Findings\n\n8.5.2.2 Histopathology\n\n8.5.2.3 MR Features\n\n8.6 Trauma\n\n8.7 Vascular Thoracic Outlet Syndrome\n\n8.8 Post EVAR Evaluation\n\n8.9 Pulmonary Vessels\n\n8.9.1 Normal MR Pulmonary Vessels Anatomy\n\n8.9.2 Bronchial Artery Anatomy\n\n8.9.3 Magnetic Resonance Imaging and Magnetic Resonance Angiography\n\n8.9.3.1 Perfusion Imaging and Ventilation\n\n8.9.3.2 Time-Resolved MRA\n\n8.9.3.3 BFFE Imaging\n\n8.9.3.4 Thrombus Imaging\n\n8.9.3.5 Blood-Pool Imaging\n\nReferences\n\nAbstract\n\nMagnetic Resonance technology's fast development has permitted a wider application of MR angiography for an accurate and noninvasive imaging of thoracic vessel disease. ", "Diseases such as aortic dissection, aneurysm or pulmonary embolism can now be reliably studied with a very high degree of accuracy and reproducibility and much less feasibility limitation.", "\n\n## 8.1 Introduction\n\nMRI is characterized by intrinsic sensitivity to detect and highlight the phenomenon of flow, meaning proton movements. ", "Since its debut, the initial applications of MR were aimed at the quantitative analysis of flow and they were essentially on the basis of two principles: (1) interaction between the moving protons and radiofrequencies, the so called \"amplitude\" or \"Time of flight\" (TOF) effects; (2) detection and measurement of flow phenomenon in the presence of a magnetic gradient, the so called \"Phase\" effects. ", "In 1950, Suryan was the first to observe the \"time of flight\" effect; afterwards Bowman e Kudracev, Morse, and Singer improved the quantification of flow velocity using TOF technique by introducing the use of surface phased arrays, coils, and saturation technique.", "\n\nThe use of techniques based on measurement of flow phenomenon in the presence of a magnetic gradient was introduced after the TOF technique. ", "MR images are obtained using two fundamental and relatively independent phenomena: proton excitement and saturation by radiofrequency pulse; signal sampling and proton localization by using magnetic field gradients. ", "While stationary blood signal is dependant on T1 and T2 relaxation times, which are relatively prolonged as for other fluids, the flowing blood signal, on the opposite, is dependant on two phenomena: the time of flight effect, determined by spin wash-in/wash-out because of the emission of radio-pulses and the phase shift of spin moving along a magnetic field gradient, which is dependant on the type of flow and on the gradient along the flow direction. ", "These phenomena may cause, in different sequences, the appearance of lack of signal (flow void) or an increased signal (flow related enhancement) and are considered as the fundamentals of both MR angiography (MRA) and flow quantification technique.", "\n\n## 8.2 Thoracic Aorta\n\nThoraco-abdominal aortic diseases represent the main indication for an MRA study. ", "In fact, MRA allows representation of the vessel in various planes and may be performed even without the administration of contrast material and without using ionizing radiations. ", "Moreover, it allows precise and high resolution depiction of arterial wall details, with an accuracy equal to that of trans-oesophageal echo and MDCT angiography. ", "The wide field of view, the non-invasiveness and the possibility to gather information about the dynamics of aortic blood flow makes MRA the method of first choice for the elective study of aortic disease in cooperative patients. ", "The main difference is the known limitation with respect to CTA, regarding the inability, inherent to the MR physics, to evaluate vessel wall calcifications.", "\n\n### 8.2.1 Spectrum and Prevalence of Disease\n\nThoracic aortic diseases may often result in life-threatening conditions that require immediate diagnosis and treatment (AHA 2002 Heart and stroke statistical update). ", "Such conditions remain major causes of morbidity and mortality throughout the world (Olsson et al. ", "2006), despite continuous progress in identification of clinical risk factors, prevention, and early diagnosis of these conditions, including aneurysms, acute aortic syndromes (i.e., aortic dissection, intramural hematoma [IMH], and penetrating ulcer), trauma, congenital abnormalities, vasculitis (Scheel et al. ", "2004), and steno-occlusive diseases. ", "Once relying uniquely on digital subtraction angiog-raphy (DSA), the imaging of the aorta now benefits from the multi-planar information available with magnetic resonance angiography (MRA) (Prince et al. ", "1996). ", "Volumetric and multiplanar capabilities of magnetic resonance imaging (MRI) have overcome the issue of tortuous vessels, enabling the accurate evaluation of the real transverse aortic plane (i.e., for aortic aneurysms), the assessment of intramural and perivascular abnormalities, and the evaluation of relations between the aorta and its branches.", "\n\n### 8.2.2 Normal Aortic Anatomy\n\nThe aorta begins at the base of the left ventricle of the heart, where it is about 3 cm in diameter. ", "After ascending for a short distance, it arches backward and to the left side, over the left pulmonary artery. ", "It then descends on the left side of the vertebral column, passes into the abdominal cavity through the aortic hiatus in the diaphragm and ends, considerably diminished in size (1.5-1.75 cm in diameter), at the level of the lower border of the fourth lumbar vertebra; here it branches into the right and left common iliac arteries. ", "Thoracic aorta is commonly referred to as three distinct and arbitrary sections: the ascending aorta, the arch of the aorta, and the descending aorta. ", "The descending aorta then continues into the abdominal aorta. ", "The length of ascending aorta is about 5 cm. ", "At its origin three small dilatations called the aortic sinuses are present: the right, the left, and the posterior (non coronary). ", "Part of the ascending aorta is contained within the pericardium, similar to the pulmonary artery. ", "For this reason a rupture of the wall of the ascending aorta (i.e., an aortic dissection) whereupon the abdominal aorta begins (Fig. ", "8.1). ", "Numerous vessels branch off from the thoracic aorta to supply oxygenated blood to the chest cage and the organs within the chest. ", "Like other sections of the aorta (the ascending aorta, aortic arch, and abdominal aorta), the thoracic aorta is considered as an arbitrary anatomic entity.", "\n\nFig. ", "8.1\n\nCE-MRA MIP reconstruction in a para-sagittal plane clearly shows the aortic anatomy, the origin of supra-aortic vessels, and the aortic spindle\n\n## 8.3 MR Technique\n\nThe Patient is positioned supine on the moving table, with the specific vascular thoracic or thoracic-abdominal phased array coil wrapped around the torso (in case of lack of the specific vascular phased array coil, a generic abdominal/torso phased array coil may instead be used).", "\n\nIt is necessary to link the patient to the respiratory trigger system because some of the sequences used would need that synchronization. ", "It is possible, when needed, to use some ECG-gated sequences typically used for \"cardiac\" imaging, for example the cine Fast Gradient Echo, which are useful for the evaluation of the aortic blood flow in case of dissection or coarctation. ", "In this case the acquisition will need to be ECG-gated.", "\n\nUp to date many techniques have been developed for imaging structures and blood flow within great vessels and pulmonary arteries. ", "Non contrast-enhanced methods are generally referred to as \"black blood\" and \"bright blood\" techniques, depending on the signal intensity of the blood within the vessels.", "\n\nBoth un-enhanced and contrast-enhanced techniques are available, and in many examinations, depending on the clinical query, it is common to use a combination of the two techniques to obtain a comprehensive evaluation of the vasculature. ", "Three-dimensional contrast-enhanced MR angiography (CE-MRA) is a fast sequence that generates a 3D data set with high signal to noise ratio images of the intra-vascular space during a rapid bolus of a gadolinium chelate.", "\n\n### 8.3.1 Contrast-Enhanced Magnetic Resonance Angiography (CE-MRA)\n\nCE-MRA is a fast, accurate, and flexible method for noninvasive imaging of the arterial and venous system (Earls et al. ", "1998). ", "Since its development 10 years ago, the method has been tremendously refined (Prince 1994). ", "CE-MRA is performed by acquiring a 3D gradient echo sequence during a rapid intravenous bolus of gadolinium. ", "It is both reliable and relatively easy to perform, given the automation and speed of current MR systems. ", "Gadolinium chelates can be used with relative safety because of the very low rate of allergic reactions; recently more attention has been aimed to their use in patients with renal failure because of the possibility to induce the NSF (nephrogenic systemic fibrosis) (Sadowski et al. ", "2007). ", "CE-MRA depicts the arteries and, when desired, venous structures in a 10-30-s acquisition, depending on the field strength and other technical factors of the MR system used for the study. ", "Acquisition can be performed during a breath hold if the patient is non sedated and able to comply with breath-holding instructions. ", "For most thoracic cardiovascular examinations, a 3D spoiled gradient echo (SPGR) volume that includes the heart, pulmonary arteries, thoracic aorta, and proximal great vessels is used. ", "The parameters for the 3D SPGR sequence are optimized to attain the highest-quality images. ", "In general, faster is better for data acquisition with 3D CE-MRA and low repetition time (TR) and echo time (TE) values are usually selected. ", "Excessive spin dephasing can cause signal loss at stenoses, although this can be reduced or eliminated by selecting a TE less than 3 ms. ", "Faster data acquisitions allow the gadolinium contrast material to be injected with a higher injection rate, producing a higher arterial gadolinium concentration and optimized enhancement of the relevant anatomy. ", "The high arterial signal to noise (S/N) ratio may then compensate for reduced T1 relaxation and signal averaging. ", "Fast data acquisition minimizes motion artefacts and makes it easier for patients to successfully suspend breathing for the entire data acquisition window. ", "In addition to minimizing TR and TE, one needs to select the smallest number of sections, sufficient to cover the arterial anatomy and to keep the acquisition time to a minimum. ", "Widening the bandwidth also makes the acquisition faster, but it may also reduce S/N, especially if a very small field-of-view is used, as required for small children and infants. ", "The signal of background tissue is also reduced or eliminated by obtaining a 3D data set \"mask\" before gadolinium administration to use for digital subtraction (Lee et al. ", "1996). ", "The imaging volume is prescribed to depict all of the relevant anatomy while minimizing the actual acquisition time. ", "In almost all cases, a coronal plane volume is used, the exception being adult patients in whom the thoracic aorta is the only region of interest. ", "In this scenario, a para-sagittal imaging plane is used.", "\n\n### 8.3.2 Contrast Injection Synchronization\n\nIn larger patients, correct timing of the contrast medium injection with peak vascular enhancement during acquisition of central k-space data is essential for good quality studies. ", "There are several ways to synchronize contrast delivery. ", "Fluoroscopic triggering (i.e., Bolus-Track, Philips), although not yet widely available, is reliable and fast for achieving optimal enhancement in almost every case (Riederer et al. ", "1999). ", "In infants and small children, it is difficult to achieve a well-timed examination that results in a pure arterial- or venous-phase acquisition. ", "Because the circulation time is so rapid, both arteries and veins enhance within a short period of time following contrast infusion. ", "Reduction of the acquisition time to a point, where a timed acquisition can be effective, may sacrifice image resolution and reduce SNR. ", "Usually simultaneous initiations of contrast infusion and data acquisition result in diagnostic CE-MRA studies that have adequate resolution and SNRs, although both venous and arterial structures are enhanced (Prince et al. ", "1997).", "\n\n### 8.3.3 Contrast Dose and Administration\n\nThe dose of gadolinium is an important determinant of image quality, and widely ranging doses have been advocated. ", "Three-dimensional CE-MRA studies have used doses of gadolinium ranging from 0.5 mmol/kg (\"half dose\") to 0.3 mmol/kg (\"triple dose\"). ", "However, for most vascular studies a dose of 0.2 mmol/kg is routinely used (Weiger et al. ", "2000). ", "In children and infants, careful attention must be given to the volume of infused gadolinium chelate in order to not exceed the clinically accepted upper limit of 0.3 mmol/kg. ", "After the gadolinium has been injected, a saline flush of approximately twice the gadolinium volume is infused to clear the line and to ensure that the patient receives the entire gadolinium dose. ", "Contrast may be administered either by hand or by a MR compatible power injector. ", "For larger children or adults, a 20- or 22-gauge angio-catheter is routinely inserted in an antecubital vein prior to the start of the study. ", "In smaller children or infants, a smaller angio-catheter can be used if needed and this can be positioned elsewhere as long as it can handle a rapid bolus of 1-2 mL/s. A long extension tube is used to connect to a power injector located inside the MR scanning room. ", "The power injector ensures a reliable rate of contrast delivery with an infusion rate of 1-2 mL/s immediately followed by a 15-30-mL saline flush at the same infusion rate.", "\n\n### 8.3.4 Image Processing\n\nInterpretation of CE-MRA requires interactive examination of the 3D data sets. ", "The reconstructed images greatly enhance diagnostic confidence. ", "In the past, the most widely used postprocessing technique for CE-MRA was maximum-intensity projection. ", "The diagnostic accuracy of contrast-enhanced MR angiog-raphy using the MIP technique is well described and accepted clinically (Mallouhi et al. ", "2002). ", "In the thorax, sub-volume MIPs, made from only a selected portion of the original data set, are useful to exclude nonrelevant anatomy. ", "Multiplanar reconstructions (MPR) are useful in the evaluation of thoracic vascular anomalies. ", "Because both MIPs and volume-rendered images are projectional images, adjacent structures may overlap and obscure the relevant anatomy. ", "MPRs are generated using any angle through the original data set. ", "Orientations that depict the blood vessel(s) of interest in an optimal manner are selected interactively. ", "This is a very practical method to accurately determine the size of a vessel or its angulation and relationship with respect to other structures. ", "Volume rendering (VR) is another useful method for depicting thoracic vessels. ", "Mallouhi et al. ", "found that VR performed slightly better than MIP for quantification of renal stenoses greater than 50% and significantly better for severe stenoses. ", "VR also had a substantial improvement in positive predictive value and renal vascular delineation on VR images was significantly better. ", "In another series, MIPs were statistically less reliable for determining renal artery stenoses compared with digital subtraction angiography (Baskaran et al. ", "2002). ", "The MIP algorithm selects only the voxel with the highest attenuation along a ray projected through the data set; volume-averaged voxels may be erroneously excluded from the final image, resulting in overestimation of stenoses. ", "VR is on the basis of the percentage classification technique, which is used to estimate the probability of a material being homogeneously present in a voxel. ", "This provides an accurate determination of the amounts of materials when the voxel consists of two or more materials, which are volume averaged. ", "With VR, the volume-averaged voxels are included in the final image because VR calculates a weighted sum of data from all voxels along a ray projected through the data set.", "\n\n### 8.3.5 Black Blood Techniques\n\nSpin echo (SE) was the first sequence used for evaluating cardiac and thoracic vascular morphology. ", "The development and introduction of ECG-gating made SE technique especially useful by substantially reducing motion artifacts (Pettigrew et al. ", "1999). ", "Spin echo sequences generally provide good contrast between the vessel wall and blood. ", "These are called black blood images because of the signal void created by flowing blood. ", "Blood signal may appear brighter in slowly flowing areas, such as areas immediately adjacent to the vessel wall. ", "Presaturation with radio frequency and reduction of the echo time minimize blood signal and increase contrast on gated SE images. ", "Although widely available, SE imaging has limited temporal resolution and is degraded by respiratory and other motion-related artifacts. ", "Shorter acquisition times are achieved with fast (or turbo) spin echo (FSE) pulse sequences, also known as rapid-acquisition relaxation enhancements (RARE) (Haddad et al. ", "1995). ", "Several adjustments to the basic FSE sequence have been made, including the use of one or more inversion pulses, increased echo train length, half-Fourier reconstruction, and echo planar techniques. ", "Single-shot FSE (SSFSE) sequences use a very long echo train in tandem with half-Fourier reconstruction (Semelka et al. ", "1996). ", "The center of k-space is acquired in a short time, minimizing motion blurring. ", "The rapid acquisition of multiple phase lines for a single TR allows for coverage of the entire heart and thorax in the time frame of one or two breath holds. ", "SSFSE technique has the advantage of being faster than the FSE technique in the evaluation of thoracic aortic disease. ", "The SSFSE sequence can be modified for better cardiac results by reducing the echo train length, lowering the effective TE, and using a blood-suppressed preparation method (Vignaux et al. ", "2001). ", "T2-weighted inversion recovery imaging is now used as the front-line sequence for depiction of cardiac and thoracic vascular morphology. ", "This technique uses a selective and a nonselective 180° inversion pulse followed by a long inversion time to null blood magnetization (Simonetti et al. ", "1996). ", "A second selective 180° inversion pulse can also be applied to null fat. ", "This is referred to as double or triple inversion recovery (DIR or TIR). ", "The sequence is acquired either with breath-hold or a non-breath-hold technique and provides for excellent delineation of vessel wall or myocardial blood interfaces. ", "It effectively nulls blood and depicts blood-vessel interfaces in an optimal way.", "\n\n### 8.3.6 Bright Blood Techniques\n\nBright blood imaging depicts both morphologic and functional data. ", "In this sequence, blood has a bright signal intensity. ", "Multiple consecutive images are acquired and can be viewed dynamically to depict cardiac motion. ", "Sequences include gradient echo (GRE), fast GRE, segmented k-space fast GRE, and steady state free precession (SSFP) techniques. ", "GRE imaging is well suited for cardiac and vascular imaging because of its short echo and repetition times. ", "Blood appears bright compared with adjacent myocardium because of time-of-flight effects, as well as the relatively long T2. ", "Markedly turbulent blood induces a signal because of to intravoxel dephasing, which in some instances may be a \"helpful\" artifact for assessing areas of stenoses (Jara et al. ", "1999). ", "A segmented k-space approach provides high-resolution dynamic images and can be performed much more rapidly than other techniques (Pruessmann et al. ", "1999). ", "Using short echo times (2 ms) and short TRs (<10 ms), multiple lines (segments) of k-space are acquired during each cardiac cycle. ", "In GRE techniques, only a single line of k-space is acquired per cycle. ", "Segmented k-space fast GRE imaging remains a mainstay for dynamic vascular imaging and has been improved and adapted for fastest possible acquisition times (Reeder et al. ", "1999). ", "Nevertheless, the technique is limited by the need to maintain adequate enhancement of inflowing blood. ", "At lower TRs, now available with high-performance gradient systems, inflow enhancement of the cardiac blood pool diminishes and saturation occurs, reducing vessel wall-blood contrast. ", "The inability to further reduce TR effectively limits achievable spatial and temporal resolution. ", "Steady state free precession is a state-of-the-art approach to the improvement of cine imaging. ", "Image contrast in SSFP depends on the T1/ T2 ratio of tissue and, unlike GRE techniques, is less dependent on flow. ", "SSFP is susceptible to magnetic field inhomogeneities and requires very short TRs, limiting its use until recently. ", "With technical improvements in magnetic field homogeneity and the development of higher performance gradient systems, diagnostic SSFP images can now be obtained with limited artifacts (Plein et al. ", "2001). ", "This technique is also known as BFFE (balanced fast field echo), FIESTA (fast imaging employing steady state acquisition), FISP (fast imaging with steady precession), and true FISP depending on the vendor.", "\n\n### 8.3.7 Fundamental Sequences\n\n * Triple plane (axial, sagittal, coronal) low resolution survey.", "\n\n * Phased array coil \"reference\" sequence.", "\n\n * Spin echo (SE) T1-weighted sequences in the near-sagittal or axial plane, going through the ascending and descending aorta, and on the axial plane; these \"black blood\" sequences (Fig. ", "8.2), allow to obtain a sharp contrast between the hypointense (dark) flowing blood and stationary tissues (aortic wall). ", "These sequences need to be ECG-gated (Stemerman et al. ", "1999).", "\n\n * As an alternative, inversion recovery fast spin echo (IR FSE) sequences could be used; these sequences allow to shorten the acquisition time to around 10-20 s by using additional radio-frequency pulses with multiple echoes sampling for every phase encode. ", "So it becomes possible to acquire the entire data set in a single breath-hold, with a definite improvement in image quality.", "\n\n * T2-weighted ad IR sequences both in the near-sagittal plane, parallel to the vessel major axis and on the axial plane, perpendicular to the vessel major axis. ", "These sequences allow to characterize the vessel wall signal for the evaluation of endovascular thrombotic apposition, intra-plaque hemorrhage, intramural hemorrhage/hematoma or vessel wall oedema in case of acute/subacute vasculitis.", "\n\n * Additional sequences like GRE or fast spoiled gradient echo (FSGR) (with TR and TE <10 ms), even called BFFE (Philips), true FISP (Siemens), or FIESTA (General Electric), are extremely fast and do not need contrast medium; if acquired on near-sagittal or coronal plane these sequences allow the dynamic qualitative study of the blood flow and the modifications induced by arterial wall disease (intimal flap, coarctation, etc) (Kersting-Sommerhoff et al. ", "1987), eventually showing vascular stenoses jet or aortic valvular regurgitation.", "\n\n * Three dimensional contrast enhanced sequences to obtain an MRA (3D Spoiled GE like FFE or FISP): these are modified 3D TOF and allow a breath-hold high contrast and spatial resolution volumetric acquisition (Persson et al. ", "2004); these are acquired on a near sagittal plane for the study of the thoracic aorta and on the coronal plane, when an evaluation of the thoracic-abdominal aorta and the iliac-femoral vessels is needed. ", "To speed up the acquisition in poorly cooperative patients it is possible to widen the reception bandwidth (i.e., ±128 kHz) or using parallel imaging. ", "Parallel Imaging technique like SENSE (Philips) (Sodickson and Manning 1997), ASSET (General Electric), or GRAPPA (Siemens) (Griswold et al. ", "2002) allow the simultaneous acquisition of multiple data sets by different phased array coil receiving channels, reducing acquisition time to 5-20 s, depending on the acceleration factor selected.", "\n\n * Phase contrast (PC) sequences may be used to quantitatively evaluate the blood flow in a specific location, making it possible to calculate flow velocity and acceleration for the estimation of stenoses.", "\n\nFig. ", "8.2\n\nAxial TSE T1-weighted sequence. ", "The aortic wall is clearly visible because of the high contrast with respect to the \"black blood\" lumen\n\n## 8.4 Normal MR Aortic Anatomy\n\nOn SE or FSE T1-weighted images the aorta shows an even diameter, with a maximum of less than 3.5 cm in the thoracic district and less than 2.5 cm in the abdominal district.", "\n\nAortic wall has to appear smooth and with an even thickness, usually less than 3 mm. ", "In T2-weighted images, the aortic wall has to appear hypointense, in order to exclude the presence of oedema or intramural hemorrhage.", "\n\n## 8.5 Aortic Diseases\n\nClinically relevant aortic pathologies may be grouped into four entities:\n\n * Aneurism\n\n * Dissection\n\n * Intramural hematoma\n\n * Trauma\n\n### 8.5.1 Aortic Aneurysm\n\n#### 8.5.1.1 Clinical Findings\n\n * The pathogenesis of the development of aneu-rysms is not fully understood.", "\n\n * They are associated to atherosclerosis, without this being a direct causing agent, and to arterial hypertension.", "\n\n * Usually asymptomatic, they are frequently discovered by accident during examinations performed according to other requests (Grathwohl et al. ", "1999; Stefens et al. ", "1994; Van Dyke and White 1994).", "\n\n * Sometimes they are associated with genetically transmitted pathologies such as Marfan or Ehlers-- Danlos syndrome, Cystic Medial necrosis.", "\n\n * They are sometimes associated with infective processes (Syphilis).", "\n\n#### 8.5.1.2 Histopathology\n\n * The clinical definition of an aneurysm is \"a vessel which has a diameter at least 1.5 times lager than attended.\"", "\n\n * It could assume different geometrical shapes; fusiform as frequently seen in atherosclerosis, or sac-cular as frequently seen in post-traumatic or post infective cases (so called mycotic-aneurysm).", "\n\n * They could present with parietal homogeneous or irregular thrombotic stratification which can be either concentrically or eccentrically positioned.", "\n\n#### 8.5.1.3 MR Features\n\n * FSE, BTFE, GRE and 3D FFE T1-weighted sequences allow to evaluate the maximal external vessel diameter, which is to diagnose an aneu-rysm that can be >4-5 cm for the thoracic aorta or >3 cm for the abdominal aorta (Figs. ", "8.3a, b).", "\n\n * After performing the contrast-enhanced 3D FFE sequences, the evaluation of the MIP reconstruction alone highlights solely the internal surface of aneurysm (Fig. ", "8.3c), not taking into account the eventual presence of parietal thrombotic stratification, causing an underestimation of the vessel diameters (Fig. ", "3.3d). • ", "FSE T1, T2-weighted, and FSE IR sequences on the axial or coronal plane can be helpful for depiction of endoluminal parietal thrombosis. ", "Homogeneous and stable thrombus will show an even hypo intense signal in all sequences (Fig. ", "8.3a) whereas unstable thrombus or intra-plaque hemorrhage will show a hyper or hypo-intense signal on T2 and IR weighted sequences, depending on the phase of blood degradation: oxyhemoglobin (0- 12 h, hypo intense on T1 and T2 weighted), deoxy-hemoglobin (12-72 h, hypo intense on T1 and T2 weighted), early metahemoglobin (3-7 days, early sub-acute phase, sharply hyper intense signal on T1 weighted and hypo intense on T2 weighted), late metahemoglobin (7-15 days, hyper intense on both T1 and T2-weighted sequences) or hemo-siderin (>15 days, hypo intense signal on both T1 and T2-weighted sequences) (Fig. ", "8.4).", "\n\n * In case an infective or inflammatory cause is suspected, it is useful to acquire a GRE T1-weighted fat suppressed sequence (i.e., BFFE or true FISP) on the axial plane: in positive cases, the vessel wall will show a hyper intense signal (Fig. ", "8.5a) because of contrast media accumulating in the interstitial space, with or without an increase in arterial wall thickness (Choe et al. ", "1999; Nastri et al.2004).", "\n\n * It is also necessary to complete the evaluation of peri-aortic tissues, in order to highlight oedema (hyper intense in FSE IR T2-weighted sequences) (Fig. ", "8.5b) and eventually a warning signal of instability or imminent rupture of the aneurysm itself (Hartnell GG 2001).", "\n\nFig. ", "8.3\n\nMRA study of a patient with thoraco-abdominal aortic aneurysm (a) Axial BTFE T1-weighted sequence clearly showing the aortic diameter of the descending tract. ", "Notice the homogeneously hypo-intense thrombus on its right lateral wall. (", "b) Axial BTFE T1-weighted sequence at a cranial level with respect to 1a, showing the aortic diameter without evidence of parietal thrombus; it is mandatory to measure the aortic diameter on multiple planes because of the possible twisting course of this vessel in advanced atherosclerosis. (", "c) CE-MRA MIP reconstruction: MIP stand-alone evaluation may cause a substantial underestimation of aortic diameters because such electronic reconstruction represents a \"lumen\" image not taking into account parietal thrombotic apposition or regions of slow flow, which are both quite peculiar to aneu-rysm or atherosclerotic vessels. (", "d) CE-MRA source images. ", "Source images stand-alone evaluation in this case would have masked the thrombotic apposition seen in 3° because of its position, which is parallel to the acquisition plane\n\nFig. ", "8.4\n\nAxial T2-weighted image showing a parietal thrombus in the descending aorta. ", "Note the hypo-intense signal in the external layer, due to hemosiderin deposition and a homogeneous iso-intense internal layer representing stable thrombus\n\nFig. ", "8.5\n\n(a) Black blood post contrast fat suppressed T1-weighted sagittal images showing diffusely hyper-intense signal from the aortic outer wall. (", "b) Black blood fat suppressed T2-weighted axial images showing hyper intense aortic wall (adventitia) signal due to inflammatory oedema in a case of aortitis (MR was requested after a positive FDG-PET had been performed)\n\n#### 8.5.1.4 Differential Diagnosis\n\n * Posttraumatic Pseudo-aneurysm: Usually saccu-lar, it is located mostly on the ventral aspect of the aortic arch, close to the arteriosus ligament of Botallo. ", "Post-traumatic pseudo-aneurysms of the abdominal aorta are rare. • ", "Mycotic Aneurysm: usually saccular, focal, and limited in size, could eventually show hyper intense wall signal on IR and T2-weighted sequences in case of active disease.", "\n\n * Retroperitoneal fibrosis: diffuse hyperintensity of the arterial wall and surrounding structures due to chronic inflammatory process.", "\n\nThe main consideration regarding an aneurysm is the maximum axial diameter. ", "Four millimeter per year is the estimated average increase in size of an abdominal aortic aneurysm. ", "The vessel wall has to oppose to the effect of the internal blood pressure with a circumferential force, regulated by Laplace law, on which depend the odds of rupture. ", "The literature reports say that the rupture odds/year of aortic aneurysm based on his size are variable, depending on the multi-factorial aetiology and eventual presence of other co-morbidities (diabetes, hypertension, etc), ranging from 20% per year in aneurysm larger than 5 cm to 40% per year if larger than 6 cm to more than 50% per year if larger than 7 cm. ", "Maximal axial diameters have to be evaluated on more planes or projections, taking into account the total longitudinal extension and side branches involved (supra aortic vessels, renal arteries). ", "In some cases, using the 3D contrast enhanced sequences it is possible to distinguish between the origin of small lumbar or spinal cord feeding vessels and Adamkievicz artery (Fig. ", "8.6), which is of utmost importance, in case an endovascular aortic repair (EVAR) procedure is being planned.", "\n\nFig. ", "8.6\n\nHi-resolution CE-MRA source images in a patient with thoraco-abdominal aortic aneurysm: the Adamkievicz spinal artery and a lumbar artery are clearly visible\n\nIn such cases it is important to correctly measure diameter and length of the aneurysm proximal neck, the maximal axial diameter, and longitudinal extension and to evaluate the presence of angulations or kinking. ", "Measurements have to be performed on CE MRA images and on FSE, GRE, and 3D FFE T1-weighted images in order to correctly evacuate the external vessel size. ", "The evaluation of the presence and extension of vessel wall calcification has to be demanded on CT examination.", "\n\n### 8.5.2 Aortic Dissection and Intramural Hematoma\n\n#### 8.5.2.1 Clinical Findings\n\n * Sudden onset of excruciating, stabbing-like thoracic or abdominal pain, sometime associated with hypotension or shock and asymmetric peripheral pulse, often in a patient with pre-existing aneurysm (dissecting aneurysm).", "\n\n * Often associated to arterial hypertension (hypertensive fit being one of the cause of dissection).", "\n\n * Very common in a patient with connective tissue pathology such as Marfan, Ehlers--Danlos, or cystic medionecrosis syndrome.", "\n\n * When the ascending aorta is involved it is termed \"type A\" dissection as per Stanford classification (or previous De Bakey type I).", "\n\n * When the aortic arch or descending/abdominal aorta is involved it is termed \"type B\" dissection as for Stanford classification (previous De Bakey type II and III).", "\n\n * Dissection could extend to side branches (coronary arteries, supra-aortic, renal, splancnic or iliac vessels) causing ischemia or acute infarction of the respective vascular territories, or towards external rupture when the adventitial layer becomes disrupted.", "\n\n#### 8.5.2.2 Histopathology\n\n * Aortic dissection is caused by a sudden tear in the intimal layer of the vessel wall, with high pressure arterial blood forming a false lumen into the medial layer. ", "Entry site is often situated in correspondence to an atheroma or to an ulcerated claque. ", "The \"point-break\" could be represented by an intra-plaque hemorrhage or by an intramural hematoma (often post traumatic). ", "In the latter case the intramural bleeding with the increasing size of the hematoma ultimately causes the intimal tear. ", "In connective tissue pathology such as Marfan syndrome, an eventual adventitial tear determinates an aortic fissura-tion, with active extravasation of blood in peri-aortic spaces (mediastinum, pericardium etc.).", "\n\n * Intimal flap usually presents a spiral ascending or descending path.", "\n\n#### 8.5.2.3 MR Features\n\n * In FSE T1-weighted images, the intimal flap appears as a thin hy per-intense line within the hy po-intense aortic lumen (Khan and Nair 2002).", "\n\n * In BTFE images the intimal flap will appear as a thin hypo-intense line within a hyper-intense aortic lumen (Figs. ", "8.7 and 8.8) (Pereles et al. ", "2002).", "\n\n * In time resolved or cine GRE 3D contrast enhanced sequences, usually acquired into a para-sagittal plane, it is possible to distinguish the progressive enhancement of true and false lumen (Figs. ", "8.9 and 8.10) and sometimes to identify the dissection \"entry site\" (Fig. ", "8.11).", "\n\n * Contrast enhanced MRA allows to identify and distinguish true and false lumen, both for morphological features (the true lumen is usually half-moon shaped with respect to the false lumen, which tends to be oval or circular in shape) and dynamic features of the vascular enhancement (flow in true lumen is usually faster then in false lumen). ", "Moreover, CE MRA allows to correctly evaluate and confirm the origin of the side branches from true or false lumen.", "\n\n * It is usually recommended to perform a multiphase contrast enhanced MRA acquisition in order to avoid missing features because of the slow flow in false lumen and side branches.", "\n\nFig. ", "8.7\n\nAxial BTFE T1-weighted sequence at aortic arch level shows an intimal flap in a Stanford type A dissection. ", "Intimal flap is represented by a thin hypo-intense linear structure within the hyper-intense lumen\n\nFig. ", "8.8\n\nAxial BTFE T1-weighted sequence at the level of descending aorta level shows the intimal flap in a Stanford type A dissection extending downstream. ", "Intimal flap shows the same signal features as in Fig. ", "8.7\n\nFig. ", "8.9\n\nTime resolved CE-MRA acquired on a para-sagittal plane: in early arterial phase the contrast medium is filling the true lumen-TL (anterior), where the blood flow is usually faster with respect to the false lumen-FL (posterior)\n\nFig. ", "8.10\n\nTime Resolved CE-MRA acquired on a para-sagittal plane immediately after the early arterial phase shown in Fig. ", "8.9. ", "True lumen has been completely filled whereas the false lumen filling is still incomplete\n\nFig. ", "8.11\n\nUn-enhanced ECG-gated BFFE T1-weighted sequence acquired on the axial plane in correspondence to the supposed \"entry site\" of the aortic dissection. ", "In cine mode it is possible to evaluate blood flow dynamics where high speed flow show hyper intense signal with respect to slower flow. ", "In this case it was possible to highlight a small hyper intense high speed jet (arrow) indicating the dissection entry site\n\n## 8.6 Trauma\n\n * Taking into account that a trauma patient with suspected aortic lesion is frequently hemody-namically unstable, CT angiography and trans-oesophageal echo are still the preferred imaging methods.", "\n\n * In a hemodynamically stable patient or in those in a sub-acute phase, MRA allows a comprehensive evaluation of main complication of aortic trauma, namely pseudo-aneurysm, dissection, and intramural hematoma, using the sequences that have been previously described for the evaluation of such pathologies.", "\n\n## 8.7 Vascular Thoracic Outlet Syndrome\n\nThoracic outlet syndrome is a group of disorders that occur when the blood vessels or nerves in the thoracic outlet, that is, the space between the clavicle and the first rib become compressed. ", "The vascular type of thoracic outlet syndrome occurs when one or more of the subclavian vessels are compressed. ", "The diagnosis of this condition is usually clinical and eventually confirmed by color-doppler US. ", "Multiphase (arterial and venous) CE-MRA performed with the arms first adducted and then abducted over the head is a very accurate technique for the study of this condition (Figs. ", "8.12a, b and 8.13a, b).", "\n\nFig. ", "8.12\n\nCE-MRA acquired on a coronal plane for suspected thoracic outlet syndrome. (", "a) Arms in resting position. (", "b) Arms extended over the head. ", "There is no evidence of any vascular compression\n\nFig. ", "8.13\n\nCE-MRA acquired on a coronal plane for suspected thoracic outlet syndrome. (", "a) Arms in resting position. (", "b) Arms extended over the head. ", "In (b) the presence of significant compression and stenosis of the proximal left subclavian artery becomes evident. ", "The patient was subsequently successfully treated by means of surgical release\n\n## 8.8 Post EVAR Evaluation\n\nThe number of Endovascular Aortic Repair (EVAR) procedures is still increasing worldwide, because of the introduction of new materials and better performance and durability of prosthesis, most of which are actually MRI compatible. ", "With MR it is now possible to perform multiple follow up evaluation in patients submitted to EVAR to gain control of prosthesis positioning nd to search endoleaks (leakage of blood between the endoprosthesis and the vessel wall) using time resolved or cine GRE 3D contrast enhanced sequences as used for the evaluation of aortic dissection (Figs. ", "8.14 and 8.15)\n\nFig. ", "8.14\n\nTime Resolved CE-MRA acquired on a para-sagittal plane in a patient submitted to EVAR procedure for an aneu-rysm of the descending aorta. ", "In the early phase the enhancement of the external para-prosthetic space, starting from its proximal end (so called type I endoleak) becomes evident\n\nFig. ", "8.15\n\nTime Resolved CE-MRA acquired on a para-sagittal plane immediately after the early arterial phase shown in Fig. ", "8.14. ", "Type I endoleak is clearly depicted because of the progressive enhancement of the para-prosthetic space\n\n## 8.9 Pulmonary Vessels\n\nImaging of the pulmonary vasculature is a demanding MRA application, because a large volume has to be covered with short imaging times. ", "The need for short imaging times is a consequence of the high susceptibility of the lung tissue. ", "Dedicated MRA sequences use high readout bandwidths in order to achieve short echo times (TE) and to prevent increased intra-voxel spin dephasing. ", "Correct contrast bolus timing is crucial to obtain a pure arterial image as the artero-venous transit times of the pulmonary vessels are in the order of 3-6 s (Schonberg et al. ", "1999).", "\n\n### 8.9.1 Normal MR Pulmonary Vessels Anatomy\n\nThe pulmonary arteries, one on each side, arise from the bifurcation of the pulmonary trunk. ", "The left main pulmonary artery goes posterior and it arches over the left main bronchus before dividing into upper and lower trunks. ", "The right main pulmonary artery is longer than the left following a horizontal or slightly inferior course passing under the concavity of the aortic arch before dividing into a smaller upper and a larger lower trunk. ", "The subsequent branching pattern of the pulmonary arteries then mirrors that of the segmental bronchi. ", "The right gives rise to the apico-posterior, anterior, and posterior segmental arteries that feed the right upper lobe, a middle lobe artery that immediately divides into medial and lateral segmental arteries, and five segmental arteries to the right lower lobe (apical, anterior, posterior, medial, and lateral). ", "On the left side, the arrangement is analogous presenting some variations--the lingu-lar artery, a branch of the left upper lobe pulmonary artery, divides into superior and inferior branches. ", "The apical and posterior arteries are shared on the left (the apico-posterior segmental artery) as are the medial and posterior segmental arteries on the left (the mediobasal segmental artery), thus giving a total of ten segmental arteries on the right and eight seg-mental arteries on the left.", "\n\nNomenclature of the pulmonary arteries on the basis of the distance from the right ventricle is widely used as follows: first order the branch and the pulmonary trunk; second order, the left and right main pulmonary arteries; third order, the upper and lower trunks and \"lobar\" arteries; fourth order, all ten segmental arteries; fifth order, sub-segmental arteries arising directly from a segmental artery; sixth order, arteries arising directly from the first division of a sub-segmental artery; and so on.", "\n\n### 8.9.2 Bronchial Artery Anatomy\n\nBronchial artery anatomy is extremely variable, with most (>70%) arising from the descending thoracic aorta close but usually slightly below the carina (T5- T6 level). ", "Anomalous bronchial arteries are defined as bronchial arteries that originate outside the T5-T6 range. ", "Bronchial arteries typically run parallel to the bronco-vascular axes. ", "A large published anatomic series described four classical branching patterns, as follows (52):\n\n * Two arteries on the left and one on the right that arises as an intercostobronchial trunk (ICBT) (40.6%)\n\n * One artery on the left and one ICBT on the right (21.3%)\n\n * Two on the left and two on the right, one of which is an ICBT (20.6%)\n\n * One on the left and two on the right, one of which is an ICBT (9.7%)\n\n### 8.9.3 Magnetic Resonance Imaging and Magnetic Resonance Angiography\n\nThe presence of diaphragmatic and cardiac motion artifacts, long scan times, susceptibility artifacts at air-tissue interfaces, and poor contrast between flowing blood and emboli limited the early approaches to pulmonary vessel imaging. ", "With the introduction of contrast-enhanced (CE) MRA techniques many of those limitations were overcome, enabling high-quality diagnostic images of the pulmonary arteries to be generated during one breath-hold (Fig. ", "8.16). ", "Initial studies reported good success for detection of PE compared with catheter angiography up to the segmental level, but spatial resolution was still suboptimal for an accurate detection of PE in smaller sub-segmental arteries (Oudkerk et al. ", "2002). ", "With the introduction of parallel imaging techniques, the improvements in gradient technology, and the optimization of acquisition protocols actual MRA techniques are almost comparable to CTA as for spatial and temporal resolution. ", "The acquisition parameters for pulmonary MRA and MR perfusion imaging could be different among institutions, depending on scanner performance and clinical scenario. ", "Acquisition time for one 3D data set ranges usually between 15 and 30 s. Acquisition is performed during a single breath-hold (in inspiration), and the k-space readout scheme is usually centrically reordered. ", "Because of the asymmetric sequential k-space readout scheme, image acquisition has to start a few seconds before the estimated arrival of the contrast material bolus. ", "Pre-contrast MR angiograms are then subtracted from the post-contrast images and then MPR and MIP reconstructions of the complete data are obtained for image analysis (Figs. ", "8.17 and 8.18). ", "Fast imaging is essentially accomplished with short TR (typically ≤5 ms) and short TE (typically ≤2 ms) 3D sequences. ", "With sufficiently strong gradients, extremely short TR/TE combinations can be achieved (i.e., 2.9/1.2 ms, respectively). ", "A flip angle of 15-25° will be satisfactory for these sequences (Nikolaou et al. ", "2005).", "\n\nFig. ", "8.16\n\nCE-MRA MIP reconstruction in a healthy volunteer showing the pulmonary artery main trunk and its main branches up to the sub-segmental ones. ", "Obviously non fill-ing defect related to thrombus was detected\n\nFig. ", "8.17\n\nCE-MRA MIP reconstruction selectively showing the right pulmonary artery with no peripheral or central perfusion defects\n\nFig. ", "8.18\n\nCE-MRA MIP reconstruction selectively showing the left pulmonary artery with no peripheral or central per-fusion defects\n\n#### 8.9.3.1 Perfusion Imaging and Ventilation\n\nPerfusion imaging with MRI offers substantial ben-efit in terms of spatial and temporal resolution.", "\n\nSeveral studies compare scintigraphy and MR pulmonary perfusion in a variety of disorders. ", "Although results with both techniques are similar, reproducibility is significantly greater with MR. ", "Differential lung perfusion, which may be of value in assessing patients with chronic obstructive pulmonary disease prior to and after lung volume reduction surgery, is also well demonstrated with MR lung perfusion.", "\n\n#### 8.9.3.2 Time-Resolved MRA\n\nBecause of the short transit time from pulmonary artery to pulmonary vein, some researchers have implemented extremely rapid imaging of the pulmonary vasculature, in an effort to capture an arterial phase, similar to what is obtainable in the study of aortic dissections as shown previously. ", "In order to achieve this goal, however, images must be acquired in 4 s or less per scan, thus requiring lower resolution than might otherwise have been employed (Korosec et al. ", "1996). ", "With this approach, a \"clean\" arterial phase is acquired in favor of a higher resolution scan that can depict sub-segmental arteries. ", "Often, in-plane resolution is sacrificed to achieve a sufficient combination of in-plane spatial resolution and rapid temporal resolution. ", "That will limit the number of useful projections that can be generated.", "\n\n#### 8.9.3.3 BFFE Imaging\n\nBFFE imaging is an acquisition sequence that depicts vessels as bright structures and held promises for the diagnosis of both deep venous thrombosis (DVT) and PE (Kluge et al. ", "2004). ", "Images can be acquired in any plane and although breath-holding is essential, small imaging volumes tailored to the breath-hold capability can be acquired. ", "However, recent evidences suggest that some small clots may go undetected with True-FISP imaging (Pedrosa et al. ", "2005).", "\n\n#### 8.9.3.4 Thrombus Imaging\n\nSimilar to the depiction of the intramural hematoma in case of aortic dissection previously reported (see Fig. ", "8.4), direct thrombus imaging is on the basis of the principle that changes in blood clots over time correspond to changes in MR signal intensity, offering a promising new tool for noninvasive diagnosis of PE without the need contrast material injection. ", "As time-dependent changes in MR appearance reflect evolution of the clot, the high signal is seen in new clots only. ", "Further advantages include the ability to scan in the coronal plane, thereby allowing time-efficient coverage of the lower extremity veins with two coronal overlapping acquisitions in a relatively short scan time.", "\n\n#### 8.9.3.5 Blood-Pool Imaging\n\nBlood-pool agents play a promising role in pulmonary vascular diagnosis, especially in situations where higher spatial resolution is required (Kroft and de Roos 1999). ", "To date, no prospective comparative study of blood-pool agent compared with DSA has been performed. ", "Because of their long vascular persistence time, high-resolution breath-hold images of the entire pulmonary vasculature can be performed in multiple acquisitions tailored to the breath-hold capability of the patient. ", "Another possibility that is attractive for patients with severe respiratory compromise is the use of navigator-echo techniques to eliminate the need for breath-holding. ", "The long vascular persistence of blood-pool agents may offer the adjunctive potential to detect clots within the lower extremities (Perreault et al. ", "2003) in patients with suspected PE.", "\n\nReferences\n\nAHA, American Heart Association (2002)Heart and Stroke Statistical Update.", "\n\nBaskaran V, Pereles FS, Nemcek AA, Jr., et al. 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", "J Magn Reson Imaging 12(5):671-677CrossRef12%3A5<671%3A%3AAID-JMRI3>3.0.CO%3B2-F)PubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_9(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 9. ", "Heart and Coronary Arteries\n\nMassimo Lombardi1 and Matteo Milanesi1\n\n(1)\n\nU.O.C. Cardiovascular RM, C.N.R./\"G. Monasterio\" Foundation, Via Moruzzi, 1, Pisa, 56124, Italy\n\n9.1 Introduction\n\n9.2 Technological Requirements\n\n9.3 Pulse Sequence Aspects\n\n9.3.1 Cardiac and Respiratory Motion Suppression\n\n9.3.2 Making a Good Contrast\n\n9.3.3 From 2D to 3D: Whole Heart CMRA\n\n9.3.4 New Benefits from Parallel Imaging\n\n9.3.5 Contrast Agents to Improve Image Quality\n\n9.4 Clinical Applications\n\n9.5 MRA Coronary Stenting and Bypass\n\n9.6 Functional Evaluation of Coronary Arteries and Bypass\n\n9.7 Conclusion\n\nReferences\n\nAbstract\n\nThe current status of technological development is such that coronary magnetic resonance angiog-raphy (MRA) has a marginal role in the field of noninvasive evaluation of this arterial district. ", "Nevertheless, in several clinical applications, such as congenital abnormalities of coronaries or pathologies affecting young patients, coronary MRA is considered as the fi rst choice tools and accredited with high diagnostic accuracy. ", "New technical improvements such as high-field scanners (3 T) and multichannel surface coils may turn in favor of coronary MRA because of the intrinsic fl exibility and lack of ionizing radiations. ", "In this chapter, the main technological aspects as well the more relevant clinical applications and limitations are commented.", "\n\n## 9.1 Introduction\n\nThe lack of ionizing radiations, the use of a noniodine contrast agent, and the possibility of obtaining reliable and clinically accepted information such as cardiac function, rest and stress myocardial perfusion as well as the presence and extension of necrotic and viable tissue within the myocardium make MRI (magnetic resonance imaging) a very fl exible tool for the evaluation of coronary artery disease. ", "However, there is still a weak point which is in someway reducing the clinical relevance in a large cohort of patients. ", "Coronary artery angiography is in fact hard to be proposed systematically because of heavy technological limitations which confi ne the use of this approach within the research centers. ", "However, there are already some published results and some research lines which are addressing the main limitations of this technology such as the poor spatial resolution and the long acquisition time. ", "While these results are still preliminary and far from a practical clinical application, they have the clear value to indicate that there are no intrinsic limits which cannot be overcome. ", "The technological territories which are going to be explored are comprehensive of the whole aspects of the methodology such as the field strength (3 T at least), the receiving coil (32 channels at least) (Fig. ", "9.1), three-dimensional sequences of acquisition (the whole heart coverage in single breath hold or free breathing with multiple gating), acceleration factor (4 or more), etc.", "\n\nFig. ", "9.1.", "\n\nPicture of a new designed multichannel coil for cardiac acquisition. ", "Courtesy of Dr. Christopher J Hardy, GE Global Research, Niskayuna, NY\n\nThough biomedical companies and research laboratories are involved in this effort, the use of coronary MRA still remains limited to a small number of patients and within a few referral centers. ", "Nevertheless, the present reduced use is still somehow useful because it avoids the uncontrolled application of a method for noninvasive coronary angiography which might be charged of unrealistic expectation as it is happening for multidetector computed tomography (Redberg and Walsh et al. ", "2008).", "\n\nIn the present chapter, besides the on-going developments, the few clinical indications and appropriateness criteria will be discussed.", "\n\n## 9.2 Technological Requirements\n\nThe use of MRI is becoming progressively and extensively benefi cial in the practice of cardiology. ", "All the leading cardiology centers are routinely using MRI to answer the morphological as well as the functional aspects of congenital and adult cardiac disease. ", "In the vast majority of clinical applications, the use of a field strength of 1.5 T is considered optimal as at this field the signal/noise ratio is reasonable and artifacts are usually negligible. ", "There are a few and still preliminary indications on the advantages of performing cardiovascular examinations using a field of 3 T. Myocardial perfusion is one of the applications, which seems to have signifi cant advantages, shifting toward a higher field strength in terms of contrast/noise ratio and temporal resolution (Araoz et al. ", "2005). ", "In the case of coronary MRA, there are several advantages because of the increased signal available, which makes possible technical approaches that are not at 1.5 T such as the acquisition of the whole coronary tree in a single breath hold (Santos et al. ", "2006) or allowing the acquisition of images of coronary arteries during both the systolic and diastolic phase (Gharib et al. ", "2007), or improving the spatial resolution up to 0.6 mm, which is one of the prerequisites for the clinical use (Wittlinger et al. ", "2005).", "\n\n## 9.3 Pulse Sequence Aspects\n\n### 9.3.1 Cardiac and Respiratory Motion Suppression\n\nIn order to produce coronary arteries images not affected by cardiac motion artifacts, the acquisition must be ECG-gated and data must be collected over multiple cardiac cycles, hinging on a technique known as k-space segmentation. ", "Typically, data acquisition is performed in a period of minimal myocardial motion that is found in mid-late diastole. ", "Several methods have been proposed to determine such a period, like the standardized formula introduced in (Stuber et al. ", "1999a), based on the current subject heart rate, or more subject-specifi c techniques like those based on ECG-triggered M-mode navigator echo. ", "However, the interval of minimal myocardial motion can be optimized also by visually inspecting cine MR images acquired prior to playing the actual CMRA sequence.", "\n\nAnother problem faced in CMRA is the respiratory motion, which can dramatically invalidate image quality. ", "Two possible solutions are represented by breath-hold and free-breathing imaging. ", "The former approach has the advantage of being fast and easy to implement but its success is strictly related to the ability of the patient to repeat sustained breath-holds. ", "On the contrary, the development of respiratory navigator techniques have allowed free-breathing CMRA imaging by gating the acquisition to the movement of the right lung--diaphragm interface measured using a two-dimensional selective excitation pulse. ", "Initially, in the retrospective gating approach data were over-sampled regardless of respiratory motion, and are discarded a posteriori if they did not fi t a certain gating window. ", "But, almost all the current free-breathing pulse sequences have adopted the prospective gating control, where both navigator and CMRA data are acquired at each cardiac cycle (Stuber et al. ", "1999a; Kim et al. ", "2001). ", "In this case, if the lung--diaphragm interface is found to be in a previously defi ned gating window (typically adjusted by the user at the end-expiratory period) the following k-space segment is accepted for data reconstruction, otherwise the acquisition is repeated in the next cardiac cycle. ", "Prospective gating techniques also require adaptive motion correction, given that the diaphragm motion is defi nitely larger than coronary artery.", "\n\n### 9.3.2 Making a Good Contrast\n\nThe pulse sequences developed for CMRA employ preparatory RF pulses to maximize the contrast between the coronary blood pool and the surrounding tissue.", "\n\nThe so-called \"bright blood\" gradient echo-based sequences are based on the suppression of the myocardium signal. ", "Usually, in order to image the coronary arteries the natural difference between myocardium and blood T2 values, respectively 50 and 250 ms at 1.5 T. With a fi rst preparation T2 pulse (T2prep), the longitudinal magnetization of both myocardium and blood is tipped to the transverse plane, where the myocardium experiences the T2 decay more quickly than the coronary blood. ", "As a consequence, when the magnetization is turned back to longitudinal after a tip-up pulse, the signal would be higher for the arterial blood pool. ", "Blood arteries will accordingly appear bright, with respect to the myocardium and other short T2 tissues like fat and venous blood, leading to an enhanced contrast. ", "Fat signal can be also suppressed separately through a frequency-selective fat suppression.", "\n\n\"Bright blood\" images can also be obtained taking advantage of the T1 shortening related to the paramagnetic contrast agent (CA), such as gadolinium chelated with diethylenetriaminepentaacetic acid (Gd-DTPA). ", "An inversion recovery prepulse is usually applied and the imaging sequence is started when the longitudinal magnetization of the myocardium crosses zero. ", "By this time, the coronary blood magnetization will be fully relaxed thanks to the presence of the contrast agent, which shortens the T1 form 1,200 ms to about 100 ms at 1.5 T, whereas the myocardium T1 still remains round 850 ms.", "\n\n\"Black Blood\" CMRA is instead realized by a double-inversion prepusle in combination with a fast spin-echo imaging sequence. ", "A fi rst nonselective 180° pulse inverts the magnetization throughout the body and is immediately followed by a second selective pulse that reinverts the magnetization in the whole imaged slice without affecting the blood about to come in.", "\n\n### 9.3.3 From 2D to 3D: Whole Heart CMRA\n\nInitially, coronary artery images were obtained with 2D spin-echo-based pulse sequences. ", "But a signifi -cant increase to CMRA was given in the early 1990s by the development of breath-hold 2D segmented k-space gradient echo, and most recently, in the late 1990s, by the steady-state free precession techniques (SSFP), also known as true fast imaging in steady-state precession (TrueFISP), balanced turbo field echo (FFE) or fast imaging employing steady-state acquisition (Fiesta). ", "In SSFP, in fact, the high T2/T1 level of the blood acts as an intrinsic contrast agent producing high image quality in term of both SNR (signal-to-noise ratio) and CNR especially in combination with T2prep and fat saturation.", "\n\nHowever, 2D imaging pulse sequences, though easy to implement, show a lot of drawbacks related to long scan time, low SNR because of thin slices and slice misgragation due to the diaphragmatic and cardiac position drifts. ", "Furthermore, following the coronary arties, a rather tortuous path, the success of the exam is often bound up with the capability of the operator to prescribe a good set of slices.", "\n\nFor all these reasons, 3D pulse sequences were developed and have currently completely replaced 2D. Volume coronary angiography with targeted volumes was proposed for a 3D breath-hold technique to image each arterial segment. ", "In spite of high resolution, this technique was still time-consuming and rather operator-dependent; so the effort is nowadays completely devoted to whole-heart 3D pulse sequence (Weber et al. ", "2004). ", "By covering the entire myocardium, whole-heart imaging is made possible to reach not only major coronary arteries, like proximal and middle coronal segments, but also more distal coronary segments.", "\n\nCurrently, most whole-heart studies employ 3D SSFP pulse sequences, which can achieve higher blood signal intensity as compared to 3D gradient echo sequences (Fig. ", "9.2). ", "The combination of 3D SSFP with radial k-space sampling strategy has proven to attain superior vessel sharpness (Spuentrup et al. ", "2004). ", "Though a radial approach is less sensitive to motion artifacts, it is also true that the image SNR is lower than with Cartesian k-space strategy. ", "On the other hand, the combination of 3D Cartesian SSFP with the variable sampling in time (VAST) technique (Foo et al. ", "2005) has allowed to get an optimal tradeoff between the degree of segmentation, i.e. the temporal resolution, and the spatial coverage while reducing cardiac motion-related blurring.", "\n\nFig. ", "9.2.", "\n\nImage obtained by a 3D SSFP sequence (FIESTA) and a 32-channel coil on a 1.5T scanner. ", "TE/TR = 1.7/4.4 ms, ±125 kHz, 2.1 mm partitions, 256 × 224/0.5 NEX, 24 s breath-hold 12 partitions/slab, 24 s overall scan time. ", "Courtesy of Dr. Christopher J Hardy, GE Global Research, Nisk-ayuna, NY\n\nThree dimension breath-hold approaches have advantaged in term of time effi ciency with respect to free-breathing 3D CMRA. ", "This makes breath-hold the only approach suited for fi rst-pass contrast enhancement studies that employ extracellular contrast agents like the aforementioned Gd-DTPA.", "\n\nSince the imaging time can be lengthened without any constraints on patient breath-holds, 3D free-breathing CMRA can achieve larger heart coverage along with improved spatial resolution and SNR. ", "Still, the scan time remains too long (up to 13-15 min). ", "For instance, in (Stehning et al. ", "2004) an isotropic volumetric CMRA using free-breathing 3D radial SSFP was obtained, but the scan time could not be pushed down to 10-14 min. ", "It is worth noting that in such a long acquisition period a drift of the diaphragm position over time might happen that can impair the diagnostic value of the images. ", "Cardiac motion is not always entirely solved by correction factors like in prospective gating control. ", "To overcome this problem, a self-navigated image reconstruction approach associated with 3D radial free-breathing has been proposed in (Stehning et al. ", "2005), where the myo-cardial motion information is extracted directly from the imaged data. ", "Most recently, a 3D SSFP pulse sequence has been used in conjunction a cardiac fat navigator (Nguyen et al. ", "2006), proving better image quality and similar SNR and CNR when compared to conventional diaphragm navigator.", "\n\n### 9.3.4 New Benefits from Parallel Imaging\n\nAn additional technological effort have been recently carried out also in the fi led of phase-array coil design and parallel imaging technique development. ", "Parallel imaging has defi nitely speeded up image acquisition, though at expense of reduced SNR. ", "However, for higher fields like 3.0 T experience an increasing conventional, full gradient encoding SNR, parallel imaging techniques can provide an alternative means of treading SNR for acquisition speed. ", "Another help might come also from phased array with an increased number of coils, which have been demonstrated to reduce the geometry factor for the benefi t of SNR, while allowing also acceleration in two dimensions (2D acceleration), i.e. in both the view and slice direction. ", "Such technological development has brought benefits not only for the breath-hold approach, where the whole-heart coverage in a single breath-hold became feasible, but also for the free-breathing approach.", "\n\nFor instance, in (Hardy et al. ", "2006) a FOV equal to 40 × 40 × 12 cm3 with up to 120 slice partitioning was covered with a 32-channel coil yielding a nominal voxel of 1.5 × 1.5 × 1.0-2.0 mm3 in a single breath-hold (acceleration factor up to R = 4 × 4 = 16) with a 3D SSFP sequence. ", "A high-density 128 system has been recently employed (Shankaranarayanan et al. ", "2008) for 3D CMRA in a single breath-hold, with an acceleration in both dimensions up to R = 4 × 4 = 16, and nominal voxel size of 1.6 × 1.6 × 2.6 mm3 By attaining a temporal resolution of 210 ms (data for each slice-encoding step was acquired in a single hearth cycle), this study demonstrated the importance of high acceleration factor to reduce both the breath-hold time and the imaging window in the cardiac cycle, which is responsible for motion blurring. ", "Both in (Hardy et al. ", "2006; Shankaranarayanan et al. ", "2008) a SSFP sequence was used for image data, preceded by a fat suppression RF pulse.", "\n\nRegarding free-breathing approach, the use of 2D acceleration strategies were compared with 1D in a recent study that employed a 10-element phased array coil (Okada et al. ", "2009). ", "A reduction of the scan time up to 45% and a decrease in SNR and CNR (though not statistically signifi cant) were observed for the 2D parallel imaging (Bornstedt et al. ", "2008). ", "Besides, a 32-channel coil has attained an isotropic voxel of 1.3 × 1.3 × 1.3 mm3 with 2D acceleration factor up to R = 3 × 3 = 9 in a scan time between 90 and 450 s for a heart rate of 60 bpm.", "\n\nThus, although there are important and signifi cant advances present high-channel MR systems, further research work is needed to perform a whole-heart isotropic 3D imaging with the same resolution and ease obtained by cardiac CT imaging in a reasonable scan time.", "\n\n### 9.3.5 Contrast Agents to Improve Image Quality\n\nThe sequences suitable for coronary MRA can be provided with an inversion prepulse which usually precedes the acquisition part of the sequence; the purpose of the prepulse being to null the signal from the myocardium (Hoffman et al. ", "1999). ", "Fur thermore, the contrast between the blood and the surrounding tissue can be further enhanced by the combined use of contrast agents (Brenner et al. ", "1999; Goldfarb et al. ", "1998). ", "As the extravascular contrast agent rapidly move toward the interstitium, the acquisition of the images should be performed during the fi rst pass. ", "This implies the use of breath-holding sequences (Brenner et al. ", "1999). ", "This peculiar problem can also be overcome by using the injection of intravas-cular contrast agent (Hoffman et al. ", "1999; Li et al. ", "1998; Stuber et al. ", "1999b). ", "Because these contrast agents remain confi ned within the intravascular compartment for hours, this can be used in combination with free-breathing coronary MRA.", "\n\n## 9.4 Clinical Applications\n\nDespite the fact that the first description of the coronar-ies by MRI had been published more than 20 years ago (Paulin et al. ", "1987), the current technological limitations are such that it is virtually impossible to obtain images constantly of good quality with a spatial resolution suitable for a routine clinical use. ", "In the unique multicenter study which has been published so far, the comparison between MR coronary angiography and invasive angiography (positive and negative predictive values of 70 and 80%, respectively) has been shown. ", "This diagnostic accuracy can be considered not satisfactory for the clinical use. ", "However, it is to be mentioned that in the same study the patients with a left main or three vessel disease were detected with a sensitivity and specifi city of 100 and 85%, and with positive and negative predictive values of 54 and 100%, respectively. ", "However, the same authors correctly admitted that the false-positive was an unresolved issue (Kim et al. ", "2001).", "\n\nIn recent years, several methodological approaches have been proposed for the clinical use. ", "The current hardware frontier is represented by the three-dimensional acquisition of the whole cardiac mass using a 3T scanner (Sakuma et al. ", "2005; Santos et al. ", "2006) employing a surface acquisition coil equipped with 32 channels (Niendorf et al. ", "2006). ", "However, there is still no consensus about the acquisition methodology (single apnea, repeated apnea, free breathing, etc). ", "The latter is obviously easier but affected by breathing artifacts and long acquisition time. ", "These artifacts are only partially reduced by the use of techniques as the navigator approach, where not only ECG gating is employed for acquiring the images during the diastolic phase but also the position of the diaphragm is monitored allowing the acquisition only when the muscle is close to a predefi ned position. ", "The double gating has the disadvantage of a prolonged acquisition time (5-10 min) and a relatively low success rate. ", "For these reasons, the evaluation of coronary artery disease by MRA is still confi ned in few research laboratories and it should not be proposed for clinical purposes.", "\n\nThe guidelines of the scientifi c societies recognize to this method a position far from clinical use in coronary artery disease atherosclerotic in origin (Class III, level of evidence C) (Bluemke et al. ", "2008).", "\n\nA different position can be attributed to the method with regard to the evaluation of congenital abnormalities (Figs. ", "9.3 and 9.4) and changes of the vessel caliber as in Kawasaky syndrome (Fig. ", "9.5). ", "Such an application is reported by the guide lines as Class IIa, evidence b. where the weight of evidence/opinion is in favor of usefulness/effi cacy. ", "Interestingly, MDCT is recognized within the same class of appropriateness in this group of patients and probably there is no sig-nifi cant difference between the two methodologies. ", "However, these are usually rather young patients and in the case of Kawasaky disease there is the clinical neediness of repeated examinations to follow-up the evolutive nature of the disease. ", "Thanks to the lack of ionizing radiations in such patients, MRA is the fi rst choice of imaging technology to be used, if available. ", "Furthermore, in several cases the association of a suspected course anomaly of the coronary artery with multiple congenital abnormalities, such as in the Fallot tetralogy, is in favor of MRI (Bluemke et al. ", "2008).", "\n\nFig. ", "9.3.", "\n\nCoronary MRA (CE-MRA technique) in a patient with an intramyocardial course of left descending artery. ", "The young patient was referred for recurrent chest pain on effort\n\nFig. ", "9.4.", "\n\nCoronary MRA (CE-MRA technique) in a patient with a previous intervenction for transposition of great arteries. ", "Arterial switch procedure. ", "One of the main target of the follow-up remains the evaluation of the course and the exclusion of stretching of native coronary arteries which have been reimplanted during the surgical procedure. ", "Left panel: the origin and the proximal course of the two reim-planted arteries are visible in the 3D reconstruction. ", "Right panel: the proximal and mid-part of the left coronary artery and its main branches are visible in the 3D reconstruction\n\nFig. ", "9.5.", "\n\nCoronary MRA (CE-MRA technique) in a patient affected by Kawasaki disease. ", "Left panel: 3D image of left anterior descending artery. ", "Right panel: the same 3D image after volume rendering postprocessing. ", "The aneurism affecting almost the whole proximal part of the artery is clearly visible (arrow)\n\n## 9.5 MRA Coronary Stenting and Bypass\n\nThe visualization of a coronary artery where a stent has been placed simply can be unfeasible because of the presence of signal artifacts induced by the metallic nature of the stent itself. ", "MRI compatible and artifact free stents have been reported, but their use is still relatively limited (White et al. ", "1987).", "\n\nIt is well known that the visualization of bypass is feasible both in the case of venous graft and probably with better results and arterial bypass (Aurigemma et al. ", "1989; Von Smekal et al. ", "1997; Kessler et al. ", "1997; Langerak et al. ", "2002). ", "The sensitivity in detecting occluded bypass is up to 100%; sensitivity in correctly describing a patent graft is slightly lower, 90% (Van Rossum et al. ", "1999) (Fig. ", "9.6).", "\n\nFig. ", "9.6.", "\n\nCoronary MRA (CE-MRA technique) in a patient with two arteria bypass. ", "The right internal mammarian artery which was supposed to support the right coronary artery is occluded after approximately 8 cm from the origin. ", "The left internal mammarian artery connected to the left anterior descending artery shows a critical stenosis (subocclu-sion) in the distal part\n\nIn this field also, the different methods used to detect the vessel can give some variability in terms of results and in a recent paper a sensitivity of 83% and a specifi city of 98% has been shown in the diagnosis of occluded bypass (Spuentrup et al. ", "2005). ", "Furthermore, no multicenter data are available and no methodolo-cally consistent approach can be proposed. ", "Finally, as for other non invasive techniques, the evaluation of existing bypass has a reduced value \"per se\" unless also the native coronary arteries are evaluated. ", "For these reasons, although the capability of MRA in accurately describing the morphology of bypass has been proven, it can be considered still clinically non suitable.", "\n\n## 9.6 Functional Evaluation of Coronary Arteries and Bypass\n\nThe residual function of the coronary artery can be effectively evaluated measuring the fl ow distal to the stent using phase-contrast velocity quantifi cation at rest and during adenosine-stimulated hyperemia. ", "Using this method and adopting a threshold of 1.2, a sensitivity of 83% with a specifi city of 94% has been achieved for ≥75% stenoses (Nagel et al. ", "2003).", "\n\nFlow velocity and volume fl ow in bypass grafts can be measured by applying velocity-encoded phase contrast cine MRI sequences, thus allowing assessment of graft function in addition to a morphologic evaluation (Sakuma et al. ", "1999; Ishida et al. ", "2001; Kreitner et al. ", "2000; Walpoth et al. ", "1999). ", "Galjee et al. (", "1996) demonstrated that adequate velocity pro-fi les throughout the cardiac cycle could be obtained in 85% of angiographically patent vein grafts, using non-breath-hold MR velocity mapping. ", "Graft fl ow velocity was characterized by a biphasic pattern, with one peak in systole and a second peak in diastole.", "\n\nBreath-hold segmented k-space sequences have been applied to measure fl ow velocity and volume fl ow at rest and after pharmacological stress. ", "A preliminary report by Voigtlander et al. (", "2001) demonstrates the feasibility of measuring the fl ow reserve in bypass grafts and its potential to differentiate between patent and stenotic grafts. ", "In 21 grafts without stenoses compared with 6 grafts with >75% stenoses, a fl ow velocity reserve was found to be 2.6 ± 1.5 vs. 0.8 ± 0.4 (p, 0.005) and a fl ow reserve to be 2.9 ± 1.9 vs. 1.2 ± 0.5 (p, 0.05). ", "Using non-breath-hold and breath-hold techniques, functional results were also obtained in IMA grafts, despite the imaging artifacts due to metallic clips (Voigtlander et al. ", "2001; Debatin et al. ", "1993; Sakuma et al. ", "1996; Kawa d a et al. ", "1999). ", "The diastolic/ systolic peak velocity ratio was found to be higher in IMA grafts than in native IMA (Kawa d a et al. ", "1999). ", "Findings obtained in a small cohort of patients with internal mammary artery grafts by (18 patients without and 5 patients with >75% stenosis) indicate a higher sensitivity and specifi city for the detection of IMA graft stenosis using measurements of the mean fl ow rate and diastolic/systolic peak fl ow ratio at rest, than using the fl ow reserve after administration of dipyridamole (Kawa d a et al. ", "1999).", "\n\n## 9.7 Conclusion\n\nWhile in other aspects of cardiology the use of MRI is nowadays considered an unavoidable step in the diagnostic process, in the field of coronary artery angiography the methodology still suffers unresolved technological limitations and cannot be proposed as a clinical tool to be used systematically for the diagnosis of atherosclerotic coronary artery disease. ", "The current developments are very promising but still they are confi ned within a few research centers. ", "The use of high-field scanners (3T or more) together with sophisticated multichannel surface coils and new acquisition sequences are expected to give a substantial improvement toward this direction. ", "However, at present the only accepted use in the clinical setting is the detection of course anomalies and non atherosclerotic morphological disorders. ", "Limited to this application, coronary MRA is competitive with regards to MDCT (Von Smekal et al. ", "1997). 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Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_10(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 10. ", "Abdominal Aorta and Renal Arteries\n\nVirna Zampa1 , Francesca Turini1, Lorenzo Faggioni1 and Gabriele Caproni1\n\n(1)\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, Pisa, 56100, Italy\n\n10.1 Introduction\n\n10.2 Technical Approaches\n\n10.2.1 CEMRA\n\n10.2.2 Phase Contrast\n\n10.2.3 Perfusion\n\n10.2.4 Balanced Fast Gradient Echo\n\n10.2.5 Arterial Spin Labeling (ASL)\n\n10.3 Clinical Applications\n\n10.3.1 Abdominal Aorta\n\n10.3.1.1 Atherosclerotic and Inflammatory Aneurysms\n\n10.3.1.2 Infected Aneurysm\n\n10.3.1.3 Dissection\n\n10.3.1.4 Aortic Occlusion and Leriche's Syndrome\n\n10.3.1.5 Control of Vascular Stents and Endoleak\n\n10.3.1.6 Retroperitoneal Fibrosis and Erdheim-Chester Disease\n\n10.3.2 Renal Arteries\n\nReferences\n\nAbstract\n\nThe recent advent of newer multidetector computer tomography (MDCT) scanners has dramatically changed the role of magnetic resonance imaging (MRI) in the evaluation of the abdominal aorta and its peripheral branches, due to its faster acquisition times, higher spatial resolution allowing to obtain submillimetric sections with voxel isotropy, greater technical simplicity, wider availability, and lower overall cost. ", "However, lack of ionizing radiation and of intravenous administration of iodinated contrast material remain substantial advantages of MRI over MDCT, that make it the technique of choice for young patients and individuals with high serum creatinine values. ", "Moreover, for the assessment of renal arteries MRI offers not only adequate anatomical detail but, and more importantly, is also able to provide quantitative data relative to renal blood flow, as well as to yield functional information about the parenchymal effect of a vascular stenosis by means of phase contrast and perfusion techniques, respectively. ", "In this particular concern, MRI may be successfully proposed as a novel noninvasive tool for functional evaluation of the kidneys.", "\n\n## 10.1 Introduction\n\nWhile the widespread use of multislice computed tomography (MSCT) has dramatically changed the role of magnetic resonance imaging (MRI) in the assessment of abdominal aorta, the evaluation of renal arteries still remains an important application of MRI.", "\n\nThe higher speed of MSCT, its excellent spatial resolution with the possibility of achieving voxel isotropy, and its wider volume coverage make it more attractive than MRI for studying the abdominal aorta and its pathology, allowing the assessment of peripheral visceral branches with greater accuracy than contrast-enhanced MR angiography (CEMRA). ", "This is particularly true for preinterventional evaluation of aortic aneurysms, in which morphological data must be extremely accurate and the depiction of cal-cified plaques of the aortic wall is a crucial diagnostic element. ", "Therefore CT angiography (CTA) has taken over the prime role in imaging of the abdominal aorta, while CEMRA has become a second-choice imaging modality in this clinical setting. ", "Nevertheless, the lack of radiation and of administration of iodi-nated contrast agent associated with MRA make it the technique of choice for young patients and individuals with high serum creatinine values (Bockler et al. ", "2007; Shih and Hagspiel 2007).", "\n\nConversely, for the assessment of renal arteries MRI offers not only acceptable anatomical details of vessels but, and more importantly, is also able to provide quantitative data relative to renal flow and is able to assess the parenchymal effect of a vessel stenosis by means of phase contrast and perfusion techniques. ", "The feature of functional assessment of the kidneys makes MRI preferable to CT.", "\n\n## 10.2 Technical Approaches\n\n### 10.2.1 CEMRA\n\nCEMRA still represents the elective, widely used technique for studying the aorta and its main branches, providing images with high diagnostic value.", "\n\nTechnical advances, such as parallel imaging and k-space sharing methods (time-resolved imaging of contrast kinetics, or TRICKS), have allowed a further increase in the spatial and temporal resolution of the technique.", "\n\nWhen studying the aorta or the renal arteries, images are acquired on the coronal plane and CEMRA is usually associated with fat saturation to increase vessel conspicuity and to avoid the problems connected with image subtraction, such as imperfect overlap between unenhanced and contrast-enhanced series caused by patient motion.", "\n\nProper bolus timing is crucial for obtaining high quality CEMRA images, as it is essential to synchronize the sampling of the centre of the k-space (which retains information about contrast resolution) with the peak intravascular concentration of gadolinium. ", "Indeed, too early sampling of the k-space centre leads to poor enhancement of the vascular lumen and ringing artefacts (also called the Maki effect), while a late acquisition will result in suboptimal arterial enhancement with venous overlap. ", "Therefore, contrast material administration for CEMRA now relies on the test bolus technique or real-time bolus detection tools (such as fluoroscopic triggering or automatic signal intensity detection system [Smart Prep]).", "\n\nContrast material is usually administered at a flow-rate of 2 mL/s by means of an automatic power injector, which provides more precise control over injection parameters compared to manual injection.", "\n\nThe sampling scheme of the k-space also plays an important role in maximizing contrast resolution while reducing imaging time, thereby optimizing usage of contrast material. ", "This goal is accomplished by using centric or elliptical k-space filling schemes, in which the centre of the k-space is sampled at the beginning of the acquisition, corresponding to the peak intravascular concentration of contrast material.", "\n\nCurrently, the adoption of 3 T MR equipment is increasing and angiographic exams will especially benefit directly from the higher field strength. ", "The theoretically doubled signal-to-noise ratio at 3 T allows for abdominal MRA exams with sub-millimetre spatial resolution and very short acquisition time. ", "Furthermore, as longitudinal relaxation time is longer at 3 T compared with lower field strength, MRA exams can be performed with a significantly reduced amount of contrast material (Michaely et al. ", "2007).", "\n\n### 10.2.2 Phase Contrast\n\nThe information provided by CEMRA can be further enriched by Phase-Contrast (PC) technique.", "\n\nPC exploits the spin-induced phase shift to differentiate flowing blood from stationary tissue. ", "Based on the phase accumulation of the spins, it is possible to calculate the speed of spins and flow direction. ", "For PC-MRA, signal intensity reflects the absolute velocity of voxels, and it is always positive and independent from the direction of flow.", "\n\nThe three-dimensional (3D) PC-MRA has the advantage of high sensitivity to turbulent flow that can be associated with vascular stenoses. ", "It is mainly used to study renal vessels, because it immediately reveals the hemodynamic significance of a stenosis caused by the flow dropout related to turbulent flow.", "\n\nThe bidimensional (2D) no-breath cine PC technique has been used to calculate the flow value obtaining flow curves. ", "The limited spatial and temporal resolution of the cine PC technique has been overcome by the fast implementation of the sequence with k-space segmentation, in which more phase encodings per cardiac cycle (views per segment) are acquired. ", "This sequence is performed on breath-hold on a plane perpendicular to the target vessel. ", "Images are reconstructed on an independent workstation by means of automatic detection of the area of the vessel under investigation, thus obtaining graphs that display the velocity and the flow as a function of time.", "\n\nPC sequences are a useful complement to MRA morphological data in assessing the hemodynamic significance of a stenosis.", "\n\n### 10.2.3 Perfusion\n\nThe perfusion technique has been widely used for studying different anatomical districts, especially the heart and the brain. ", "Nowadays, its application has been extended to other anatomical districts, with a high interest in evaluating renal function.", "\n\nIn the literature, different technological approaches have been proposed; an important technical requirement is high spatial and temporal resolution. ", "In particular, a temporal resolution of one acquisition per second is recommended for detecting the first pass of contrast material.", "\n\nPerfusional images have to be analyzed by dedicated software aimed at providing quantitative data.", "\n\n### 10.2.4 Balanced Fast Gradient Echo\n\n[Steady state free precession (SSFP) -- FIESTA -- true FISP]\n\nBalanced SSFP sequences have enjoyed a recent resurgence of interest across a wide range of applications. ", "The technique can be used for angiographic studies because image contrast is determined by the T2/T1 ratio, yielding bright-blood imaging without reliance on inflow.", "\n\nSome limitations are the susceptibility to field inhomogeneities, such as at air-tissue interfaces or in the presence of metallic implants; moreover, the sequence is not specific for arteries or veins.", "\n\n### 10.2.5 Arterial Spin Labeling (ASL)\n\nThe ASL technique relies on the replacement of blood in the imaging volume with tagged blood. ", "Protons are \"tagged\" as they experience an inversion pulse in a target region, typically in a blood vessel upstream of the imaging field of view. ", "After a fixed interval or delay time, when tagged protons enter the field of view, imaging is performed. ", "The time delay depends on the distance between tagged and imaged areas and the rate of blood flow. ", "This process is repeated, with alternate acquisition of tagged and untagged images, and the two sets are then subtracted from each other, thus resulting in a bright-blood angio-gram with no background signal.", "\n\nThe combination of ASL with tagged and untagged balanced SSFP provides bright-blood, venous-free angiographic images with high signal-to-noise ratio. ", "This approach is particularly well suited to evaluating renal vessels, because the sequence is flow-compensated in all three spatial directions and, therefore, the complex orientation of the aorta, as relative to the renal arteries, can be well depicted.", "\n\nBecause the ASL technique is based on continuous refilling of blood in the imaging volume, the method requires reasonably high arterial velocity to be successful (Miyazaki and Lee 2008).", "\n\n## 10.3 Clinical Applications\n\n### 10.3.1 Abdominal Aorta\n\n#### 10.3.1.1 Atherosclerotic and Inflammatory Aneurysms\n\nMost aneurysms in the abdominal aorta are atherosclerotic and are usually located below the origin of renal arteries. ", "They usually have a fusiform shape and, in rare cases, a saccular morphology.", "\n\nThe radiological findings of a vessel aneurysm are well-known and crucial for a correct presurgical evaluation. ", "This requires the exact measurement of the maximum diameter of the aneurysm and of its superior neck, the precise definition of its longitudinal extension, the caliber of the patent lumen in case of throm-botic wall deposit, the spatial relationship with the renal and visceral arteries, as well as the evaluation of iliac vessels. ", "These measurements must be taken along the plane perpendicular to the vessel's greater axis.", "\n\nIn addition, evidence of rupture, complications of the aortic wall, supernumerary renal arteries, obstructive disease of renal, celiac, or mesenteric vessels, or an anatomical anomaly (such as a horseshoe kidney) may significantly modify the surgical plan (Ho and Corse 2003). ", "MIP and MPR reconstructions are particularly helpful for the identification of stenotic branch vessels, which should preferably be revascularized at the time of the aortic aneurysm repair (Fig. ", "10.1).", "\n\nFig. ", "10.1.", "\n\nAortic aneurysm. ", "The MIP coronal reconstruction shows an infrarenal aortic aneurysm as well as stenoses of both the renal arteries and diffuse atherosclerosis of the iliac arteries\n\nGadolinium-enhanced 3D MRA has been shown to be accurate for the detection of significant occlusive celiac, renal, mesenteric, or iliac arterial disease (94% sensitivity and 98% specificity) (Ho and Corse 2003). ", "The critical diagnostic point is represented by the assessment of the presence and extension of wall calcification that requires a CT exam, since this element may condition the therapeutic choice. ", "Calcification can actually hinder clamping and suturing and impair the mechanical support to be provided to an endoprosthesis.", "\n\nIn view of a percutaneous treatment with endo-prosthesis placement, the overall evaluation of the iliac-femoral vessels is required, since tortuous courses or stenoses may jeopardize the technical outcome of the procedure.", "\n\nFive to twenty-three percent of all aneurysms of the abdominal aorta are inflammatory. ", "By the term \"inflammatory\" we refer to several histopathological findings: thickening and fragmentation of the elastic lamina, loss of smooth muscle cells from the media, presence of dense neovascularized connective tissue surrounding the aortic wall and seeping of lymphocytes, plasma cells, and histiocytes; furthermore, there may be adherences to visceral organs (duodenum, ureters) (Nitecki et al. ", "1996).", "\n\nIn MR images, the aneurysmatic inflammatory reaction can be recognized by high signal intensity on T2-weighted images, which can be better appreciated with fat suppression, and by marked enhancement following the administration of a contrast agent (Fig. ", "10.2).", "\n\nFig. ", "10.2.", "\n\nInflammatory aortic aneurysm with the typical feature of periaortic tissue showing contrast enhancement on gadolinium-enhanced LAVA images on the sagittal and axial planes (a, b)\n\n#### 10.3.1.2 Infected Aneurysm\n\nAn infected or mycotic aneurysm is defined as an infectious break in the wall of an artery with the formation of a blind, saccular outpouching that is contiguous with the arterial lumen (Kaufman et al. ", "1978) and usually occurs in portions of the aorta that are not commonly affected by atherosclerosis.", "\n\nEarly changes of aortitis preceding aneurysm formation include an irregular arterial wall, periaortic edema, periaortic soft-tissue mass, and periaortic gas.", "\n\nOn MRI, periaortic edema is characterized by high signal intensity on T2-weighted images that are better appreciable when fat saturation is applied. ", "Concentric or eccentric periaortic inflammatory soft-tissue may develop and usually exhibits uniform enhancement (Lee et al. ", "2008).", "\n\nNecrosis may develop from the inflammatory mass and shows heterogeneous signal intensity on MRI, together with a rim of poor enhancement after administration of contrast material. ", "Periaortic mass or stranding is the most common imaging finding with infected aortic aneurysms and is found in 48% of cases (Macedo et al. ", "2004), while periaortic gas is an uncommon feature.", "\n\nLack of or delayed treatment of infected aneurysms may lead to fulminant sepsis, spontaneous arterial rupture, and death. ", "Early detection of infected aneu-rysms is critical for timely treatment aimed at optimizing patient outcome (Lee et al. ", "2008).", "\n\n#### 10.3.1.3 Dissection\n\nDissections arise much more frequently in the thoracic aorta and often extend inferiorly into the abdominal aorta involving the renal, celiac, mesen-teric, and iliac arteries. ", "The main concern with dissections is the involvement of visceral branch vessels, which may result in their obstruction.", "\n\nCEMRA can display the extent of the dissection and the involvement of branch vessels with exquisite clarity. ", "At least two delayed phase contrast-enhanced acquisitions are advisable to guarantee optimal visualization of the false channel, where blood flow is much slower than in the true lumen (Mcguigan 2005).", "\n\nMPR of the 3D datasets enables selective view of individual aortic branch vessels and the identification of their blood supply (i.e., true vs. false channel). ", "The extension of an intimal tear into the abdominal aorta typically spirals posterior laterally about the arch with the false channel coursing to the left of the aorta, potentially to involve the left renal artery and possibly the celiac and superior mesenteric arteries. ", "Delayed-phase imaging is recommended because the flow within the false channel may be slow and not adequately mixed with contrast medium during the initial acquisition (Ho and Corse 2003).", "\n\n#### 10.3.1.4 Aortic Occlusion and Leriche's Syndrome\n\nAbdominal aortic occlusion may occur as a result of several causes, but in the acute setting, it most commonly results from embolism. ", "Thrombosis superimposed on severe atherosclerotic involvement of the distal abdominal aorta and common iliac arteries is the main cause of chronic occlusion. ", "Chronic occlusion may produce Leriche's syndrome, which refers to the clinical syndrome that results from occlusion of the infrarenal aorta. ", "The syndrome is characterized by the absence of femoral pulses, gluteal claudication, impotence, and, when symptoms persist over time, by hypotrophy of the muscular masses of the lower limbs.", "\n\nInvariably, patients with chronic occlusion develop a rich collateral circulation.", "\n\nIn these individuals arterial access is limited and CEMRA is sufficient for the primary assessment of the occlusion (Ho and Corse 2003).", "\n\n#### 10.3.1.5 Control of Vascular Stents and Endoleak\n\nThe degree of safety and reliability of CEMRA in evaluating the positioning of aortic prostheses has been demonstrated since the introduction of pros-theses made of MR-compatible materials. ", "Stents made of nitinol are generally more suitable for MR imaging; elgiloy stents may obscure the lumen, and stainless steel stents cause extensive artefacts that render the study nondiagnostic (Stavropoulos and Charagundla 2007). ", "In several studies involving small numbers of patients with predominantly nitinol stents, MRA was at least as sensitive as CTA, and in some cases, highlighted endoleaks that were not detected by CTA.", "\n\nThe protocol for the MRI study of prostheses and stents positioned at the level of the abdominal aorta requires the use of axial sequences performed before and after administration of contrast material. ", "Such a procedure allows the evaluation of retroperitoneal peri-aortic tissues, and the correct diagnostic assessment of potential complications (such as periprosthesic hematoma, abscess, thrombosis, or pseudoaneurysm). ", "CEMRA examinations feature high sensitivity as required for the evaluation of graft patency and for the detection of prosthetic deformation. ", "In addition, they can provide a complete visualization of the entire aorto-iliac axes and their collaterals (Fig. ", "10.3). ", "CEMRA is also accurate in the depiction of endoleaks, and new techniques, such as time-resolved MR angio-graphy, may allow a better characterization of the endoleak type by demonstrating the gradual passage of contrast material into the aneurysm sac, analogous to a conventional angiogram (Stavropoulos and Charagundla 2007). ", "Moreover, the availability of blood pool contrast media has opened new perspectives for studying endoleaks; in particular, type IV endoleaks, which are caused by stent-graft porosity and may take advantage of blood pool contrast media. ", "By using such contrast agents, which remain intravascularly longer than ordinary intravascular-interstitial contrast agents, the temporal window between contrast medium injection and imaging can be extended. ", "Such a long delay allows the accumulation of a higher amount of contrast material in the endoleak while maintaining adequate contrast resolution between the blood and the surrounding tissues (Cornelissen et al. ", "2008).", "\n\nFig. ", "10.3.", "\n\n(a, b) Obstruction of left iliac branch of aorto-bisiliac prosthesis, as depicted from CEMRA images (MIP reconstructions). ", "Notice the presence of retroperitoneal and inferior epigastric collateral pathways\n\n#### 10.3.1.6 Retroperitoneal Fibrosis and Erdheim-Chester Disease\n\nRetroperitoneal fibrosis is characterized by a proliferation of fibrous tissue extending along the aorta through a plaque-like infiltrative soft-tissue process that is typically localized to the distal abdominal (infrarenal) aorta and the common iliac arteries; involvement of the pelvis is uncommon. ", "About two-thirds of cases are idiopathic.", "\n\nThis entity may be considered as an isolated disease or as part of a systemic syndrome known as multifocal fibrosclerosis, which may also include autoimmune pancreatitis, sclerosing cholangitis, scleroderma, Riedel thyroiditis, fibrotic pseudotumor of the orbit, and fibrosis involving multiple organ systems. ", "Typical imaging manifestations of perirenal fibrosis include a soft-tissue mass that envelops the kidneys without displacing them.", "\n\nThree stages of the disease have been described, ranging from chronic active inflammation to fibrous scarring. ", "On MRI signal intensity on T2-weighted images and contrast enhancement on dynamic acquisitions depend on the disease stage. ", "While areas affected by active inflammation demonstrate high signal intensity on T2-weighted images and early contrast enhancement, areas of fibrosis show low signal intensity on T2-weighted images and delayed contrast enhancement.", "\n\nErdheim-Chester disease is a rare form of systemic non-Langerhans cell histiocy tosis of unknow n etiology. ", "Histologically, this disease is defined by a mononuclear infiltrate consisting of lipid-laden, foamy histiocytes. ", "It affects middle-aged individuals without any specific sex predilection; lower extremity bone pain is a typical symptom.", "\n\nRetroperitoneal involvement has been noted in approximately a third of patients. ", "The fibrotic involvement of the retroperitoneum demonstrates decreased signal intensity in T1-weighted, T2-weighted, fast inversion recovery, gradient-echo chemical shift in-phase/out-of-phase, and gadolinium-enhanced T1-weighted images (Fig. ", "10.4) (Gottlieb and Chen 2002).", "\n\nFig. ", "10.4.", "\n\nErdheim-Chester disease: (a) coronal FIESTA image shows periaortic tissue with low signal intensity. (", "b) Axial FSE T2-weighted image shows the typical perirenal low band. ", "Also notice periaortic tissue surrounding the aorta\n\nPerirenal involvement in Erdheim-Chester disease is characteristic and shows as rind-like soft-tissue lesions surrounding the kidneys and ureters (Murray et al. ", "2001). ", "Severe compression of the renal parenchyma and ureters as a consequence of fibrous perinephritis may lead to progressive renal failure (Surabhi et al. ", "2008).", "\n\nSkeletal involvement, characterized by symmetric sclerosis of the meta- and diaphyses of long tubular bones, is a typical sign. ", "Other extraskeletal manifestations, including central nervous system, lungs, skin, and heart involvement, are seen in about half of patients (Surabhi et al. ", "2008).", "\n\n### 10.3.2 Renal Arteries\n\nRenal artery stenosis (RAS) frequently manifests clinically as systemic hypertension (70%), which can often be reversed by renal revascularization using balloon angioplasty, stenting, or vascular surgery. ", "Patients with RAS may progress to end-stage renal disease if left untreated (Ho and Corse 2003).", "\n\nAtherosclerotic disease is the most common pathologic condition of RAS, which typically involves the ostium or the proximal 1-2 cm of the renal arteries, and usually also affects the abdominal aorta. ", "Fibro-muscular dysplasia is the second most common cause of RAS. ", "This condition typically involves the distal two-thirds of the main renal artery with bead-like stenosis alternating with small fusiform or saccular aneurysms (Fig. ", "10.5).", "\n\nFig. ", "10.5.", "\n\nMaximum Intensity Projection (MIP) reconstruction shows involvement of the middle tract of the left renal artery and a small aneurysm, both typical signs of fibro-muscular dysplasia\n\nLike atherosclerotic RAS, fibromuscular dysplasia may result in reversible systemic hypertension. ", "Patients with fibromuscular dysplasia, however, are more typically young women, whereas atherosclerosis tends to occur in older men.", "\n\nThe preoperative identification of RAS is important and may augment or change the surgical plan (Ho and Corse 2003).", "\n\nThe MRI protocol for the examination of the renal arteries includes the 3D PC and 3D CEMRA techniques. ", "The first sequence gives diagnostic elements relative to the hemodynamic significance of a stenosis, while the second one is useful for morphological depiction and grading of vessel stenosis.", "\n\nThe MRA assessment of hemodynamic signifi-cance of RAS can be further refined by considering additional factors, such as arterial stop of signal, post-stenotic dilatation, delayed renal enhancement, and functional changes in the renal parenchyma (i.e., reduced kidney longitudinal length and paren-chymal thickness, and loss of corticomedullary differentiation).", "\n\nA precise evaluation of the degree of stenosis requires the use of dedicated software.", "\n\n3D PC images are acquired in the axial plane, with the slab positioned on a coronal plane to cover the renal arteries. ", "An inferior saturation band is applied to null signal from the venous flow.", "\n\nOn PC MRA, spin dephasing is invariably present in hemodynamically significant RAS (Ho and Corse 2003).", "\n\nAs with digital angiography, CEMRA is a lumi-nography, and as such provides exclusively morphological information. ", "Data from the literature indicate that CEMRA has 97% sensitivity and 93% specificity in the grading of RAS. ", "However, CEMRA alone has a tendency to overestimate stenosis, as has been documented in several other vascular districts. ", "This overestimation is caused by the limited spatial resolution of CEMRA as compared to digital angiogra-phy (which remains the diagnostic gold standard), as well as by artefacts related to bad contrast bolus timing (blurring and ringing artifacts), and an intra-voxel dephasing component that, albeit to a lesser extent than for PC sequences, also affects CEMRA (Fig. ", "10.6).", "\n\nFig. ", "10.6.", "\n\nRAS depicted with CEMRA. (", "a) Severe stenosis with post-stenotic dilation of right renal artery, and severe stenosis of the left renal artery. (", "b) Severe stenosis of the left renal artery overestimated because of the intravoxel dephasing. ", "Both dephasing and post-stenotic dilation are indicative of severe, hemodynamically significant vascular stenosis\n\nCEMRA images are usually acquired on a coronal plane in order to minimize acquisition time by reducing the number of phase encoding steps. ", "Usage of a phased array body coil with a wide cranio-caudal coverage (such as a torso or a cardiac coil) is recommended so as to ensure adequate panoramicity, potentially allowing to assess accessory renal arteries stemming from the distal aorta or the iliac arteries, as well as to keep imaging time down to a reasonable level. ", "The CEMRA acquisition is carried out in a single breath-hold with a high matrix in slice and frequency direction, with at least 160 phase-encoded steps as a compromise between sufficiently short imaging time and adequate spatial resolution. ", "A slice thickness of usually 2-3 mm with partial overlap (typically 50%) yields good spatial resolution while maintaining adequate signal-to-noise ratio and acquisition time. ", "The k-space is usually sampled with a centric filling scheme.", "\n\nIn addition, MRI-based flow measurements can be performed to evaluate the hemodynamic signifi-cance of RAS. ", "The new ultrafast ECG-triggered PC sequence is able to provide quantitative measurements of the renal flow for each renal artery by calculating renal blood flow as a function of time (Fig. ", "10.6). ", "For the assessment of the renal artery, the acquisition plane is placed 1 cm past the ostium or downstream of a stenosis; the calculation of the flow value is obtained by multiplying the average velocity by the vessel surface area. ", "In this respect, it is noteworthy that the renal volume and flow ratio seem to have a prognostic value in predicting the outcome of angiographic percutaneous procedures.", "\n\nOne of the most recent and promising implementations of MRI for functional evaluation of the kidneys is MR perfusion imaging (PWI). ", "Its applications include the evaluation of segmental RAS, the assessment of in-stent restenosis, or the detection of paren-chymal disease in the absence of RAS.", "\n\nImaging is performed in the oblique coronal plane, with a coverage including the abdominal aorta and both kidneys. ", "Signal intensity (SI)-time curves can be obtained from a region of interest over the renal cortex, consisting of two parts that represent the first pass of the contrast agent through the renal circulation and its excretion phase, respectively. ", "A normal SI-curve is characterized by three distinct morphological features: a steep upslope, an early SI peak, and a slow signal decline.", "\n\nA gamma-variate fit is required to take interstitial dispersion of contrast material into account when an intravascular-interstitial contrast agent is used, as usual in clinical practice. ", "The gamma-vari-ate function has useful analytical properties that allow to derive semiquantitative perfusion parameters from signal intensity-time curves, such as time to peak (TTP), mean transit time (MTT), maximum upslope (MUS), and maximum signal intensity (MSI). ", "It has been shown that a modification of these parameters reflects an alteration of renal perfusion, such as in patients with hemodynamically signifi-cant RAS. ", "For instance, in patients with hemody-namically significant RAS an increase of TTP and MTT occurs (indicating that longer time is needed for the contrast bolus to pass through the renal vas-culature), together with lower MUS and MSI values (which reflect decreased parenchymal perfusion). ", "This results in an altered shape of the perfusion curve in high grade RAS, characterized by a slower upslope, flattened peak, and delayed signal decay (Fig. ", "10.7).", "\n\nFig. ", "10.7.", "\n\nOn CEMRA MIP (a) a severe stenosis of the right renal artery. ", "Flow analysis of renal arteries with ECG-gated PC technique reveals a substantial decrease of flow values (89 mL/min, normal >350 mL/min) of the right renal artery compared with the left one (568 mL/min) (b). ", "Note the different morphology of the curves (c) of renal perfusion as well as the values of quantitative perfusion parameters (increased MTT and reduced MUS and MSI at the stenosis site) reported on the right top of the graphs (c1) right renal artery (c2) left renal artery\n\nReferences\n\nBockler D, Hylik-Durr A, von Tengg-Kobligk H, et al. (", "2007) Clinical requirements of aortic imaging. ", "Radiologe 47(11):962-973CrossRefPubMed\n\nCornelissen SA, Verhagen HJ, Prokop M, et al. (", "2008) Visualizing type IV endoleak using magnetic resonance imaging with a blood pool contrast agent). ", "J Vasc Surg 47(4):861-864CrossRefPubMed\n\nGottlieb R, Chen A (2002) Pictorial essay MR findings of Erdheim-Chester disease. ", "J Comput Assist Tomogr 26(2):257-261CrossRefPubMed\n\nHo VB, Corse WR (2003) MR angiography of the abdominal aorta and peripheral vessels. ", "Radiol Clin N Am 41(1):115-144CrossRef00062-3)PubMed\n\nKaufman SL, White RI Jr, Harrington DP, et al. (", "1978) Protean manifestations of mycotic aneurysms. ", "AJR Am J Roentgenol 131(6):1019-1025PubMed\n\nLee WK, Mossop PJ, Little AF, et al. (", "2008) Infected (mycotic) aneurysms: spectrum of imaging appearances and management. ", "Radiographics 28(7):1853-1868CrossRefPubMed\n\nMacedo TA, Stanson AW, Oderich GS, et al. (", "2004) Infected aortic aneurysms: imaging findings. ", "Radiology 231(1):250- 257. ", "Erratum in: Radiology 2006;238(3):1078CrossRefPubMed\n\nMcGuigan EA, Sears ST, Corse WR, et al. (", "2005) MR angiogra-phy of the abdominal aorta. ", "Magn Reson Imaging Clin N Am 13(1):65-89CrossRefPubMed\n\nMichaely HJ, Attenberger UI, Kramer H, et al. (", "2007) Abdominal and pelvic MR angiography. ", "Magn Reson Imaging Clin N Am 15(3):301-314CrossRefPubMed\n\nMiyazaki M, Lee VS (2008) Nonenhanced MR angiography. ", "Radiology 248(1):20-43CrossRefPubMed\n\nMurray D, Marshall M, England E, et al. (", "2001) Erdheim-Chester disease. ", "Clin Radiol 56:481-484CrossRefPubMed\n\nNitecki SS, Hallet JW Jr, Stanson AW, et al. (", "1996) Inflammatory abdominal aortic aneurisms: a casa control study. ", "J Vasc Surg 23:860-868CrossRef70249-5)PubMed\n\nShih MC, Hagspiel KD (2007) CTA and MRA in mesenteric ischemia: part 1, Role in diagnosis and differential diagnosis. ", "AJR 188(2):452-461CrossRefPubMed\n\nStavropoulos SW, Charagundla SR (2007) Imaging techniques for detection and management of endoleaks after endovascular aortic aneurysm repair. ", "Radiology 243(3):641-655CrossRefPubMed\n\nSurabhi VR, Menis C, Prasad SR, et al. (", "2008) Neoplastic and non-neoplastic proliferative disorders of the perirenal space: cross-sectional imaging findings. ", "Radiographics 28(4):1005-1017CrossRefPubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_11(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 11. ", "Peripheral Vessels\n\nFrancesco De Cobelli1 , Elena Belloni1 and Alessandro Del Maschio1\n\n(1)\n\nRadiology Department, Vita-Salute University, San Raffaele Scientific Institute, Via Olgettina, 60, Milan, 20132, Italy\n\n11.1 Introduction\n\n11.2 Lower Limb\n\n11.2.1 Steno-Occlusive Disease\n\n11.2.1.1 Leriche's Syndrome\n\n11.2.2 Aneurysms\n\n11.2.2.1 Popliteal Aneurysms\n\n11.2.2.2 Femoral Aneurysms\n\n11.2.3 Popliteal Entrapment\n\n11.3 Upper Limb\n\n11.3.1 Steno-Occlusive Disease\n\n11.3.1.1 Subclavian Steal Syndrome\n\n11.3.2 Aneurysms\n\n11.3.2.1 Subclavian Aneurysms\n\n11.3.3 Takayasu's Arteritis\n\n11.3.4 Thoracic Outlet Syndrome\n\nReferences\n\nAbstract\n\nMagnetic resonance angiography (MRA) has become a fundamental imaging modality in the assessment of peripheral arterial disease. ", "Three-dimensional contrast-enhanced MRA (3D CE-MRA) provides a luminographic study of the arteries, which resembles digital subtraction angiography (DSA). ", "In the literature, 3D CE-MRA has been compared to DSA, which is the standard of reference, and it has shown its superiority in terms of sensitivity and specificity. ", "For this reason and for its high accuracy, nowadays, 3D CE-MRA represents the preferred technique for MRA of the peripheral vessels. ", "The chapter will focus on the clinical applications of MRA in the evaluation of arterial disease of upper and lower limbs, with particular attention on the steno-occlusive disease and on aneurysms. ", "Specific topics will also be addressed, which are the popliteal entrapment, the Takayasu's arteritis, and the thoracic outlet syndrome. ", "The recent introduction of the blood pool contrast agents in the clinical routine will also be discussed.", "\n\n## 11.1 Introduction\n\nIn recent years, because of significant technical advances, magnetic resonance angiography (MRA) has become a fundamental imaging modality in the assessment of peripheral arterial disease. ", "Among non-contrast-enhanced MRA sequences, phase contrast angiography has been progressively dropped for peripheral vascular studies, while time-of-flight (TOF) angiography has still some specific clinical applications in the distal runoff vessels (Ho et al. ", "1997; Mcdermott et al. ", "1995; Unger et al. ", "1995). \"", "Black blood\" sequences are spin-echo derived sequences, which allow a better depiction of mural or intralumi-nal abnormalities, such as thickening of walls, thrombi, atherosclerotic plaques, penetrating atherosclerotic ulcers, and intramural hematomas. ", "In fact, the signal produced by flowing blood is intentionally suppressed and this allows an excellent delineation of the vessel wall (Dellegrottaglie et al. ", "2007; Tatli et al. ", "2003). ", "Three-dimensional contrast-enhanced MRA (3D CE-MRA) provides a luminographic study of the arteries, which resembles digital subtraction angiography (DSA). ", "For the first time, 3D CE-MRA was described by Prince et al. (", "1993) and nowadays it represents the preferred technique for MRA of the peripheral vessels (Ho et al. ", "1999). ", "In fact, 3D CE-MRA is highly accurate in the assessment of limbs arteries, as demonstrated in a large meta-analysis performed for lower extremity vasculature. ", "In the same article, 3D CE-MRA proved to offer a better diagnostic performance compared to that offered by two-dimensional MRA (2D MRA), with higher sensitivity and specificity (Koelemay et al. ", "2001). ", "Moreover, 3D CE-MRA has been compared to DSA and again it showed its superiority also because of the possibility of extensive postprocessing of the images (Loewe et al. ", "2004; Vavrik et al. ", "2004; Winterer et al. ", "2002; Wytten bach et al. ", "2003). ", "Duplex ultrasound (DUS) may play a role for a fast, widely available and less expensive evaluation of the peripheral vessels, but its use is limited to specific clinical settings and selected vessels because the technique cannot guarantee the panoramic assessment of long segments of vas-culature, as DSA and CE-MRA do. ", "Moreover, CE-MRA is more sensitive and specific for the diagnosis and pre-surgical assessment in patients with peripheral arterial occlusive disease (Visser and Hunink 2000; Gjonnaess et al. ", "2006; Leiner et al. ", "2005). ", "The chapter will focus on the clinical applications of MRA in the evaluation of upper and lower limb arterial disease, with particular attention on the latter. ", "The recent introduction of the blood pool contrast agents in the clinical routine will also be discussed.", "\n\n## 11.2 Lower Limb\n\nAssessment of the lower limb arterial disease with CE-MRA requires the representation of long segments of vessels, from the abdomen to the ankle, whose lumen is enhanced by a gadolinium-based contrast agent: for this reason, the contrast agent bolus should be rapidly followed distally. ", "This is obtained by means of a fast field-echo (FFE) T1-weighted 3D coronal sequence, which requires state-of-the-art 1.5 T scanners with high performance gradients providing very short TEs and TRs for dynamic acquisition (Ersoy and Rybicki 2008). ", "MRA of peripheral vessels requires the imaging of 3-4 stations: aorto-iliac, thigh, calf and foot, depending on the patient's height. ", "The introduction of the \"moving-table\" technology allowed the chasing of a single bolus of contrast agent in its distal progression (Carriero et al. ", "2002; Ho et al. ", "1998; Meaney et al. ", "1999). ", "The patient is placed in the magnet, feet first, making sure that all the vascular structures to be examined are in the same anterior-posterior level. ", "Scout and mask images (before contrast administration) are acquired for three locations, typically the pelvis, the thigh and the calf; low resolution TOF images can also be added for optimal planning. ", "Usually, 0.2 mmol/kg of a gadolinium-based contrast agent is administered with an automatic injector, with a flow rate of 0.8 mL/s, followed by 20 mL of saline flush with a flow rate of 1.5 mL/s. The slow flow rates allow to obtain a \"long\" bolus which enhances the vascular structures for a longer period of time. ", "Immediately after the injection starts, a fast, low resolution coronal T1-weighted sequence is performed repeatedly to visualize the influx of the contrast in the iliac arteries. ", "As soon as the contrast enhancement is visible in the iliac arteries, the standard FFE T1-weighted 3D diagnostic imaging is acquired, first of all on the aorto-iliac region; then the table moves automatically and thigh imaging is performed; finally the table again moves and the calf imaging is obtained. ", "The table moves at a speed rate of 10 cm/s. Another method to obtain an optimal timing of the imaging, after contrast infusion, is to estimate the contrast agent travel time with the \"test-bolus\" technique (Dellegrottaglie et al. ", "2007; Earls et al. ", "1996). ", "A small amount of contrast (1-2 mL) and 20 mL of saline solution are injected at the same flow rate, which will be used for the diagnostic imaging and a fast, low resolution coronal T1-weighted sequence is performed repeatedly to visualize the influx of the contrast in the arteries of interest and to choose the best acquisition time for the following diagnostic imaging with the proper amount of contrast agent. ", "Imaging of the lower limb arterial vasculature can be performed either with the combined use of a body coil and a surface coil, or with a dedicated lower extremity reception coil. ", "The latter has been introduced recently in the clinical practice and it allows to obtain an optimized, more homogeneous signal reception. ", "It is also characterized by a higher signal-to-noise ratio than the body coil and this in turn can be exploited to provide higher resolution images, to shorten the acquisition time or to increase the anatomic coverage (Huber et al. ", "2003; Leiner et al. ", "2004). ", "Even if the \"moving-table\" technique is robust and accurate, some problems can be associated with multiple stations imaging. ", "The nonlinearity of gradients can be associated with distortions of the images, no standard protocols can be applied to all scanners, venous superimposition in the calf can lead to suboptimal imaging, and finally the imaging is not isotro-pic and there is the tendency towards overestimation of the stenosis. ", "However, 3D MRA is considered an accurate, sensitive and specific imaging technique for the assessment of lower extremity vascular disease, when compared to DSA and 2D MRA (Deutschmann et al. ", "2006; Ho et al. ", "1998; Koelemay et al. ", "2001; Lapeyre et al. ", "2005; Meaney et al. ", "1999; Winterer et al. ", "2002). ", "A new contrast agent has been introduced in the clinical use since 2005: Vasovist® (Gadofosveset, Bayer Schering Pharma, Germany) is the first intra-vascular contrast agent approved for the use in CE-MRA in Europe. ", "Vasovist® is a small-molecule gadolinium-based contrast agent which binds revers-ibly to the albumin in the human plasma and provides extended vascular enhancement compared to conventional extracellular contrast agents. ", "In fact, its main characteristic is a 5-7 times higher relaxivity at 1.5 T if compared, for example, to Magnevist® (GD-DTPA, Bayer Schering Pharma, Germany) (Lauffer et al. ", "1998). ", "The administered dose of Vasovist® is lower than that of the conventional contrast agents: in fact, 0.03 mmol/kg is the standard to obtain good quality diagnostic images, as stated in the preliminary studies that recently appeared in the literature (Goyen et al. ", "2005; Vogt et al. ", "2007). ", "After the injection of Vasovist®, two acquisition phases can be distinguished. ", "The arterial first-pass acquisition is similar to the conventional arterial angiograms obtained with extracellular contrast agents. ", "Following this dynamic phase, the intravascular contrast agent distributes to all the body vasculature, both arterial and venous, and reaches an equilibrium phase in about 5 min. ", "In this steady-state phase, high spatial resolution images can be obtained, as lower extremities can be imaged for several minutes: in fact, Vasovist® has a half-life of about 15 h and allows to obtain a good signal-to-noise ratio for about 1 h after intravenous administration (Nikolaou et al. ", "2006). ", "However, some limitations exist for steady-state imaging of lower extremities. ", "First of all, the venous overlay may be a potential diagnostic problem, because in lower limbs the venous vascular structures are in close vicinity to arterial vascular structures. ", "Moreover, because of long imaging times, limb movement can occur, with well-evident motion artefacts. ", "Finally, the patient can experience some discomfort as a result of the prolonged permanence in the magnet bore (Nikolaou 2006). ", "For these reasons, at the present time steady-state imaging of lower limb vas-culature with Vasovist® is not considered a routine clinical application.", "\n\n### 11.2.1 Steno-Occlusive Disease\n\nAtherosclerosis is a systemic disease affecting the arterial bed of the body and represents the leading cause of steno-occlusive arterial disease in the population older than 40 years of age. ", "In particular, the vas-culature of the lower extremities is a frequent target of the atherosclerotic disease (Wasser 2003). ", "Clinical manifestation of peripheral arterial occlusive disease (PAOD) is either intermittent claudication (pain during exercise which is relieved by rest) or critical ischemia (pain also at rest; possible tissue loss due to low oxygen levels and nutrient supply in the affected tissues) (Meaney 2003). ", "In patients with acute limb-threatening ischemia, DSA should be the technique of choice because it allows to perform both imaging and endovascular therapeutic procedures (Wasser 2003). ", "On the other hand, CE-MRA can be considered a safe and accurate diagnostic tool in patients with intermittent claudication. ", "The current role of CE-MRA in patients affected by PAOD is to depict the location, the length and the severity of vascular stenosis (Fig. ", "11.1). ", "This is particularly important in patients who will undergo endovascular or surgical procedures, as it helps to plan the execution of such procedures. ", "Careful evaluation of infrapopliteal vessels is essential for treatment planning in diabetic patients, who often have long segments of arterial occlusion in the lower limbs. ", "In this kind of patients, information on distal pedal vessels is necessary and 3D MRA may reveal patent distal arteries that are not visible in DSA (Drescher et al. ", "2006; Lapeyre et al. ", "2005; Reid et al. ", "2001) Moreover, TOF angiography proved to be a useful complementary study in patients with peripheral vascular disease of the foot and the ankle (Unger et al. ", "1995). ", "It is well known that CE-MRA tends to overestimate stenosis (Ho et al. ", "1999; Lee et al. ", "2000; Winterer et al. ", "2002) and this may be an important aspect in evaluating the cases of borderline stenosis (40-60%), when its hemodynamic significance should be assessed carefully because it can be an important element when deciding if invasive therapies are needed. ", "However, the same problems may be encountered with DSA, which still represents the reference standard imaging technique but is characterized by significant pitfalls (Wasser 2003). ", "In fact, recent studies have assessed that DSA is not adequate in evaluating runoff vessels; CE-MRA seems to demonstrate more patent vessels in this case (Owen et al. ", "1992). ", "MRA may be utilized even in the evaluation of patients after surgical therapy. ", "The patients affected by PAOD, in fact, can undergo different surgical procedures involving the lower limbs, in particular aorto-bi-iliac, aorto-bi-femoral, axillo-bi-femoral bypasses proximally and popli teal and tibial bypasses distally (Tatli et al. ", "2003). ", "In these cases, CE-MRA can assess graft location, patency and stenosis, even if the bypass grafts are very small and distal; the proximal and distal anastomoses of the bypasses can be evaluated. ", "It is also accurate in the demonstration of the complications of the surgical therapy such as anastomotic pseudoaneurysms (Insko and Carpenter 2004). ", "Unfortunately, long-term failure of the grafts is a common event, because of the progression of the disease in the native outflow vessels. ", "Periodic screening is implemented with DUS, but MRA may be requested prior to graft revision. ", "In these cases, special care should be taken to avoid misinterpretation of the images because of the presence of the magnetic susceptibility artefacts created by metallic clips. ", "Source images, as well as 3D data sets, have to be evaluated in particular in these patients (Tatli et al. ", "2003). ", "If endo-vascular treatment has been performed and metallic stents have been positioned in the vessels, susceptibility artefacts may mimic stenosis or occlusion; therefore, the clinical history and the source images should be evaluated carefully (Lee et al. ", "2000).", "\n\nFig. ", "11.1\n\nSteno-occlusive disease in a 74-year-old diabetic patient. ", "Coronal MIP (maximum intensity projection) image showing diffuse atherosclerotic parietal irregularities of the common iliac arteries and of the right external iliac artery, without evidence of significant stenotic lesions. ", "Focal stenosis (60-70%) of the left external iliac artery. ", "Right lower limb: occlusion of the origin of the superficial femoral artery, with distal revascularization due to collateral vessels from the deep femoral artery. ", "Distally to the occlusion, the superficial femoral artery has a focal significant stenosis (>50%) and wall irregularities. ", "The anterior tibial artery is nearly occluded 3 cm after its origin, it has multiple focal stenoses in the medium third and is completely occluded distally. ", "Occlusion of the distal third of the interosseous artery. ", "Left lower limb: diffuse atherosclerotic lesions of the superficial femoral artery, without significant stenotic disease. ", "The anterior tibial artery is occluded 2 cm after its origin. ", "The posterior tibial artery is nearly occluded proximally for 2 cm (with distal revascularization from the interosseous artery) and it has focal stenoses in the medium and distal third. ", "The interosseous artery is occluded distally, with evidence of small collateral vessels\n\n#### 11.2.1.1 Leriche's Syndrome\n\nThe complete obstruction of the aortic bifurcation was originally described by Leriche, and now the term Leriche's syndrome refers to the chronic occlusion of the infrarenal aorta involving the iliac arteries. ", "Common symptoms include intermittent claudication of the whole lower limb starting from the gluteus muscles, impotence in men, absence of the femoral pulses and symmetric atrophy of the lower limbs. ", "The symptoms may vary according to the formation of collateral vessels (Chan et al. ", "2005). ", "The disease can be well tolerated for years, but finally gangrene is observed (Sabiston 1997a). ", "In the clinical setting of Leriche's syndrome, CE-MRA can depict the level of aortic occlusion, the most proximal arterial segments which may possibly undergo a surgical bypass procedure, as well as the anatomy and the extent of the collateral arterial vessels (Ruehm et al. ", "2000). ", "Moreover, CE-MRA seems to be more accurate than DSA in the assessment of the distal runoff vessels (Link et al. ", "1998).", "\n\n### 11.2.2 Aneurysms\n\nAn aneurysm is a localized dilatation of an artery. ", "A true aneurysm is characterized by the involvement of all the three layers of the vessel wall: intima, media and adventitia. ", "A false aneurysm, or pseudoaneu-rysm, is characterized by the destruction of the vessel wall because of trauma, infections and invasive vascular procedures, leading to dilatation of the adventi-tial layer only.", "\n\nAneurysms may be congenital but the majority of them are acquired. ", "The most common cause of an aneurysm is atherosclerosis, followed by traumas, micotic infections, adventitial cystic medial necrosis and congenital diseases such as Ehlers-Danlos or Marphan's syndrome (Sabiston 1997b). ", "Aneurysms can affect all the lower limb arteries, but the most commonly affected arteries are the popliteal and the femoral arteries. ", "Aims of the MRA evaluation in aneurysmatic disease of the lower limb arterial vas-culature are to assess the presence, location, morphology and dimensions of the aneurysms. ", "Their patency should be evaluated as well and in this case particular attention is to be paid to the imaging timing after the contrast bolus injection. ", "In fact, in patients with diffuse atherosclerotic disease, the blood flow can be very slow because of the extension of the aneuryms in the lower limbs, because of the possible concomitant presence of aneurysms in central arteries, as well as the possible concomitant heart failure, which is frequent in patients with extensive atherosclerotic disease and leads to low cardiac output and consequently altered blood flow dynamics all over the body vasculature. ", "For these reasons, in this kind of patients the timing of CE-MRA sequence acquisition is crucial to avoid a false diagnosis of nonpatent aneurysmal lumen. ", "Apart from the two methods described in the Sect. ", "11.2 (rapid low resolution sequence to chase the bolus and test-bolus), there are other methods to ensure reliable and accurate timing of the bolus. ", "In particular, rapid temporally resolved acquisitions and automated techniques to start image acquisition after bolus arrival have been proposed (Foo et al. ", "1997; Korosec et al. ", "1996; Lee et al. ", "2000; Prince et al. ", "1997). ", "It is also possible to study the characteristics of the vessel wall with MR imaging, evaluating the presence and the signal intensity of mural thrombi, hematomas and wall thickening. ", "Atherosclerotic plaques can be depicted as well, even when they contain a considerable amount of calcium, which would be a disturbing element in multidetector computed tomography.", "\n\n#### 11.2.2.1 Popliteal Aneurysms\n\nThe popliteal artery is the peripheral artery most commonly affected by aneurysmatic disease (Tatli et al. ", "2003). ", "The leading cause of popliteal aneurysms is the atherosclerotic disease (95%) (Dawson et al. ", "1991), but the compartment syndrome, bacterial infections, collagen disorders and traumas also may play a role. ", "This kind of aneurysm is typically present in the seventh decade of life and is much more common in male than in female patients. ", "It is very often associated with aneurysms of other arteries (85%), such as the aorta, the iliac arteries or the femoral arteries, and it can be bilateral (40%) (Makhoul 1997a). ", "The majority of popliteal aneurysms present as pulsatile masses, or as nonpulsatile masses if they are thrombosed. ", "They are usually symptomatic and the patient complains of ischemic claudication, gangrene, local compressive symptoms such as venous obstruction or nervous pain and paresthesia. ", "It is fundamental to recognize and to treat surgically popliteal aneurysms because up to one third of the patients have distal embolization or limb ischemia caused by an unrecognized and nonpal-pable aneurysm (Carpenter et al. ", "1994; Ramesh et al. ", "1993). ", "The MRA study in popliteal aneurysms may depict the location, morphology and dimensions of the aneurysms, as well as the possible presence of mural thrombi and their signal intensity characteristics (Fig. ", "11.2).", "\n\nFig. ", "11.2\n\nPresurgical evaluation of a popliteal artery aneurysm in a 73-year-old man. (", "a) Coronal MIP image showing that the fusiform aneu-rysm of the left popliteal artery is extended longitudinally for 7 cm. (", "b, c) Morphologic T2-weighted (b) and T1-weighted (c) axial images at the level of the aneurysm shown in (a). ", "The aneurysm (3.5 × 3 cm) is partially occluded by a 2-cm thick eccentric thrombus (see straight arrow); the residual lumen is 9 mm. ", "The popliteal vein is compressed and dislocated by the aneurysm (see curved arrow). (", "d) Post-contrast axial T1-weighted fat-saturated image at the same level shown in (b) and in (c)\n\n#### 11.2.2.2 Femoral Aneurysms\n\nEven for femoral arteries, the most common cause of aneurysms is atherosclerosis. ", "They are often associated with aortic and politeal aneurysms and are bilateral in 50% of the cases (Makhoul 1997b). ", "Pseudoaneurysms of the femoral arteries are mostly iatrogenic, following percutaneous access during vascular procedures (Mccann 1991). ", "Anastomotic pseudoaneurysms are also fairly common, following surgical procedures such as aorto-bifemoral bypass (Makhoul 1997b).", "\n\nIn comparison to popliteal aneurysms, femoral aneurysms are characterized by less morbidity if untreated. ", "In fact, while symptomatic aneurysms should be treated surgically, the surgical treatment of small, asymptomatic aneurysms is still controversial and they and can be treated conservatively (Graham et al. ", "1980). ", "Once again, the MRA study in femoral aneurysms may depict the location, morphology and dimensions of the aneurysms, as well as the possible presence of mural thrombi and their signal intensity characteristics.", "\n\n### 11.2.3 Popliteal Entrapment\n\nPopliteal artery entrapment syndrome is a rare entity associated with an anomalous relationship between the medial head of the gastrocnemius muscle and the popliteal artery (Wasser 2003). ", "This embryological abnormality causes compression of the popliteal artery; the popliteal vein can be involved as well. ", "The syndrome may be due either to four main anatomic abnormalities or to a functional entrapment, as stated by the Popliteal Vascular Entrapment Forum in 1998. ", "The disease is much more common in young male subjects (Turnipseed 2002; Utsunomiya and Sawamura 2007; Elias et al. ", "2003; Holden et al. ", "2008; Macedo et al. ", "2003). ", "This anomalous anatomical condition results in paraesthesias and coldness of the foot and in intermittent claudication of the calf; ischemia is rare (Turnipseed 2002; Ersoy and Rybicki 2008; Macedo et al. ", "2003). ", "Surgical treatment is indicated whenever anatomic popliteal artery entrapment syndrome is demonstrated because, if left untreated, it can lead to stenosis because of repeated trauma and fibrosis development, occlusion and embolization. ", "Poststenotic aneurysms can also occur. ", "In functional entrapment, surgical treatment should be reserved to symptomatic patients (Turnipseed 2002; Elias et al. ", "2003). ", "MRA has recently become a fundamental imaging technique in the assessment of the popliteal artery entrapment syndrome. ", "In fact, it can depict both the vasculature and the muscle anatomy, and thereby help in distinguishing between anatomic and functional forms of the disease (Turnipseed 2002; Holden et al. ", "2008; Macedo et al. ", "2003) (Fig. ", "11.3).", "\n\nFig. ", "11.3\n\nPopliteal entrapment in a 21-year-old man with calf claudication during training. (", "a) Coronal MIP image showing the significant stenosis of the right popliteal artery, with the concomitant development of collateral vessels originating from the superficial femoral artery. (", "b, c) Axial T2-weighted (b) and balanced-FFE (c) images at the level showed in (a), demonstrating the presence of a tissue component of the medial head of the gastrocnemius muscle (see curved arrow) which divaricates the vein and the artery, and compresses the latter (see straight arrow). (", "d) Postcon-trast axial T1-weighted fat-saturated image at the same level shown in (b) and in (c): the divarication and the compression of the left popliteal artery are even more evident than in the precontrast images (see arrows)\n\n## 11.3 Upper Limb\n\nMRA assessment of the upper limb arterial disease is less diffuse than the assessment of the lower limb arterial disease. ", "This should be possibly related to the lower incidence of vascular diseases such as aneurysms and steno-occlusions. ", "On the contrary, inflammatory arteritis and vasospastic disease are more common in the upper limbs, and they usually involve medium and small caliber arteries. ", "In addition to the lower incidence of aneurysms and occlusions, underestimation of vascular disease in the upper limbs is frequent because patients are less commonly symptomatic. ", "In fact, only 1% of patients with diffuse peripheral vascular disease complains of ischemic symptoms also to the upper limbs. ", "The lower incidence of the symptoms is related to the extensive development of collateral vessels, to the smaller amount of muscular tissue and to its intermittent use in the normal life activities (Slocum and Silver 1997). ", "Nowadays, DSA still represents the reference standard for the imaging of upper extremity vasculature. ", "However, recent developments in hardware and software of state-of-the-art 1.5 T scanners have made MRA, in particular CE-MRA, an interesting imaging modality for the depiction of upper extremity vessel anatomy and disease because of its rapid and three-dimensional imaging over a large field of view (Planken et al. ", "2008). ", "Some studies compared the diagnostic performances of CE-MRA and DSA and concluded that CE-MRA shows high accuracy in the detection and grading of lesions involving the aortic arch vessels. ", "For this reason, its use can be recommended for screening, treatment planning, and follow-up in known or suspected arterial disease in aortic arch arteries (Carpenter et al. ", "1997; Loewe et al. ", "2004; Willinek et al. ", "2005). ", "In imaging of the subclavian and brachial arteries, precontrast and postcontrast images are obtained, both with the breath-hold technique. ", "Usually, 0.1 mmol/kg of a gadolinium-based contrast agent is administered with an automatic injector, with a flow rate of 2 mL/s, followed by 20 mL of saline flush at the same flow rate. ", "Care should be taken to avoid venous overlap, and this can be managed by injecting the contrast agent in the contralateral arm. ", "A body coil should be used to gain a higher signal-to-noise ratio. ", "MRA can not be considered the imaging modality of choice in small distal vessels (typically in the hands) because some problems still exist. ", "First of all, high resolution scanning with dedicated surface coils is necessary to obtain a good spatial resolution and the availability of this state-of-the-art equipment is still limited. ", "Moreover, the arterial transit time of the contrast bolus in the hand is very short (approximately 12 s) and this requires a very accurate timing of the imaging (Wasser 2003;Winterer et al. ", "2000). ", "DUS still can play a role for the imaging of the vessels in the upper arm, forearm and hand but, as stated in the introduction to the chapter, this is limited to particular clinical settings. ", "Assessment of the upper extremity vascula-ture prior to hemodialysis vascular access creation in the terminal-stage renal disease patients may be an example, considering also the emerging problem of systemic nephrogenic fibrosis as a late adverse event following gadolinium-based contrast agent administration in this kind of patients (Thomsen 2006; Tordoir and Mickley 2003; Bongartz et al. ", "2008; Planken et al. ", "2008). ", "As in the case of the lower limbs, Vasovist® can be used for CE-MRA of the upper limbs also, even though the literature in this field is very limited up to now. ", "The arterial first-pass acquisition is similar to the conventional arterial angiograms obtained with extracellular contrast agents and is now implemented in the routine clinical setting, while the steady-state imaging of upper extremities with Vasovist® is not.", "\n\n### 11.3.1 Steno-Occlusive Disease\n\nAtherosclerosis is a systemic disease affecting the arterial bed of the body and represents the leading cause of steno-occlusive arterial disease in the population older than 40 years of age. ", "The second most important cause of occlusive disease of the aortic arch vessels, subclavian arteries included, is the Takayasu's arteritis, which will be discussed further in the Sect. ", "11.3.4 (Krinsky et al. ", "1996). ", "In the upper limb, atherosclerosis is less common than in the abdomen and the lower limb arteries; it mainly involves the innominate artery and the origin of the subclavian artery (Wasser 2003; Shadman et al. ", "2004). ", "The stenosis or occlusion of the two arteries may be asymptomatic because of the development of collateral vessels. ", "If symptomatic, they can lead to upper extremity claudication or ischemia and to vertebrobasilar insufficiency (Krinsky et al. ", "1996; Woo et al. ", "2006). ", "The current role of CE-MRA in patients affected by steno-occlusive disease of the upper limb is to depict the location, the length and the severity of vascular stenosis. ", "This is particularly important in the work-up prior to endovascular or surgical procedures, in order to plan their execution. ", "It is well known that CE-MRA tends to overestimate stenosis (Ho et al. ", "1999; Lee et al. ", "2000; Winterer et al. ", "2002). ", "This may be an important matter in evaluating the cases of borderline stenosis (40-60%), when its hemodynamic significance should be assessed carefully because it can be an important element when deciding if invasive therapies are needed. ", "However, the same problems may be encountered with DSA, which still represents the reference standard imaging technique but is characterized by significant pitfalls (Wasser 2003). ", "MRA may be utilized even in the evaluation of patients following surgical treatment. ", "The symptomatic patients can undergo different surgical procedures involving the upper limbs, in particular transposition of the subclavian artery, carotid-to-subclavian artery bypass, in situ or extra-anatomic bypass for innominate artery disease, or even axillo-axillary bypass (Krinsky et al. ", "1998; Wo o*et al. ", "2006). ", "In these cases, CE-MRA can assess graft location, patency and stenosis; the proximal and distal anastomoses of the bypasses can be evaluated as well. ", "CE-MRA is also accurate in the demonstration of the complications of the surgical therapy, such as anastomotic pseudoaneurysms (Insko and Carpenter 2004). ", "Particular care should be taken to avoid misinterpretation of the CE-MRA images because of the presence of the magnetic susceptibility artefacts created by metallic clips. ", "Source images, as well as 3D data sets, have to be evaluated in particular in these patients (Tatli et al. ", "2003). ", "If endo-vascular treatment has been performed and metallic stents have been positioned in the vessels, susceptibility artefacts may mimic stenosis or occlusion, so the clinical history and the source images should be evaluated carefully (Lee et al. ", "2000).", "\n\n#### 11.3.1.1 Subclavian Steal Syndrome\n\nThe subclavian steal syndrome is secondary to obstruction of the proximal subclavian artery. ", "In this setting, the blood supply to the arm is maintained by the retrograde flow in the ipsilateral vertebral artery distal to the obstruction, which is obtained at the expense of the cerebral circulation by stealing from the contralateral vertebral and/or basilar arteries. ", "Therefore, vertebrobasilar hypoperfusion may develop when the arm is exercised (Wasser 2003). ", "The most common cause of the subclavian steal syndrome is the presence of an atherosclerotic lesion in the proximal subclavian artery. ", "The treatment of the syndrome is usually the surgical bypass of the stenosis. ", "Percutaneous transluminal angioplasty of the subclavian artery may be implemented as well (Van Grimberge et al. ", "2000). ", "CE-MRA may depict the obstruction of the subclavian artery; the retrograde flow in the vertebral artery can be demonstrated with flow-encoded MR sequences (Wasser 2003; Flynn et al. ", "1993; Van Grimberge et al. ", "2000).", "\n\n### 11.3.2 Aneurysms\n\nAn aneurysm is a localized dilatation of an artery. ", "A true aneurysm is characterized by the involvement of all the three layers of the vessel wall: intima, media and adventitia. ", "A false aneurysm, or pseudoaneurysm, is characterized by the destruction of the vessel wall because of trauma, infections and invasive vascular procedures, leading to dilatation of the adventitial layer only.", "\n\nAneurysms may be congenital but the majority of them are acquired. ", "The most common cause of an aneurysm is atherosclerosis, followed by traumas, micotic infections, adventitial cystic medial necrosis and congenital diseases such as Ehlers-Danlos or Marphan's syndrome (Sabiston 1997a). ", "Aneurysms of the upper limbs are less common than those of the lower limbs. ", "In the upper limb, an aneurysm is most frequently located in the subclavian artery. ", "Aims of the MRA evaluation in aneurysmatic disease of the upper limb arterial vasculature are to assess the presence, location, morphology and dimensions of the aneurysms, as in lower limb disease. ", "Their patency should be evaluated as well, and also in this case particular attention to the imaging time after the contrast bolus injection is necessary. ", "The timing of CE-MRA sequence acquisition is crucial to avoid a false diagnosis of nonpatent aneurysmal lumen. ", "Apart from the two methods described in the Sect. ", "11.2 (rapid low resolution sequence to chase the bolus and test-bolus), there are other methods to ensure reliable and accurate timing of the bolus. ", "In particular, rapid temporally resolved acquisitions and automated techniques to start image acquisition after bolus arrival have been proposed (Foo et al. ", "1997; Korosec et al. ", "1996; Lee et al. ", "2000; Prince et al. ", "1997). ", "MR imaging also allows the assessment of the characteristics of the vessel walls, as well as evaluation of the presence and the signal intensity of mural thrombi, hematomas and wall thickening. ", "Atherosclerotic plaques can be depicted as well, even when they contain a considerable amount of calcium, which would be a disturbing element in multidetector computed tomography.", "\n\n#### 11.3.2.1 Subclavian Aneurysms\n\nThe aneurysms of the subclavian artery are the most common in the upper limb. ", "They are usually secondary to atherosclerotic disease, but also to traumas. ", "A poststenotic dilatation may cause an aneurysm. ", "The lesion can have either an intra-thoracic or supra-clavicular development. ", "In the latter case, they can present as pulsatile masses. ", "The aneurysm of the subclavian artery may be bilateral.", "\n\nThe treatment of this disease is usually surgical (Sabiston 1997c; Halldorsson et al. ", "2007).", "\n\nAims of the MRA evaluation in aneurysmatic disease of the subclavian aneurysms are to assess the location, morphology and dimensions of the aneurysms, as in lower limb disease (Halldorsson et al. ", "2007). ", "Their patency can be evaluated as well. ", "MR imaging also allows the assessment of the characteristics of the vessel walls, and the evaluation of the presence and the signal intensity of mural thrombi, atherosclerotic lesions, hematomas and wall thickening.", "\n\n### 11.3.3 Takayasu's Arteritis\n\nTakayasu's arteritis is an inflammatory disease of unknown origin, which involves mainly the aorta, its principal branches and the pulmonary arteries. ", "It is more common in young female subjects. ", "The acute phase of the disease is characterized by inflammation of the vasa vasorum in the adventitia of the vessel walls. ", "In the chronic phase of the disease, the vessel walls are thickened because of fibrosis of their three layers. ", "Typical symptoms of the disease are fever, malaise, arthralgia, thoracic pain and tachycardia. ", "Cerebral and upper limb ischemias are more common in the later stage of the disease (Sabiston 1997d). ", "The diagnosis of Takayasu's arteritis and the identification of the activity of the disease are fundamental in order to implement an adequate therapy. ", "Histopatho-logic specimens are rarely available, so the diagnosis is on the basis of the American College of Rheuma-thology criteria proposed in 1990 (Arend et al. ", "1990) and the evaluation of activity is on the basis of the Kerr's criteria (Kerr et al. ", "1994). ", "In this setting, the information derived from the diagnostic imaging may also be important. ", "DSA has been considered for years the most important imaging technique in Takayasu's arteritis patients, but MRA may now be considered the technique of choice. ", "First of all, the lack of ionizing radiations is fundamental when repeated follow-up studies must be performed on young women. ", "Moreover, MRA allows both luminographic and vessel wall evaluation (Yamada et al. ", "2000). ", "At MR imaging, Takayasu's arteritis involving the upper limbs is characterized by mural thrombi, arterial wall thickening and enhancement (typically in the active phase) (Choe et al. ", "2000). ", "CE-MRA may depict the location, degree, length of the stenoses and dilatations, even in pulmonary arteries (Gotway et al. ", "2005) (Fig. ", "11.4). ", "The finding of the disease involving the pulmonary arteries is fairly typical of Takayasu's arteritis (70% of patients) and is rarely seen in atherosclerosis or other arteritides; therefore, it enables a definitive diagnosis of the disease (Yamada et al. ", "1993). ", "CE-MRA is also useful in evaluating the patency of the collateral arteries or of the surgical bypasses (Yamada et al. ", "2000; Gotway et al. ", "2005), even if the therapeutic approach in these patients is usually conservative (Kerr et al. ", "1994).", "\n\nFig. ", "11.4\n\nTakayasu's arteritis in a 30-year-old woman, (CE-MRA performed with Vasovist®). (", "a) Coronal MIP image showing a focal significant stenosis of the origin of the right subclavian artery. ", "A diffuse reduction of the caliber of the right common carotid artery is also visible. ", "Signifi-cant stenosis of the origin of the left subclavian artery, extended for 2 cm. ", "Also the origin of the left common carotid artery is stenotic for 2 cm (<50%). (", "b) Morphologic axial black-blood proton density (PD)-weighted image showing the concentric thickening of the walls of the left subcla-vian artery, which causes the significant stenosis described in (a) (see arrow). (", "c) Morphologic axial black-blood PD-weighted image showing the concentric thickening of the walls of the descending aorta (see arrow). (", "d) Axial 3D FFE T1-weighted high resolution image before contrast administration, showing the thickening of the wall of the left sub-clavian artery (see arrow). (", "e) Axial 3D FFE T1-weighted high resolution image obtained 15 min after Vasovist® intravenous administration, which shows the enhancement of the thickened wall of the left subclavian artery (see arrow). ", "This can be considered a marker of active disease in Takayasu's arteritis\n\n### 11.3.4 Thoracic Outlet Syndrome\n\nThe thoracic outlet syndrome is due to the compression of either the subclavian vessels or the brachial plexus by anomalous osseous structures or by a broad insertion of the scalenus muscle anteriorly over the clavicle. ", "For these reasons, the syndrome is characterized by vascular and neurological symptoms. ", "The patients may experience pain during elevation of the arms and loss of sensation during exercise. ", "The clinical examination may show a palpable thrill over the subclavian artery, diminished radial pulses and lowered brachial blood pressure (Wasser 2003).There are many provocative maneuvers that may be implemented to diagnose the thoracic outlet syndrome (Rayan 1998). ", "The compression of the brachial plexus is more common than the stenosis of the subclavian artery but, if the latter is present, it may be clearly depicted by CE-MRA. ", "In particular, CE-MRA should be performed with the arms in the usual position inside the magnet bore, which is with arms in adduction and also with arms in hyperabduction, which is one of the provocative maneuvers described for the clinical diagnosis of the syndrome. ", "In the latter position, CE-MRA may show the narrowing or occlusion of the subclavian artery. ", "Moreover, morphologic MR imaging may depict the cause of arterial compression (Dymarkowski et al. ", "1999) (Fig. ", "11.5).", "\n\nFig. ", "11.5\n\nSuspected thor acic out let syndrome in a 52-year-old woman with pain during elevation and exercise of the left upper limb. (", "a) Coronal MIP image with arms in abduction showing the occlusion of the origin of the left subclavian artery (see arrow). (", "b) The occlusion of the left subclavian artery is present even in the coronal MIP image with arms in adduction, thus the final diagnosis was of an occlusive lesion of the artery (see arrow). 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", "MRA in Liver and in Orthotopic Liver Transplants\n\nPiero Boraschi1 , Francescamaria Donati1, Simonetta Salemi1 and Francesca Turini2\n\n(1)\n\n2nd Unit of Radiology, Department of Oncologic and Radiological Sciences, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy\n\n(2)\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, Pisa, 56126, Italy\n\n12.1 MRA in Liver\n\n12.1.1 Introduction\n\n12.1.2 Vascular Anatomy\n\n12.1.3 Vascular Imaging\n\n12.1.4 MR Angiography\n\n12.1.4.1 MRA Study Technique\n\n12.1.4.2 MRA Postprocessing\n\n12.2 MRA in Orthotopic Liver Transplants\n\n12.2.1 Introduction\n\n12.2.2 Surgery in Orthotopic Liver Transplants\n\n12.2.3 Complications After Orthotopic Liver Transplants\n\n12.2.3.1 Vascular Complications\n\n12.2.3.2 Vascular Complications: Imaging\n\n12.2.4 MR Angiography in OLT\n\n12.3 Conclusions\n\nReferences\n\nAbstract\n\nMR imaging provides the necessary information about variations in the vascular and biliary anatomy and allows evaluation of the hepatic parenchyma for diffuse or focal abnormalities.", "\n\nMR angiography is performed in very specific cases and in particular for getting a detailed knowledge of the hepatic angio-architecture, a prerequisite for successful, uncomplicated liver surgery.", "\n\nActually, 3D MR angiography can be a useful, noninvasive technique for evaluating vascular anatomy in preoperative imaging and an appropriate substitute for repetitive follow-up examinations in liver transplant recepients for early and accurate diagnosis of vascular complications.", "\n\n## 12.1 MRA in Liver\n\n### 12.1.1 Introduction\n\nCurrently, dynamic, contrast material-enhanced magnetic resonance imaging is performed in very specific cases, particularly for getting a detailed knowledge of the hepatic angio-architecture, a prerequisite for successful, uncomplicated liver surgery.", "\n\nIndeed, a critical factor for a variety of liver surgeries including chemoembolization, transplantation, tumor resection, and laparoscopic hepatobiliary surgery is the presurgical planning of vascular anastomosis (Sahani et al. ", "2004).", "\n\nThe advantage of this technique is that it can be used as a single imaging test for comprehensive noninvasive presurgical evaluation. ", "In fact MR imaging provides the necessary information about variations in the vascular and biliary anatomy and allows evaluation of the hepatic parenchyma for diffuse or focal abnormalities.", "\n\n### 12.1.2 Vascular Anatomy\n\nPreoperative imaging, especially in the orthotopic liver transplantation (OLT) candidates, has three main objectives:\n\n1.", "\n\nAssessment of the arterial, portal and systemic venous anatomy and patency, in order to detect vascular variants or abnormalities and mismatches in donor and recipient vascular size.", "\n\n2.", "\n\nAssessment of collateral circulation as a result of portal hypertension. ", "This is needed because many patients who are candidates for liver transplantation are cirrhotic and the checking of their portal system is crucial (Caramella and Perri 2008).", "\n\n3.", "\n\nAssessment of the presence or absence of malignancy (Boevea et al. ", "2001).", "\n\nKnowledge of the exact vascularization of the liver is of utmost importance because variations in the arterial and venous anatomy occur in a large number of patients.", "\n\nThe classic hepatic arterial anatomy, with the proper hepatic artery (PHA) dividing into right and left hepatic arteries, is observed in approximately 55% of the population (Fig. ", "12.1).", "\n\nFig. ", "12.1.", "\n\nNormal course and branching pattern of the hepatic artery. ", "Coronal oblique MIP image from arterial phase of MR angiography shows the common hepatic artery (CHA) and the proper hepatic artery divides into the left hepatic artery and right hepatic artery (RHA)\n\nIn the standard, or classic, visceral anatomy, the celiac axis gives rise to three branches. ", "The first branch is the left gastric artery (LGA), after which the vessel divides into the splenic artery and the common hepatic artery (CHA). ", "The CHA then bifurcates into the gastro-duodenal artery (GDA) and PHA, and the PHA bifurcates into the right hepatic artery (RHA) and the left hepatic artery (LHA) (Covey et al. ", "2002).", "\n\nIt is important to recognize cases which present an anatomic variation, in order to plan the surgery (Figs. ", "12.2 and 12.3) (Sahani et al. ", "2004).", "\n\nFig. ", "12.2.", "\n\nReplaced RHA. ", "Coronal oblique MIP (a) and VR (b) reconstructions from arterial phase of MRA demonstrate a replaced RHA from the superior mesenteric artery\n\nFig. ", "12.3.", "\n\nReplaced RHA. ", "Coronal oblique VR image from arterial phase of MRA reveals the RHA arising from CHA\n\nThe Michel classification of hepatic arterial anatomy with the approximate frequency of occurrence of each type of variant in the general population is shown in Table 12.1 (Michel 1955).", "\n\nTable 12.1.", "\n\nMichel classification of the hepatic arterial anatomy\n\nI | 55% | Hepatic trunk arise from common hepatic artery\n\n---|---|---\n\nII | 10% | Replaced LHA arises from left gastric artery\n\nIII | 11% | Replaced RHA arises from superior mesenteric artery\n\nIV | 1% | Replaced RHA and LHA\n\nV | 8% | Accessory LHA arises from left gastric artery\n\nVI | 7% | Accessory RHA arises from superior mesenteric artery\n\nVII | 1% | Accessory RHA and LHA\n\nVIII | 4% | Replaced RHA and accessory LHA or replaced LHA and accessory RHA\n\nIX | 4.5% | Entire hepatic trunk arises from superior mesenteric artery\n\nX | 0.5% | Entire hepatic trunk arises from left gastric artery\n\nIn the classic hepatic venous anatomy, three main hepatic veins drain into the inferior vena cava (IVC). ", "The left hepatic vein drains segments II and III, the middle hepatic vein drains segments I V, V and VIII, and the right hepatic vein drains segments V-VII. ", "In approximately 60% of the population, the middle and left hepatic veins join to form a common trunk, which drains separately into the IVC (Soyer et al. ", "1996; Lerut et al. ", "1997).", "\n\nInformation relevant for the surgeon concerns the pattern of venous drainage into the IVC, the presence and number of accessory veins, as well as their size and distance from the main hepatic venous drainage site along the IVC. ", "When a parenchymal dissection plane is planned, even small hepatic venous branches need to be left intact or reconstructed in order to avoid venous congestion, segmental necrosis and atrophy (Catalano et al. ", "2008).", "\n\nThe normal portal venous anatomy consists of the main portal trunk branching, at the porta hepatis, into the right and left portal veins, with the right portal vein subsequently dividing into anterior and posterior branches (Lerut et al. ", "1997), but portal vein trifurcation can be found in 10%-16% of patients (Fig. ", "12.4). ", "Although this variant does not represent a contraindication to surgery, it needs to be known before the operation because extra surgical steps are necessary for isolation of portal vein branches (Catalano et al. ", "2008).", "\n\nFig. ", "12.4.", "\n\nPortal vein trifurcation. ", "Coronal oblique MIP (a) and VR (b) images from portal phase of MRA show trifurca-tion of the portal vein into the right anterior, right posterior, and left portal veins\n\n### 12.1.3 Vascular Imaging\n\nDifferent approaches can be used for assessing the vascularisation.", "\n\nDigital subtraction angiography (DSA) has long been considered the standard of reference for evaluation of the hepatic arterial anatomy. ", "However, the morbidity and mortality associated with DSA, and its limitations in demonstrating the hepatic venous anatomy, have stimulated the development of non invasive methods of displaying the vascular anatomy (Sahani et al. ", "2004).", "\n\nThe current tendency is to avoid invasive imaging techniques and to rely instead upon non invasive techniques, such as ultrasound (US), multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging (Catalano et al. ", "2008).", "\n\nThe use of US evaluation in the pretransplanta-tion phase requires Doppler examination of the portal and hepatic veins and real-time B-mode imaging of hepatic parenchyma and bile ducts (Leung et al. ", "1999; Pannu et al. ", "2001).", "\n\nMoreover, Doppler US (DUS) allows the investigation of flow dynamics through the hepatic veins, the portal vein and its branches, and the intra- and extra-hepatic parts of the hepatic artery, representing a sensitive tool for the detection of portal vein thrombosis as well as of arterial abnormalities. ", "It also enables an accurate evaluation of the localization and flow of varices and porto-systemic shunts (Caramella and Perri 2008).", "\n\nHowever, the limitations of the US examination are in the lack of an overall anatomic view and most importantly in its quality, which is strongly operator dependent (Boevea et al. ", "2001).", "\n\nAbdominal computed tomography is a highly accurate method for the evaluation of the hepatic vessels and the liver parenchyma alike.", "\n\nIn particular, MDCT-angiography, used according to a three/four phase acquisition by means of a double-arterial phase followed by a portal-vein dominant phase, provides a complete description of the hepatic arterial and venous anatomy, as well as an accurate evaluation of liver parenchyma.", "\n\nSeveral studies show that the use of multi-detector row scanners is effective in angiographic applications and, especially in transplantation candidates, multi-detector row CT angiography (CTA) provides results comparable to those from conventional angiography in the evaluation of the hepatic artery anatomy and in the detection of arterial abnormalities such as severe celiac artery stenosis and splenic or hepatic artery aneurysm that may lead to liver transplantation.", "\n\nFurthermore, MDCT offers a precise evaluation of splenic, superior mesenteric and portal veins, and is useful in the assessment of complications due to portal hypertension such as the presence of retroperito-neal, spleno-renal, gastro-esophageal or paraumbilical varices, splenomegaly and ascites (Caramella and Perri 2008).", "\n\n### 12.1.4 MR Angiography\n\nMR angiography (MRA) is also becoming more and more used in preoperative planning for the assessment of the hepatic vascular anatomy because it combines the advantages of minimal invasiveness with both the assessment of the hepatic parenchymal morphology and the detailed analysis of the vascular anatomy.", "\n\nHowever, we have to consider also the limitations of MRA. ", "The spatial resolution of MRA is inferior to that of CTA and DSA.", "\n\nSmaller segmental vessels that are readily seen at catheter and CTA may not be consistently visualized with MRA.", "\n\nIn addition, patients with pacemakers, metallic hardware or claustrophobia may not be suitable candidates for MR imaging. ", "Furthermore, the longer breath hold required for MRA may introduce unwanted motion artifacts (Sahani et al. ", "2004).", "\n\nDespite these limitations of MRA when compared to CTA and DSA, MRA provides a road map for planning angiographic interventions to minimize the dose of iodinated contrast material and catheter manipulation of conventional angiography (Stafford-Johnson et al. ", "1998).", "\n\nContrast-enhanced MR angiography (CEMRA) has anyway been established as a safe, accurate, non-invasive method of evaluating the hepatic vascula-ture in a single breath hold.", "\n\nThis modality exploits the transient shortening in blood T1 following the administration of gadolinium based contrast material.", "\n\nThe entire arterial system of importance to the liver blood supply can be evaluated with high diagnostic confidence; the only diagnostic problems are identified in arteries with small diameter. ", "The arterial stenoses are seen in MRA, but a hemodynamic grading of celiac artery stenoses is hardly achieved because of the limited temporal resolution. ", "Furthermore, CEMRA has a tendency to overestimate the stenosis. ", "The causes of this are the limited spatial resolution, artifacts caused by bad timing of the contrast bolus (blurring and ringing) and an intravoxel dephasing component that also affects CEMRA (Glockner et al. ", "2000).", "\n\nAnyway, improvements in gradient performance and coil design, and refinements in MRA techniques permit faster imaging with improved spatial resolution (Sahani et al. ", "2004).", "\n\nFaster three-dimensional (3D) acquisition of MR imaging data, together with multiplanar imaging capability, allows excellent depiction of hepatic vessels with no saturation or turbulence-related artifact (Sahani et al. ", "2004).", "\n\nThe detection of aneurysms of the visceral arteries with CEMRA is relatively affected by dephasing phenomena induced by turbulence. ", "Usually the aneu-rysmatic sac is completely filled by contrast agent, with a presumed diagnostic gain.", "\n\nFurthermore, the image quality and diagnostic confidence associated with CEMRA, in the evaluation of the hepatic and the portal venous systems and the delineation of the intrahepatic veins from the surrounding tissue, have been considered more convenient than those associated with CTA. ", "This has been attributed to the minimal albumin binding of the administered MR contrast agent, thereby leading to an extended intravascular phase and a higher intra-vascular signal intensity (Schroeder et al. ", "2005) that allows the evaluation of veins patency and the identi-fication of thrombosis.", "\n\n#### 12.1.4.1 MRA Study Technique\n\nUntil recently, MR imaging has been limited to two-dimensional GRE imaging with relatively thick sections (8-10 mm) and intersection gaps. ", "The interpolated 3D MR imaging approach has the advantage of providing volumetric imaging of the entire liver with near-isotropic pixel size of 2.3 mm or less, thereby offering the possibility of improved detection and characterization of small lesions. ", "Moreover, with the 3D sequence, the isotropic pixels pemit valuable angiographic reconstruction of the arterial phase data sets (Lavelle et al. ", "2001).", "\n\nMR imaging protocol usually involves a 1.5-T magnet with a phased-array multi-channel coil. ", "First, axial breath-hold T1-weighted in-phase and opposed-phase gradient-echo images and T2-weighted images of the liver have to be obtained. ", "Next, an axial breath-hold 3D interpolated spoiled gradient-echo sequence is performed after intravenous administration of 0.1 mL/kg of body weight of gadolinium chelate, injected with a power injector at a rate of 2-3 mL/s. Hepatic arterial phase and portal venous phase images are obtained after delays of 15-18 s and 70 s, respectively. ", "Breath-hold images are obtained at end inspiration and usually require less than 25-30 s.\n\nHowever, numerous improvements in the hardware (faster gradients, higher magnetic field strengths, multiple parallel receiver channels and dedicated coils), the sequence techniques (volume-interpolated breath-hold-sequences, such as VIBE, L AVA, THRIVE), the contrast agents (agents with higher relaxivity, such as Gd-BOPTA and Gadobutrol) and the postprocessing software (curved planar reformats (CPR), volume-rendering and image fusion) have become available during the past few years (Michaely 2006; Heilmaier et al. ", "2007).", "\n\nIn particular, these latter sequences (VIBE, L AVA, THRIVE) are basically very similar to 3D-GRE sequences as they are used for abdominal MRA; yet they sample only one part of the k-space and perform a zero-filling in the 3D (partition) phase-encode direction to complete the k-space. ", "As fast 3D sequences, they are mainly applied for multi-phase studies of the liver, kidneys and pancreas. ", "They are heavily T1-weighted and can provide substantial ang iographic information when acquired immediately postcontrast agent administration; they also offer morphologic information (Lee et al. ", "2000).", "\n\nAnother new type of sequence which is becoming frequently used in abdominal MRA is time-resolved imaging (TRICKS, TREAT). ", "One advantage of time-resolved MRA is that time-intensive bolus timing is avoided, with a temporal resolution of 2 s or less (Fink et al. ", "2005).", "\n\nIn addition to these above-mentioned technical improvements, alternative k-space trajectories have led to an increased quality of abdominal MRA; in fact, in centric or elliptic-centric MRA, the contrast defining k-space center is acquired first and the venous signal is suppressed as by the time the contrast agent reaches the veins the periphery of k-space is read-out (Michaely 2006).", "\n\n#### 12.1.4.2 MRA Postprocessing\n\nWith the introduction of high-performance workstations, source images can be processed on commercially available workstations for multiplanar reformation as well as 3D reconstruction with maximum intensity projection (MIP) CPR and volume rendering (VR). ", "Three-dimensional reformatted images of the hepatic vessels are rendered using MIP, shaded surface display and VR. ", "Source images are most helpful for defining vascular anatomy and 3D images are useful in understanding complex anatomy.", "\n\nAccording to Catalano et al. ", "the hepatic veins are best displayed in the axial plane, with the MHV determining the hepatectomy plane; and the portal venous anatomy is best displayed in the coronal plane (Catalano et al. ", "2008).", "\n\n## 12.2 MRA in Orthotopic Liver Transplants\n\n### 12.2.1 Introduction\n\nOLT has become an accepted therapy for acute and chronic end-stage liver disease (Stange et al. ", "2003).", "\n\nToday, liver transplant patients have a 5-year survival rate of approximately 75%. ", "The improvement in survival can be attributed to better patient selection and preparation, advances in organ preservation, improved immunosuppressive therapy agents and refinement of surgical techniques (Hussain and Nghiem 2002).", "\n\nPatients who are candidates for liver transplantation are those w ith acute liver failure (fulminant hepatic failure) or chronic liver disease for which conventional treatment is unavailable or has ceased to be effective. ", "Fulminant hepatic failure, a disorder that ordinarily affects young people, causes a large portion of liver tissue to be destroyed in a short time, leading to failure of liver function, changes in mental status (hepatic encephalopathy), infections and kidney failure. ", "Chronic liver diseases that may be treated by transplantation include chronic hepatitis B and C, autoimmune chronic hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease and drug induced liver injury. ", "Hereditary disorders of metal metabolism including hemochromatosis and Wilson disease (involving disordered iron and copper metabolism) also may require transplantation. ", "Pediatric diseases requiring liver transplantation include biliary atresia and neonatal hepatitis (Boraschi and Donati 2004).", "\n\n### 12.2.2 Surgery in Orthotopic Liver Transplants\n\nGenerally OLT is performed with standard surgical technique using a veno-venous by-pass: the retro-hepatic vena cava is resected and an end-to-end interposition of the donor vena cava is made (Glanemann et al. ", "2002). ", "Reperfusion of the graft is obtained after completion of both the portal vein and arterial anastomoses. ", "Arterial anastomosis is usually performed between the donor hepatic artery with aortic patch or celiac trunk and the CHA of the recipient at the insertion of the GDA (Figs. ", "12.5 and 12.6).", "\n\nFig. ", "12.5.", "\n\nNormal transplanted vascular anastomoses. ", "Coronal oblique MIP (a) and VR (b) reconstructions from gadolinium-enhanced MRA demonstrate both patent portal vein at anastomotic site and normal transplanted hepatic artery. ", "Coronal MIP (c) image from venous phase shows the veno-venous by-pass at the level of the retro-hepatic vena cava obtained with an end-to-end interposition of the donor vena cava\n\nFig. ", "12.6.", "\n\nNormal transplanted hepatic artery. ", "Coronal oblique VR image from arterial phase of MRA shows normal transplanted hepatic artery\n\nIn case of stenosis of the celiac trunk or small diameter of the hepatic artery of the recipient, arterial reconstruction is performed by the anastomosis between the donor hepatic artery and the recipient aorta using an (supraceliac or infrarenal) iliac artery interposition graft or connecting the donor hepatic artery and aortic patch with the splenic artery of the recipient (Stange et al. ", "2003).", "\n\n### 12.2.3 Complications After Orthotopic Liver Transplants\n\nDespite the improvement in survival due to advances in organ preservation, improved immunosuppressive therapy agents and refinement of surgical techniques, there are still significant complications following liver transplantation. ", "These complications mainly include biliary strictures, stones and leakage; arterial and venous stenosis and thrombosis; lymphoprolifeative disorders; recurrent tumors; hepatitis virus C infection; liver abscesses; right adrenal gland hemorrhage; fluid collections and hematomas. ", "The diagnosis of acute rejection, one of the most serious complications following liver transplantation, is established with graft biopsy and histologic study. ", "The role of imaging methods consists of excluding the other complications, which can have clinical signs and symptoms similar to those of acute rejection (Boraschi and Donati 2004; Pandharipande et al. ", "2001)\n\n#### 12.2.3.1 Vascular Complications\n\nAdvances in surgical techniques have contributed to the improved results of living related liver transplantation, which, however, has a high risk of vascular complications because of complex reconstruction of the hepatic artery and portal vein. ", "Thus, a significant percentage of liver grafts are still lost because of vascular complications after living related liver transplantation (Kim et al. ", "2003).", "\n\nVascular complications have been reported in approximately 9% of patients with liver transplants (Boraschi and Donati 2004).", "\n\nHepatic artery stenosis and thrombosis are the most common posttransplant vascular complications, and their incidence varies between 6% and 11% (Brancatelli et al. ", "2002) (Figs. ", "12.7-12.9).", "\n\nFig. ", "12.7.", "\n\nHepatic artery thrombosis. ", "Coronal oblique VR image from arterial phase of MRA shows abrupt cut-off of hepatic artery\n\nFig. ", "12.8.", "\n\nHepatic artery stenosis after liver transplantation. ", "Coronal oblique VR (a) image from arterial phase of MRA shows severe hepatic artery stenosis at the anastomotic site, confirmed at DSA (b)\n\nFig. ", "12.9.", "\n\nHepatic artery stenosis in hepatic-aortic anastomosis after liver transplantation. ", "Coronal oblique MIP image from gadolinium-enhanced MRA shows arterial reconstruction, performed by the anastomosis between the donor hepatic artery and aortic patch with the splenic artery of the recipient, and demonstrates hepatic artery stenosis at the anastomotic site\n\nEarly diagnosis of these complications may allow successful treatment, with urgent surgical revascularization of the graft or with percutaneous angioplasty, and avoid re-transplantation before the development of severe hepatic failure or overwhelming sepsis (Cavallari et al. ", "2000).", "\n\nHepatic artery pseudoaneurysm is an uncommon complication of liver transplantation, which causes hematobilia, hemoperitoneum and gastrointestinal bleeding that may be life threatening. ", "The most common site for pseudoaneurysm formation is the arterial anastomosis; it is generally accessible by endovascular techniques for transcatheter emboliza-tion (Leelaudomlipi et al. ", "2003).", "\n\nClinical presentations of vascular complications vary from mild elevation of hepatic function tests to fulminant hepatic failure. ", "Because the clinical presentation is so varied, their early detection and adequate management are important elements for ensuring graft and patient survival after OLT. ", "For this reason, imaging studies can be particularly helpful in finding or eliminating vascular complications with the differential diagnosis (Boraschi and Donati 2004).", "\n\nVenous complications are less common and include stenosis and thrombosis of the portal vein or IVC. ", "Portal vein stenosis and thrombosis are relatively rare complications of hepatic transplantation, occurring in fewer than 3% of transplant recipients, most commonly at the anastomotic site (Katyal et al. ", "2000; Marujo et al. ", "1991).", "\n\nPortal vein complications may be asymptomatic or may cause symptoms of portal hypertension (Ito et al. ", "2000).", "\n\nPortal vein thrombosis usually requires surgical thrombectomy, venous grafting or re-transplantation, although several studies have reported good results with trans-hepatic balloon dilation for the treatment of portal vein stenosis.", "\n\nStenosis of the IVC is a rare complication of hepatic transplantation (0.8-2.8%) (Glanemann et al. ", "2002).", "\n\nSupra-hepatic caval stenosis causes hepatic venous obstruction and may lead to Budd-Chiari syndrome. ", "Caval stenosis may occur in the early postoperative phase or several years after transplantation. ", "Its consequences are extremely serious; graft outflow obstruction leads to persistent ascites, edema of the lower limbs, protein-losing enteropathy and progressive deterioration of the graft (Cavallari et al. ", "2000).", "\n\nIVC thrombosis is rare, occurring in fewer than 3% of patients. ", "It is caused by technical problems or compression of vessels by a fluid collection (Bowen et al. ", "1996).", "\n\nHowever, if left unrecognized, caval thrombosis will develop in many patients with obstruction of the IVC and may extend into the hepatic veins (Pfammatter et al. ", "1997).", "\n\n#### 12.2.3.2 Vascular Complications: Imaging\n\nClinical presentations of vascular complications vary from mild elevation of hepatic function tests to fulminant hepatic failure. ", "Because the clinical presentation is so varied, their early detection and adequate management are important elements for ensuring graft and patient survival after OLT. ", "For this reason, imaging studies can be particularly helpful in find-ing or eliminating vascular complications with the differential diagnosis (Boraschi and Donati 2004).", "\n\nIn general OLTs are followed up routinely at 6 and 12 months and yearly after OLT, by techniques including DUS. ", "In case of suspicious findings, further diagnostic investigations with abdominal CT scan, MRI, endoscopic retrograde cholangiography (ERC), or DSA are performed (Stange et al. ", "2003).", "\n\nDUS is the primary modality used to evaluate the hepatic artery in the posttransplantation period.", "\n\nThe reported sensitivities of DUS for the detection of hepatic artery stenosis and thrombosis are 80-85% and 60-80%, respectively (Abbasoglu et al. ", "1997).", "\n\nHowever, occasionally, US is technically limited by extensive bowel gas or ascites and can show false-negative results because of the development of extensive arterial collaterals that produce an arterial signal on DUS, leading to the diagnosis of a patent artery.", "\n\nDSA is the gold standard for diagnosing hepatic artery complications and allows a concomitant angioplasty procedure under some circumstances; however, it is not an ideal screening test because of the associated high cost and invasive nature of the procedure with the associated risks and potential complications (Brancatelli et al. ", "2002).", "\n\nCTA, particularly with the development of a multi-detector row CT scanner with reconstruction algorithms, has been shown to accurately depict hepatic vasculature and its complications when compared with DSA (Katyal et al. ", "2000).", "\n\nFurthermore with CT, higher injection rates and contrast material volumes are needed for optimized angiographic evaluations compared with those for gadolinium-enhanced MR imaging.", "\n\n### 12.2.4 MR Angiography in OLT\n\nEarly and accurate diagnosis of vascular complications after liver transplantation is critical to the survival of the graft. ", "MRA can demonstrate the entire vascular tree with a single injection of contrast material.", "\n\nThree dimension CEMRA has recently become an alternative means of accurate, non invasive and rapid evaluation for hepatic vascular disease because image quality can be improved with thinner sections and shorter TR, resulting in a faster scanning time and fewer motion artifacts from incomplete breath-holding. ", "Improved temporal resolution and repeated sequences after contrast administration allow optimal and separate enhancement of the arteries and veins (Watanabe et al. ", "2000).", "\n\nA growing body of literature supports the accuracy of 3D CEMRA compared with that of DSA and in particular there has been good agreement between these techniques for the depiction of arterial and venous abnormalities, despite some limitations in small intrahepatic arteries (Hany et al. ", "1997; Ernst et al. ", "2000).", "\n\nGlockner et al. ", "reported high sensitivity of MRA in detecting vascular complications in liver-transplant recipients (86%) (Glockner et al. ", "2000).", "\n\nKim et al. ", "reported a sensitivity of 100% for the detection of hepatic artery stenosis; however, the authors obtained a specificity of 74%, with 7 out of 23 false-positive cases, indicating that CEMRA tends to overestimate hepatic artery stenosis (Kim et al. ", "2003).", "\n\nThis fact might be explained by the following factors. ", "First, the susceptibility artifact from the surgical clips adjacent to the hepatic arterial anastomotic site creates focal signal loss of the hepatic artery, mimicking stenosis. ", "Second, low-flow states can play an important role in creating false-positive findings of arterial disease. ", "Low-flow states are caused by the inflow of small amounts of contrast material into the intrahepatic artery because of elevated end-organ resistance (i.e., recently transplanted edematous liver, graft rejection) or a decrease of systemic (i.e., systemic hypotension) or localized (i.e., splenic artery steal) blood volume (Pandharipande et al. ", "2001).", "\n\nThird, because of the small size of the lobar hepatic artery in living related liver transplantation grafts, subtle vascular signals cannot be distinguished from background signals in a small vessel, thereby producing an overestimation of the amount of stenosis.", "\n\nNevertheless, MRA has a high sensitivity and an excellent negative predictive value for the detection of clinically significant vascular stenosis (Kim et al. ", "2003).", "\n\nIn addition MRA shows a higher sensitivity and accuracy than DSA for the detection of thrombosis or the assessment of vessel patency in any part of the portal venous system (Mori et al. ", "1992).", "\n\nMRA, may be also performed to evaluate the extent and degree of the porto-systemic collateral vessels resulting from portal hypertension. ", "It is important that a diagnosis of portal vein stenosis correlates with both the clinical findings and DUS (most cases of portal vein stenosis are accompanied by symptoms of portal hypertension, such as varices, upper gastrointestinal hemorrhage, splenomegaly, massive ascites, hepatic failure and intestinal swelling).", "\n\nBesides, CEMRA can be used to evaluate the IVC. ", "IVC thrombus is depicted as an intraluminal defect. ", "Coronal scanning is useful for determining the extent of IVC thrombus (Ito et al. ", "2000).", "\n\nFurthermore, high-performance work-station and multiplanar reformations have entered the clinical routine. ", "Most published studies on the topic state that volume rendered images are superior to MIP images for the grading of stenoses. ", "Multiplanar reformations also allow for a superior conspicuity of the vascular structures, which is most valuable in case of a complex anatomy (Mallouhi et al. ", "2002; Baskaran et al. ", "2002).", "\n\n## 12.3 Conclusions\n\nThe advances of hardware, software and contrast agents have effectively increased the quality of abdominal MRA. ", "The high image quality and the small number of side effects have made MRA of the abdominal vessels a first line imaging tool for various pathological entities. ", "Actually, 3D MRA can be a useful, noninvasive technique for evaluating vascular anatomy in preoperative imaging and an appropriate substitute for repetitive follow-up examinations for early and accurate diagnosis of vascular compromise in patients post-OLT. ", "Besides, MR imaging can provide a comprehensive assessment of parenchymal, biliary and vascular findings both in presurgical and postsurgical evaluation, restricting the use of invasive procedures to patients for whom therapeutic procedures are advocated or whose MR studies are equivocal (Boraschi et al. ", "2008).", "\n\nReferences\n\nAbbasoglu O, et al. (", "1997) Hepatic artery stenosis after liver transplantation: incidence, presentation, treatment, and long-term outcome. ", "Transplantation 63:250-255CrossRefPubMed\n\nBaskaran V, et al. (", "2002) Gadolinium-enhanced 3D MR angiog-raphy of renal artery stenosis: a pilot comparison of maximum intensity projection, multi planar reformatting, and 3D volume-rendering postprocessing algorithms. ", "Acad Radiol 9:50-59CrossRef80296-9)PubMed\n\nBoeve WJ, et al. (", "2001) Superior diagnostic strength of combined contrast enhanced MR-angiography and MR-imaging compared to intra-arterial DSA in liver transplantation candidates. ", "Magn Reson Imaging 19:609-622CrossRef00378-2)PubMed\n\nBoraschi P and Donati F (2004) Complications of orthotopic liver transplantation: imaging findings. ", "Abdom Imaging 2:189-202CrossRef\n\nBoraschi P, et al. (", "2008) Complications after liver transplantation: evaluation with magnetic resonance imaging, magnetic resonance cholangiography and 3-dimensional contrast-enhanced magnetic resonance angiography in a single session. ", "Can Assoc Radiol J 59:259-263PubMed\n\nBowen A, et al. (", "1996) Imaging in liver transplantation. ", "Radiol Clin North Am 34:757-778PubMed\n\nBrancatelli G, et al. (", "2002) Three-dimensional multislice helical computed tomography with the volume rendering techniques in the detection of vascular complications after liver transplantation. ", "Transplantation 73:237-242CrossRefPubMed\n\nCaramella D, Perri M (2008) Transplantation Liver. ", "In: Beart AL (ed) Encyclopedia of diagnostic imaging, vol 2. ", "Springer, Berlin, pp 1842-1846CrossRef\n\nCavallari A, et al. (", "2000) Complications of liver transplantation. ", "In: Bucheler E, Nicolas V, Rogiers X, Krupski G (eds) Diagnostic and interventional radiology in liver transplantation. ", "Springer, Berlin, pp 167-177\n\nCatalano O, et al. (", "2008) Vascular and biliary variants in the liver: implications for liver surgery. ", "Radiographics 28:359-378CrossRefPubMed\n\nCovey AM, et al. (", "2002) Variant hepatic arterial anatomy revisited: digital subtraction angiography performed in 600 patients. ", "Radiology 224:542-547CrossRefPubMed\n\nErnst O, et al. (", "2000) Comparing contrast-enhanced breath-hold MR angiography and conventional angiography in the evaluation of mesenteric circulation. ", "AJR 174:433-439PubMed\n\nFink C, Ley S, Kroeker R, et al (2005) Time-resolved contrast-enhanced threedimensional magnetic resonance angiogra-phy of the chest: combination of parallel imaging with view sharing (TREAT). ", "Invest Radiol 40:40-48CrossRefPubMed\n\nGlanemann M, et al. (", "2002) Results of end-to-end cavo-cavostomy in adult liver transplantation. ", "World J Surg 26:342-347CrossRefPubMed\n\nGlockner JF, et al. (", "2000) Three-dimensional gadolinium-enhanced MR angiography of vascular complication after liver transplantation. ", "AJR 174:1447-1453PubMed\n\nHany T F, et al. (", "1997) Evaluation of the aortoiliac and renal arteries: comparison of breath-hold, contrast-enhanced, three-dimensional MR angiography with conventional catheter angiography. ", "Radiology 204:357-362PubMed\n\nHeilmaier C, et al. (", "2007) Mapping of hepatic vascular anatomy: dynamic contrast-enhanced parallel MR imaging compared with 64-detector row CT. ", "Radiology 245:872-880CrossRefPubMed\n\nHussain HK and Nghiem HV (2002) Imaging of hepatic transplantation. ", "Clin Liver Dis 6:247-270CrossRef00075-8)PubMed\n\nIto K, et al. (", "2000) MR imaging of complications after liver transplantation. ", "AJR 175:1145-1149PubMed\n\nKatyal S, et al. (", "2000) Detection of vascular complications after liver transplantation: early experience in multislice CT angiography with volume rendering. ", "AJR 175:1735-1739PubMed\n\nKim BS, et al. (", "2003) Vascular complications after living related liver transplantation: evaluation with gadolinium-enhanced three-dimensional MR angiography. ", "AJR 181:467-474PubMed\n\nLavelle MT, et al. (", "2001) Dynamic contrast-enhanced three-dimensional mr imaging of liver parenchyma: source images and angiographic reconstructions to define hepatic arterial anatomy. ", "Radiology 218:389-394PubMed\n\nLee VS, et al. (", "2000) Hepatic MR imaging with adynamic contrast-enhanced isotropic volumetric interpolated breath-hold examination: feasibility, reproducibility, and technical quality. ", "Radiology 215:365-372PubMed\n\nLeelaudomlipi S, et al. (", "2003) Hepatic artery aneurysm in adult liver transplantation. ", "Transplant Int 16:257-261CrossRef\n\nLerut JP, et al. (", "1997) Adult liver transplantation and abnormalities of splanchnic veins: experience in 53 patients. ", "Transplant Int 10:125-132CrossRef\n\nLeung DA, et al. (", "1999) Diagnostic imaging in liver transplantation. ", "In: Bartolozzi C, Lencioni R (eds) Liver malignancies. ", "Springer, Berlin, pp 423-442\n\nMallouhi A, et al. (", "2002) 3D MR angiography of renal arteries: comparison of volume rendering and maximum intensity projection algorithms. ", "Radiology 223:509-516CrossRefPubMed\n\nMarujo WC, et al. (", "1991) Vascular complications following orthotopic liver transplantation: outcome and role of urgent revascularization. ", "Transplant Proc 23:1484-1486PubMed\n\nMichaely HJ, et al. (", "2006) MRA of abdominal vessels: technical advances. ", "Eur Radiol 16:1637-1650CrossRefPubMed\n\nMichel NA (1955). ", "Blood supply and anatomy of the upper abdominal organs with a descriptive atlas. ", "Lippincott, Philadelphia, pp 64-69\n\nMori K, et al. (", "1992) The introduction of microvascular surgery to hepatic artery reconstruction in living-donor liver transplantation: its surgical advantages compared with conventional procedures. ", "Transplantation 54:263-267CrossRefPubMed\n\nPandharipande P V, et al. (", "2001) Vascular and extravascular complications of liver transplantation: comprehensive evaluation with three-dimensional contrast-enhanced volumetric MR imaging and MR cholangiopancreatography. ", "AJR 177:1101-1107PubMed\n\nPannu HK, et al. (", "2001) Liver transplantation: preoperative CT evaluation. ", "Radiographics 21:133-146\n\nPfammatter T, et al. (", "1997) Suprahepatic caval anastomotic stenosis complicating orthotopic liver transplantation: treatment with percutaneous transluminal angioplasty, Wallstent placement, or both. ", "AJR 168:477-480PubMed\n\nSahani D, et al. (", "2004) Preoperative hepatic vascular evaluation with CT and MR angiography: implications for surgery. ", "Radiographics 24:1367-1380CrossRefPubMed\n\nSchroeder T, et al. (", "2005) \"All-in-one\" imaging protocols for the evaluation of potential living liver donors: comparison of magnetic resonance imaging and multidetector computed tomography. ", "Liver Transpl 11:776-787CrossRefPubMed\n\nSoyer P, et al. (", "1996) Three-dimensional helical CT of intrahe-patic venous structures: comparison of three rendering techniques. ", "J Comput Assist Tomogr 20:122-127CrossRefPubMed\n\nStafford-Johnson DB, et al. (", "1998) Vascular complications of liver transplantation: evaluation w ith gadolinium enhanced MR angiography. ", "Radiology 207:153-160PubMed\n\nStange BJ, et al. (", "2003) Hepatic artery thrombosis after adult liver transplantation. ", "Liver Transpl 9:612-620CrossRefPubMed\n\nWatanabe Y, et al. (", "2000) Dynamic subtraction contrast-enhanced MR angiography: technique, clinical applications and pitfalls. ", "Radiographics 20:135-152PubMed\nE. Neri, M. Cosottini and D. Caramella (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3_13(C) Springer-Verlag Berlin Heidelberg 2010\n\n# 13. ", "MRA in Transplanted Pancreas and Kidneys\n\nPiero Boraschi1 , Francescamaria Donati1 and Valentina Battaglia2\n\n(1)\n\nSecond Unit of Radiology, Department of Oncologic and Radiological Sciences, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy\n\n(2)\n\nDiagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologiesin Medicine, University of Pisa, Via Roma 67, Pisa, 56126, Italy\n\n13.1 Introduction\n\n13.2 Vascular Anatomy in Transplants\n\n13.2.1 Pancreas\n\n13.2.2 Kidney\n\n13.3 Transplants and Diagnostic Imaging\n\n13.4 MR Angiography\n\n13.4.1 Study Technique\n\n13.5 MR Angiography and Vascular Complications of Pancreatic Transplant\n\n13.6 MR Angiography and Vascular Complications of Kidney Transplant\n\n13.7 Conclusion\n\nReferences\n\nAbstract\n\nThanks to the technical and technological advancements, MRA has been more and more applied in the pre and postoperative evaluation of transplants, being used both in cases of presurgical analysis of kidney living donors, as well as in the follow-up of transplanted pancreas and kidneys in patients, especially in cases of suspected vascular complications.", "\n\nActually CEMRA studies show a high diagnostic accuracy in the evaluation of vascular complications of transplanted pancreas and kidneys. ", "CEMRA can therefore become an appropriate method of diagnostic angiography in the detection of transplant vessel stenosis and/or thrombosis, and can help to rapidly and noninvasively select patients for therapeutic interventional angiography, surgical correction or medical management.", "\n\n## 13.1 Introduction\n\nPancreatic and renal transplants represent the defini-tive treatment for patients affected by diabetes mel-litus of type I and chronic renal failure, respectively (Morris et al. ", "2004).", "\n\nIn these last few years, thanks to the improvements and refinement of surgical techniques and to the efficacy of posttransplant medical care, transplants have been quite frequently performed, showing high rates of peri- and postoperative survival, as well as a decreased peri-operative mortality or organ failure episodes (Hagspiel et al. ", "2007).", "\n\nAnyway, transplantation still remains a technically challenging procedure, often affected by serious complications, as for example, sepsis, rejection and, even more frequently, by graft-vessel diseases, which frequently result in transplant necrosis and necessitate graft removal (Krebs et al. ", "1995).", "\n\nSince its introduction, magnetic resonance angiog-raphy (MRA) has stirred up an increasing interest among the multiple noninvasive exploring techniques, especially because of the widespread field of appli cation. ", "Recently, thanks to the technical and technological advancements, MRA has been more and more applied also in the pre and postoperative evaluation of transplants, being used both in cases of presurgical analysis of kidney living donors, as well as in the follow-up of transplanted patients, especially in cases of suspected vascular complications (Vosshenrich and Fischer 2002).", "\n\nNowadays, vascular complications represent in fact the most common cause of early transplant failure, both in cases of renal and pancreatic allograft, while, thanks to the introduction of powerful immunosup-pressive drugs, acute or chronic allograft rejection has become only the second cause of graft loss (Hagspiel et al. ", "2007).", "\n\nAmong all possible diseases, graft vascular thrombosis is the most common cause of vascular pancreatic transplant dysfunction (Grewal et al. ", "1993; Douzdjian et al. ", "1993) with an incidence ranging between 2 and 19% (Hagspiel et al. ", "2007) and it often necessitates pancreatectomy, while in cases of renal transplant, arterial stenosis is the most common cause that usually occurs in a percentage ranging between 1 and 25% (Fervenza et al. ", "1998).", "\n\nThe importance of obtaining an accurate and early diagnosis of a suspected vascular complication after a pancreatic transplant finds its rationale in the successful treatment of a number of complications, by performing a surgical or endovascular approach, as reported in some published studies (Orsenigo et al. ", "2003).", "\n\n## 13.2 Vascular Anatomy in Transplants\n\n### 13.2.1 Pancreas\n\nApart from the different exocrine drainage (enteric or vescical), two types of vascular drainage can be applied when performing a pancreatic transplantation. ", "The first introduced technique foresees the intraperitoneal placement of the allograft in the pelvis and the subsequent anastomosis between the donor splenic and superior mesenteric artery (SMA) and the recipient's iliac arteries by way of a donor Y-graft, with pancreatic venous outflow typically collecting into the common or external iliac vein and thus achieves the systemic circulation (Hagspiel et al. ", "2007).", "\n\nA further variant of pancreatic transplantation, reintroduced in 1995, is the commonly referred \"porto-enterical\" variant. ", "In this technique, the pancreatic allograft is placed intraperitoneally but higher in the recipient's abdomen. ", "The pancreatic arteries, splenic artery and SMAs are anastomosed to the iliac arteries or aorta as well because of the higher position in the abdomen by way of a longer Y-graft formed from the donor's common, internal, and external iliac arteries. ", "Pancreatic venous outflow is in this case achieved by anastomosing the transplant portal vein with the recipient's portal venous system, typically the superior mesenteric vein and less commonly the splenic vein (Heyneman et al. ", "1999).", "\n\n### 13.2.2 Kidney\n\nDifferent from pancreatic transplantation techniques, the method adopted in cases of renal transplant is simpler and contemplates a direct anastomosis between donor and recipient vessels without the need of a Y-graft. ", "Transplanted kidney is preferentially placed extraperitoneally in the right iliac fossa. ", "Generally the harvest kidney is the left one because of the longer renal vein with respect to that of controlateral. ", "The donor artery is usually anastomosed to the ipsilateral external or common iliac artery, even if in some cases the anastomosis is realized to the recipient hypogas-tric vessel. ", "The ureter is anastomosed to the bladder (Hohenwalter et al. ", "2001).", "\n\n## 13.3 Transplants and Diagnostic Imaging\n\nAs clinical and laboratory analysis can often be insensitive and unspecific in detecting the first signs of allograft rejection, imaging modalities are nowadays considered as the reference methods in order to highlight a suspected graft dysfunction.", "\n\nDiagnostic imaging, including computed tomography (CT), color-Doppler ultrasonography (US) and digital subtraction angiography (DSA), have demonstrated to be sensitive in detecting pancreatic dysfunction but are relatively unspecific in differentiation between vascular and parenchymal causes of organ failure.", "\n\nAnyway, among all the different imaging techniques able to visualize and analyse transplanted organs and relative transplanted vessels, in these last few years MR, and particularly MRA, has stirred up an increasing interest thanks to the intrinsic characteristics of the method.", "\n\n## 13.4 MR Angiography\n\nMR angiography is actually considered as a valid and accurate alternative of DSA in the evaluation and analysis of suspected pathologies of vessels (Ta n*et al. ", "2002). ", "The strong contribution of MRA in the diagnostic imaging of both on list and transplanted patients has markedly risen up during these last few years, mainly because of the characteristics of the technique, as well as of the remarkable improvements of technology.", "\n\nAs well known, the avoidance of ionizing radiations and the possibility to obtain images on multiple spatial planes are two fundamental characteristics of MR imaging that allow the performance of the technique even in patients with chronic renal failure, often permitting tissue characterization without the use of contrast medium. ", "By acquiring conventional MR images of the abdomen before contrast administration, the same MR examination allows to evaluate not only the presence of incidental pathologies but also to accurately evaluate the graft parenchymal status, especially in cases of suspicion of acute or chronic organ failure (Choyke et al. ", "1997).", "\n\nMoreover, differently from conventional angiog-raphy, MRA requires only intravenous administration of gadolinium-based contrast material, thereby averting the catheter-related risks.", "\n\nAnyway, despite the multiple advantages in performing MRA, the technique shows some disadvantages mainly related to artefacts associated with respiratory and bulk motion, and frequent inadvertent venous enhancement.", "\n\nRecently, the use of 2D time-of-flight and phase contrast MRA has been clinically abandoned for the study of abdominal vessels, because of the advent of newer contrast-enhanced MRA (CEMRA) techniques that enable the evaluation of the vasculature in less time, with greater detail and showing a greater stability (Hagspiel et al. ", "2007).", "\n\nFaster 3D gradient-echo MR imaging pulse sequences can be in fact used within the time frame of a single breath hold without loss of spatial resolution, which help in minimizing motion artefacts, usually affecting the previously applied flow-based sequences.", "\n\nMoreover, the decreased echo times of the newer sequences can help to reduce the signal intensity loss associated with spin de-phasing and therefore may help to minimize the overestimation of stenoses that, to varying degrees, first plagued all bright-blood MRA techniques (Bosmans et al. ", "2001).", "\n\n### 13.4.1 Study Technique\n\nThe evaluation of abdominal vessels with CEMRA must be performed with high-field strength magnets (1.5-3 T), by applying a dedicated phased-array coil (Hagspiel et al. ", "2007). ", "Various improvements in the hardware (faster gradients, higher magnetic field strengths, multiple parallel receiver channels and dedicated coils), the sequence techniques (volume-interpolated breath-hold-sequences), the contrast agents (agents with higher relaxivity, such as Gd-BOPTA and Gadobutrol) and the postprocessing software have become available during the past few years (Michaely et al. ", "2006).", "\n\nBaseline MR study usually includes axial T1-weighted fast low-angle shot sequences and axial T2-weighted turbo spin-echo sequences with fat suppression, mainly applied in order to identify peri-graft fluid collections and to evaluate transplants parenchyma. ", "In cases of evaluation of pancreatic transplants, it can be also useful to perform T1-weighted images in order to evaluate normal pancreatic signal intensity (Winston et al. ", "1995) and to highlight peri-pancreatic hematoma or hemorrhagic necrosis; moreover, the use of fat suppression can aid in evaluating the signal intensity of the pancreas, which is normally hyperintense relative to the liver (Dobos et al. ", "2005).", "\n\nMore recently, CEMRA study includes a breath-hold 3D interpolated spoiled gradient-echo sequence (VIBE, L AVA, THRIVE) in the axial or more frequently in the coronal plane; these latter sequences are basically very similar to 3D-GRE sequences as they are used for abdominal MRA, yet they only sample one part of the k-space and perform a zero-filling in the 3D (partition) phase-encode direction to complete the k-space. ", "As fast 3D sequences, they are mainly applied for multi-phasic studies of the liver, kidneys and pancreas. ", "They are heavily T1-weighted and can provide substantial angiographic information when acquired immediately postcontrast agent administration, but they also offer morphologic information (Lee et al. ", "2000).", "\n\nThe average amount of contrast media injected to perform a study of the abdominal vessels has been reported to be 0.01-0.02 mmol/kg (15-30 mL), administrated at a flow rate of 2-3 mL/s, with a minimum of two acquisitions performed with an inter-imaging delay of 10 s to depict both the arterial and the venous enhancement phases (Hagspiel et al. ", "2007).", "\n\nImaging acquisition is performed during both the arterial and venous phases of enhancement to evaluate the arterial and venous components of the transplant, respectively, followed by delayed axial fat-suppressed T1-weighted imaging (Dobos et al. ", "2005).", "\n\nAll examinations are acquired in breath-hold, sometimes with subtraction technique, both for the arterial and the venous phase. ", "Imaging dataset is then analyzed at dedicated workstation, where it is possible to perform also 3D reconstructions such as multi planar volume reconstruction (MPVR), curved planar volume reconstruction (CPVR), maximum intensity projection (MIP), and volume rendering (VR). ", "Even if these algorithms can furnish a paramount vision of the focused abdominal region, artefacts must be always be detected and considered; MIP reconstruction often results in an overestima-tion of the degree of stenosis and can also obscure small intraluminal filling defects such as dissection flaps, but it has proved to be very useful in the detection of small accessory vessels (Bakker et al. ", "1998).", "\n\n## 13.5 MR Angiography and Vascular Complications of Pancreatic Transplant\n\nThe role of MR angiography in the detection of vascular complications of pancreatic transplants has been investigated till now in a limited number of studies (Hagspiel et al. ", "2007).", "\n\nMultiphasic breath-hold gadolinium-enhanced 3D MR imaging is nowadays considered as an extraordinarily accurate diagnostic technique, which can provide information to make the specific diagnosis of vessel complications and to assess parenchymal viability after pancreas transplantation (Hagspiel et al. ", "2005). ", "The technique allows the evaluation of the normal venous and arterial anatomy of pancreatic allograft (Fig. ", "13.1), showing the appearance of the major vascular complications.", "\n\nFig. ", "13.1.", "\n\nMIP reformations (a, b) obtained from arterial phase of CEMRA show the vascularization of the pancreas in a case of combined kidney--pancreas transplantation with enteric-portal pancreatic drainage. ", "Mesenteric and splenic branches of the arterial graft anastomosed with the right common iliac artery are depicted. ", "MIP reconstructions (c, d) of the venous vessels from venous phase of CEMRA show the anastomotic junction between the donor's portal vein and the recipient's superior mesenteric vein which allows the insulin drainage in the portal vein\n\nThe performance of diagnostic MRA, revealing a vascular complication amenable to intraluminal therapy, would in fact obviate the need for invasive procedure such as diagnostic conventional angiogra-phy. ", "Instead, in case of a pathological finding, MRA furnishes anyway an accurate diagnosis, allowing the reduction of imaging frames and the amount of contrast medium when performing an eventual therapeutic DSA.", "\n\nVascular thrombosis is the most common cause of pancreatic allograft dysfunction, with a reported incidence of 2-19%, followed by rejection (Fernandez et al. ", "1991).", "\n\nTransplanted pancreas is believed to be more vulnerable to thrombosis than renal graft because of the lower rate of blood flow received in transplanted pancreas (approximately the 1.3% instead of the 5% of cardiac output) (Krebs et al. ", "1995).", "\n\nGraft thrombosis can be classified as early or late according to the time after surgery.", "\n\nEarly graft thrombosis is usually the result of vascular graft anastomotic error or microvascular damage from preservation injury. ", "Late thrombosis (i.e., that which occurs more than a month after surgery), usually results from severe acute rejection with alloimmune arteritis and causes occlusion of small vessels, which leads to complete major vessel occlusion. ", "Identification of total graft thrombosis and infarction is important, because the transplanted organ should be removed immediately to avoid the severe systemic effects of graft.", "\n\nThe evaluation with MR angiography has moreover the advantage to allow also the graft parenchymal status study. ", "Initially in fact, MR study is performed as a standard baseline MR evaluation, in which T1-and T2-weighted images are performed in the axial plane more frequently than in the coronal plane, especially for the detection of areas of altered signal intensity with respect to normal parenchyma, consisting mainly in either partial or complete lack of enhancement of the graft parenchyma after the intravenous administration of Gadolinium-chelates, as well as the detection of fluid collections (Eubank et al. ", "2000). ", "Then, contrast enhanced examination permits to highlight areas of altered parenchymal perfusion and moreover the presence of a graft vessel disease.", "\n\nIn the evaluation of a transplanted pancreas, the vessels usually analyzed are: (1) the distal aorta, the common, external and internal iliac arteries; the iliac Y-graft as well as the splenic artery (Fig. ", "13.2), SMA (Fig. ", "13.3) and the respective anastomoses; (2) the inferior cava vein; the common, external and internal iliac veins, the superior mesenteric vein, the portal vein and their respective anastomoses (Hagspiel et al. ", "2007).", "\n\nFig. ", "13.2.", "\n\nMIP (a) and volume-rendered (b) images obtained from arterial phase of CEMRA, exhibit the complete thrombosis of the splenic branch of the pancreatic arterial graft in a case of combined kidney-pancreas transplantation with enteric-portal pancreatic drainage. ", "Mesenteric branch of the arterial graft anastomosed with the common iliac artery is identified. ", "Volume-rendered reconstructions (c, d) show regular patency of the venous vessels\n\nFig. ", "13.3.", "\n\nMIP (a) and volume-rendered (b, c) reconstructions of CEMRA show the complete thrombosis of the mes-enteric branch and the mild stenosis of the splenic branch of the pancreatic arterial graft anastomosed with the right common iliac artery in a case of isolated pancreas transplantation with enteric-portal drainage\n\nThe signs of vascular pathologies are anyway the same as those depicted in common DSA, as well as in the CT evaluation (Krebs et al. ", "1995).", "\n\nThe typical appearance of an acute thrombosis on contrast-enhanced MR angiography consists of a very dark hypointense filling defect occluding the arterial (Fig. ", "13.4) or the venous lumen (Fig. ", "13.5), with or without a trailing edge (Hagspiel et al. ", "2005). ", "In cases of arterial thrombosis, parenchymal status can anyway appear as normal, because patency of only one allograft artery is sufficient to supply adequate perfu-sion to the entire gland (Hagspiel et al. ", "2005).", "\n\nFig. ", "13.4.", "\n\nMIP (a, b) and volume-rendered (c) images obtained from arterial phase of CEMRA demonstrate the complete thrombosis of both the splenic and the mesenteric branch of the pancreatic arterial graft anastomosed with the right common iliac artery in a case of isolated pancreas transplantation with enteric-portal drainage. ", "A stenosis at the level of the anastomotic junction between the donor's portal vein and the recipient's superior mesenteric vein is showed on MIP reformation (d) obtained from venous phase of CEMRA in the same case\n\nFig. ", "13.5.", "\n\nMIP (a) and volume-rendered (b, c) images obtained from arterial phase of CEMRA highlight the pancreatic arterial graft anastomosed with the right external iliac artery (splenic branch is not visualized) and the renal graft anastomosed with the left external iliac artery in a case of combined kidney-- pancreas transplantation performed by means of the systemic-bladder drainage technique. ", "On MIP reconstructions (d, e) obtained from venous phase of CEMRA the splenic and the superior mesenteric veins are patent, while the anastomotic junction between the donor's portal vein (very thin) and the recipient's right iliac vein is completely obstructed. ", "The venous graft of the kidney anastomosed with left external iliac vein is patent and normally represented\n\nApart from acute or chronic thromboses, other frequent complications that can occur are stenoses of anastomoses (Figs. ", "13.3 and 13.4) and kinking of the graft, especially in cases of porto-enteric drainage grafts, in which the longer Y-graft can undergo no such complication. ", "In these cases, MR can furnish a detailed, non invasive, first diagnosis, permitting to accurately assess or exclude the presence of vascular complication and allowing then the performance of a therapeutic DSA only in true positive cases (Hagspiel et al. ", "2005).", "\n\n## 13.6 MR Angiography and Vascular Complications of Kidney Transplant\n\nKidney transplantation can be single or double (Fig. ", "13.6).", "\n\nFig. ", "13.6.", "\n\nAxial T2-weighted image (a) shows a double renal transplantation in the right iliac fossa. ", "MIP reconstructions (b, c) show the renal grafts anastomosed with the right common iliac artery and with the right external iliac artery\n\nVascular thrombosis after renal transplantation usually occurs more frequently than in cases of pancreatic allografts (Krebs et al. ", "1995).", "\n\nVascular complications associated with renal transplantation merit urgent investigation as they are often correctable and timely intervention can help to keep the graft kidney safe. ", "Renal transplantation is associated with a 1-15% incidence of vascular complications (Jain and Sawhney 2005).", "\n\nThe most important complication after renal transplantation is represented by arterial stenosis (TRAS), that can occur either in the native or in the donor artery as well as at the anastomosis (Fig. ", "13.7) and represents by itself the 75% of all posttransplant vascular complication (Hohenwalter et al. ", "2001).", "\n\nFig. ", "13.7.", "\n\nMIP (a, b) and volume-rendered (c, d) images obtained from arterial phase of CEMRA demonstrate a stenosis at the anastomotic site between the donor's renal artery and the recipient's right external iliac artery in a case of isolated kidney transplantation in the right iliac fossa\n\nIt usually becomes apparent between 3 months and 2 years after renal transplantation, but it can present at any time. ", "It frequently shows with worsening or refractory hypertension and/or graft dysfunction in the absence of rejection, ureteric obstruction, or infection.", "\n\nIt has been shown by some recent studies that CEMRA offers a diagnostic evaluation comparable to that of DSA, with the advantage of not exposing the patient to ionizing radiations (Bakker et al. ", "1998) and it can be applied as a screening method in suspected cases, with DSA reserved to selected patients who may be amenable to angioplast y (Hohenwalter et al. ", "2001). ", "If the main renal artery shows a normal morphology and a normal intravascular blood flow at CEMRA, DSA can infact be avoided.", "\n\nStenosis at the peri-anastomotic site (Fig. ", "13.8) is the most common vascular complication of renal transplantation, with a 1-15% incidence; in the diagnosis, CEMRA has proved to be highly accurate, showing a sensitivity and specificity of 100 and 96%, respectively (Hohenwalter et al. ", "2001).", "\n\nFig. ", "13.8.", "\n\nMIP (a, b) and volume-rendered (c, d) images obtained from arterial phase of CEMRA well exhibit a stenosis immediately distal to the anastomotic site between the donor's renal artery and the recipient's left external iliac artery in a case of combined kidney--pancreas transplantation with enteric-portal pancreatic drainage. ", "A prestenotic dilation of left external iliac artery is also appreciable. ", "On MIP reconstruction (e) obtained from venous phase of CEMRA we can visualize both the renal vein (v) anastomosed with the left external iliac vein and the left external iliac artery (a)\n\nDonor renal artery stenosis is a rarer cause of TRAS: Fibromuscular dysplasia, vasculitis and extrinsic compressions due to fluid collections and masses can result in donor artery stenosis. ", "Renal artery branch stenoses are also forms of donor artery stenosis.", "\n\nOn the contrary, older transplant recipients are prone to peripheral vascular disease and may have pseudo-TRAS because of atherosclerotic vascular disease involving their iliac system. ", "Pretransplant assessment of the native arteries with CEMRA may be useful in high-risk diabetic and chronic hypertensive patients, in order to prevent this complication.", "\n\nOn imaging examination, the presence of TRAS can be indirectly assessed by many signs, as for example the arterial occlusion (visualized as a filling defect of the vessels), a poststenotic dilation, as well as a delayed renal enhancement or a parenchymal mass reduction (cortical thinning and reduced renal length), especially in cases of chronic stenoses. ", "Other signs of chronic arterial stenosis or occlusion of smaller branch arteries or thin accessory vessels are perfusion defects and infarcts, very well depicted as inhomogenously enhancing areas, especially in the arterial phase. ", "MRA has revealed moreover an excellent method in identifying not only the main renal artery stenoses but also the possible kinking of the vessel that can occur in cases of excessively long donor artery. ", "In CEMRA the kinking can be both morphologically and functionally detected, as a turbulent blood flow (Amante and Kahan 1994).", "\n\nDifferently from pancreatic transplants, renal vein diseases are much more uncommon than arterial ones. ", "Renal vein thrombosis is not so common and generally it occurs within the first week after transplantation, in up to 4% of patients. ", "It is usually related to inadequate surgical technique, hypo-volaemia or systemic venous thrombosis. ", "Renal vein thrombosis often results in transplant infarction and graft loss. ", "Even if the diagnosis is usually made by a not expensive, as well as not invasive, techniques (color-Doppler US), both contrast-enhanced CT and CEMRA can easily demonstrate the abnormality.", "\n\nRenal vein stenosis as well as anastomotic stenosis or extrinsic renal vein compression caused by local fluid collections or local fibrosis represent even much rarer complications.", "\n\n## 13.7 Conclusion\n\nActually CEMRA studies show a high diagnostic accuracy in the evaluation of vascular complications of transplanted pancreas and kidneys. ", "CEMRA can therefore become an appropriate method of diagnostic angiography in the detection of transplant vessel stenosis and can help to rapidly and noninvasively select patients for therapeutic interventional angiog-raphy, surgical correction or medical management.", "\n\nReferences\n\nAmante AJM, Kahan BD (1994) Technical complications of renal transplantation. ", "Surg Clin North Am 74:1117-113PubMed\n\nBakker J, Beek FJA, Beutler JJ, et al. (", "1998) Renal artery stenosis and accessory renal arteries: accuracy of detection and visualization with Gadolinium-enhanced breath-hold MR angiography. ", "Radiology 207:497-504PubMed\n\nBosmans H, Wilms G, Dymarkowski S, et al. (", "2001) Basic principles of MRA. ", "Eur J Radiol 38:2-9CrossRef00284-4)PubMed\n\nChoyke PL, Walther MM, Wagner JR, et al. (", "1997) Renal cancer: preoperative evaluation with dual phase three-dimensional MR angiography. ", "Radiology 205:767-771PubMed\n\nDobos N, Roberts DA, Insko EK et al. (", "2005) Contrast-enhanced MR angiography for evaluation of vascular complications of the pancreatic transplant. ", "Radiographics 25:687-695CrossRefPubMed\n\nDouzdjian V, Abecassis MM, Cooper JL, et al. (", "1993) Pancreas transplant salvage after acute venous thrombosis. ", "Transplantation 56:222-223CrossRefPubMed\n\nEubank WB, Schmiedl U P, AE Levy, et al. (", "2000) Venous thrombosis and occlusion after pancreas transplantation: evaluation with breath-hold Gadolinium-enhanced three-dimensional MR imaging. ", "AJR Am J Roentgenol 175:381-385PubMed\n\nFernandez M P, Bernardino ME, Neylan JF, et al. (", "1991) Diagnosis of pancreatic transplant dysfunction: value of gadopentetate dimeglumine-enhanced MR imaging. ", "AJR Am J Roentgenol 156:1171-1176PubMed\n\nFervenza FC, Lafayette RA, Alfrey EJ, et al. (", "1998) Renal artery stenosis in kidney transplants. ", "Am J Kidney Dis 31:142-148CrossRefPubMed\n\nGrewal H P, Garland L, Novalk K, et al. (", "1993) Risk factors for postimplantation pancreatitis and pancreatic thrombosis in pancreas transplant recipients. ", "Transplantation 56:609-612CrossRefPubMed\n\nHagspiel KD, Nandalur K, Burkholder B, et al. (", "2005) Contrast-enhanced MR angiography after pancreas transplantation: normal appearance and vascular complications. ", "AJR Am J Roentgenol 184:465-473PubMed\n\nHagspiel KD, Nandalur K, Pruett TL, et al. (", "2007) Evaluation of vascular complications of pancreas transplantation with high-spatial-resolution contrast enhanced MR angiogra-phy. ", "Radiology 242:590-599CrossRefPubMed\n\nHeyneman LE, Keogan MT, Tuttle-Newhall JE, et al. (", "1999) Pancreatic transplantation using portal venous and enteric drainage: the postoperative appearance of a new surgical procedure. ", "J Comput Assist Tomogr 23:283-290CrossRefPubMed\n\nHohenwalter MD, Skowlund CJ, Erickson SJ, et al. (", "2001) Renal transplant evaluation with MR angiography and MR imaging. ", "Radiographics 21:1505-1517PubMed\n\nJain R, Sawhney S. (2005) Contrast-enhanced MR angiography (CE-MRA) in the evaluation of vascular complications of renal transplantation. ", "Clin Radiol 60:1171-1181CrossRefPubMed\n\nKrebs TL, Daly B, Wong JJ, et al. (", "1995) Vascular complications of pancreatic transplantation: MR evaluation. ", "Radiology 196:793-798PubMed\n\nLee VS, Lavelle MT, Rofsky NM, et al. (", "2000) Hepatic MR imaging with a dynamic contrast-enhanced isotropic volumetric interpolated breath-hold examination: feasibility, repro-ducibility, and technical quality. ", "Radiology 215:365-372PubMed\n\nMichaely HJ, Dietrich O, Nael K, et al. (", "2006) MRA of abdominal vessels: technical advances. ", "Eur Radiol 16:1637-1650CrossRefPubMed\n\nMorris MC, Santella RN, Aaronson ML, et al. (", "2004) Pancreas transplantation. ", "SDJ Med 57(7):269-272\n\nOrsenigo E, De Cobelli F, Salvioni M, et al. (", "2003) Successful endovascular treatment for gastroduodenal artery pseudo-aneurysm with an arteriovenous fistula after pancreas transplantation. ", "Transpl Int 16:647-696CrossRef\n\nTan KT, Van Beek EJR, Brown PWG, et al. (", "2002) Magnetic resonance angiography for the diagnosis of renal artery stenosis: a meta-analysis. ", "Clin Radiol 57:617-624CrossRefPubMed\n\nVosshenrich R, Fischer U (2002) Contrast-enhanced MR angiography of abdominal vessels: Is there still a role for angiography? ", "Eur Radiol 12:218-230CrossRefPubMed\n\nWinston CB, Mitchell DG, Outwater EK, et al. (", "1995) Pancreatic signal intensity on T1-weighted fat saturation MR images: clinical correlation. ", "J Magn Reson Imaging 5:267-271CrossRefPubMed\nEmanuele Neri, Davide Caramella, Mirco Cosottini, M. Anzidei, V. Battaglia, E. Belloni, F. Bianchi, P. Boraschi, G. Caproni, C. Catalano, A. Carriero, F. de Cobelli, M. Cosottini, F. Donati, L. Faggioni, R. Fossaceca, M. Francone, I. Iacucci, A. Laghi, M. Lombardi, P. Lucchesi, A. del Maschio, M. Milanesi, E. Neri, P. Paolantonio, I. Pesaresi, M. Rengo, A. Roberta, S. Salemi, M. di Terlizzi, F. Turini, V. Vallini, A. Vanzulli, C. Vignali, F. Vullo, V. Zampa and A. L. Baert (eds.)Diagnostic ImagingMR Angiography of the Body10.1007/978-3-540-79717-3(C) Springer-Verlag Berlin Heidelberg 2010\n\nSubject Index\n\nA\n\nAbdomen and pelvic veins\n\ncommon iliac veins\n\nexternal iliac vein\n\nhepatic veins\n\nhypogastric vein\n\ninferior vena cava\n\nlumbar veins\n\novarian veins\n\nportal system\n\nrenal veins\n\nspermatic veins\n\nAbdominal aorta\n\nSee alsoSee also Thoracic aorta\n\naortic occlusion\n\narterial spin labeling (ASL)\n\natherosclerotic and inflammatory aneurysms\n\nbalanced fast gradient echo\n\ncomputed tomography angiography (CTA)\n\ncontrast-enhanced MR angiography (CEMRA)\n\ndissection\n\nErdheim-Chester disease\n\ninfected aneurysm\n\nLeriche's syndrome\n\nmultislice computed tomography (MSCT)\n\nperfusion technique\n\nphase-contrast (PC) technique\n\nretroperitoneal fibrosis\n\nvascular stents and endoleak\n\nAneurysm\n\naortic aneurysm\n\nCE-MRA\n\nclinical manifestation\n\nfemoral\n\nlower limb\n\npopliteal\n\nsubclavian\n\nupper limb\n\nAortic dissection\n\nCEMRA\n\nclinical findings\n\nhistopathology\n\nMR features\n\nAortic occlusion\n\nAortic prostheses\n\nArterial anastomosis\n\nArterial spin labeling (ASL)\n\nArteries\n\nSee alsoSee also Thoracic aorta\n\nabdominal arteries\n\nlimb arteries\n\npulmonary arteries\n\nthoracic aorta\n\nArtifacts\n\nclassification\n\nflow artifacts\n\ngeometric artifacts\n\nhinge artifact\n\nmagnetic susceptibility artifacts\n\nMaki artifacts\n\npatient artifacts\n\npostprocessing\n\nradiofrequency artifacts\n\nvascular blurring\n\nAtherosclerotic disease\n\nadvantages\n\nclassification error\n\ncontrast enhancement\n\ndiagnostic accuracy\n\nhistopathology\n\nMIP coronal reconstruction\n\npreoperative evaluation\n\nradiological findings\n\nstenosis overestimation\n\nB\n\nBalanced fast field echo (BFFE) imaging\n\nbright blood technique\n\ndissection entry site\n\npulmonary vessel\n\nBalanced fast gradient echo\n\nBlack blood technique\n\nBlood-pool imaging\n\nBreath-hold imaging\n\nBright blood technique\n\nC\n\nCarotid arteries\n\natherosclerotic disease\n\ncervical artery dissection (CAD)\n\nCarotid endarterectomy (CEA)\n\nCervical artery dissection (CAD)\n\naneurismal dilation\n\nhematoma\n\npredisposing factors\n\nChemical exchange saturation transfer (CEST)\n\nComputed tomography angiography (CTA)\n\nContrast agents\n\nchemical exchange saturation transfer (CEST)\n\ndose and administration\n\ngadolinium\n\ngadolinium-based particulate agents\n\nhigh field\n\nhyperpolarized contrast agents\n\nmagnetic properties\n\nrelaxivity\n\nsafety\n\nsusceptibility effect\n\nvascular imaging\n\nvasovist®\n\nContrast-enhanced magnetic resonance angiography (CE-MRA)\n\n3D-GRE sequences\n\nabdominal aorta\n\natherosclerotic disease\n\nSee(see Atherosclerotic disease)\n\ncontrast administration\n\nimaging and acquisition technique\n\nk-space filling strategies\n\nliver\n\nlower limb arterial disease assessment\n\nneck vessel examination\n\nSee(see Neck vessel examination, CE-MRA)\n\nparallel imaging\n\nprinciple\n\npulmonary vessels\n\nrenal arteries\n\nsteady-state imaging\n\nthoracic aorta\n\nupper limb arterial disease assessment\n\nCoronary magnetic resonance angiography (CMRA)\n\nadvantages\n\narterial switch procedure\n\ncardiac and respiratory motion suppression\n\nclinical application\n\ncontrast agent\n\ncoronary artery and bypass functional evaluation\n\nflow measurement\n\nguidelines\n\nimage quality\n\nIMA grafts\n\nintravascular contrast agent\n\nKawasaki disease\n\nk-space segmentation\n\nlimitations\n\nparallel imaging technique\n\nphase-array coil design\n\nphase-contrast velocity quantification\n\nstenting and bypass\n\ntechnological requirement\n\nthree-dimensional image acquisition\n\nwhole heart CMRA\n\nCoronary stenting and bypass\n\nSeeSee Stenting and bypass\n\nD\n\nDiethylenetriaminepentaacetic acid\n\nDigital subtraction angiography (DSA)\n\nDipyridamole\n\nDonor renal artery stenosis\n\nE\n\nEndoleak\n\nEndovascular aortic repair (EVAR) procedure\n\nErdheim-Chester disease\n\nF\n\nFast imaging employing steady-state acquisition (FIESTA) image\n\nFast spin echo (FSE) pulse sequences\n\nFemoral aneurysm\n\nFlow-based MRA\n\nMR sequences\n\nphase contrast (PC) MR angiography\n\nT2-based MR angiography\n\ntime-of-flight MR angiography\n\nFlow quantification technique\n\nFree-breathing imaging\n\nG\n\nGadolinium\n\nGadolinium-based particulate agents\n\nGeometric artifacts\n\nGradient echo (GRE) imaging\n\nGraft thrombosis\n\nH\n\nHinge artifact\n\nHyperpolarized contrast agents\n\nI\n\nIMA graft stenosis\n\nInfected aortic aneurysm\n\nSee alsoSee also Mycotic aneurysm\n\nInferior vena cava (IVC) stenosis\n\nInflammatory aneurysms\n\nSeeSee Atherosclerotic disease\n\nIntramural hematoma\n\nCEMRA\n\nclinical findings\n\nhistopathology\n\nMR features\n\nK\n\nKawasaki disease\n\nK-space\n\nfilling strategies\n\nsegmentation\n\nL\n\nLeriche's syndrome\n\nLiver\n\n3D-gradient-echo sequence\n\ncontrast enhanced MR angiography (CE-MRA)\n\ndigital subtraction angiography (DSA)\n\nDoppler ultrasound (DUS)\n\nimage postprocessing\n\nMDCT angiography\n\nMichel hepatic artery classification\n\nMR angiography (MRA) vs. CTA and DSA\n\nportal vein trifurcation\n\ntime-resolved MRA\n\nvascular anatomy\n\nvascular imaging\n\nvolumetric imaging\n\nLuminography\n\nM\n\nMagnetic resonance sequences\n\nSee alsoSee also Pulse sequence imaging\n\nMagnetic susceptibility artifacts\n\nMaki artifacts\n\nMaximum intensity projection (MIP)\n\naortic aneurysm\n\npopliteal artery aneurysm\n\npulmonary vessels\n\nrenal artery\n\nrenal artery stenosis (RAS)\n\nsteno-occlusive disease\n\nthoracic aorta\n\nMichel hepatic artery classification\n\nMultifocal fibrosclerosis\n\nMultiplanar reconstruction (MPR)\n\naortic dissection\n\nimage analysis\n\nstenotic branch vessel\n\nthoracic vascular anomalies\n\nMultislice computed tomography (MSCT)\n\nMycotic aneurysm\n\nN\n\nNeck vessel examination, CE-MRA\n\nacquisition timing\n\nadvantages\n\nALS-based MRA\n\nartifacts\n\nbolus geometry\n\ncarotid arteries\n\nconsequences\n\ncontrast media and agent\n\nnonenhanced MRA technique\n\nparallel imaging technique\n\nsubclavian arteries\n\ntime resolution improvement\n\nvertebral arteries\n\nNephrogenic systemic fibrosis (NSF)\n\nNitinol\n\nO\n\nOrthotopic liver transplants (OLT)\n\nclinical manifestation\n\ncomplications\n\nIVC stenosis\n\nMR angiography\n\nsurgery\n\nP\n\nPancreatic transplants\n\nacute thrombosis\n\narterial stenosis\n\ncontrast-enhanced MRA (CEMRA) techniques\n\ncontrast media\n\ndiagnostic imaging\n\ndiagnostic performance\n\nevaluation\n\nMR angiography study technique\n\nmultiphasic breath-hold gadolinium-enhanced 3D MR imaging\n\npre and postoperative evaluation\n\nvascular anatomy\n\nvascular and graft thrombosis\n\nvascular complication\n\nParallel imaging technique\n\nPara-sagittal imaging\n\nPatient artifacts\n\nPelvic veins\n\nSeeSee Abdomen and pelvic veins\n\nPerfusion imaging\n\nabdominal aorta and renal arteries\n\npulmonary vessels\n\nPeriaortic edema\n\nPeripheral arterial occlusive disease (PAOD)\n\nPeripheral vessels\n\naneurysm\n\ncontrast agents\n\ndigital subtraction angiography (DSA)\n\nduplex ultrasound (DUS)\n\nfast field-echo (FFE) T1-weighed 3D diagnostic imaging\n\nimaging modality\n\ninflammatory arteritis\n\nmoving table technology\n\npopliteal artery entrapment syndrome\n\nsteady-state imaging\n\nsteno-occlusive disease\n\nTakayasu's arteritis\n\ntest-bolus technique\n\nthoracic outlet syndrome\n\nthree-dimensional contrast-enhanced MRA (3D-CEMRA)\n\ntime-of-flight (TOF) angiography\n\nvasospastic disease\n\nvasovist®\n\nPhase-array coil design\n\nPhase contrast (PC) MR angiography\n\n3D acquisition\n\nabdominal aorta and renal artery\n\nbipolar gradient\n\nencoding gradient characteristics\n\nlimitations\n\nPopliteal aneurysm\n\nPopliteal artery entrapment syndrome\n\nPortal vein trifurcation\n\nProton movement\n\nPulmonary vessels\n\nanatomy\n\nBFFE imaging\n\nblood-pool imaging\n\nMIP reconstruction\n\nperfusion imaging and ventilation\n\nthrombus imaging\n\ntime-resolved MRA\n\nPulse sequence imaging\n\n2D spin-echo\n\n3D gradient echo\n\nblack blood images\n\nbright blood images\n\ncontrast agent\n\nimage quality\n\nmotion suppression\n\nparallel imaging\n\nself-navigated image reconstruction approach\n\nSSFP sequence\n\nvariable sampling in time (VAST) technique\n\nR\n\nRadiofrequency artifacts\n\nRenal artery stenosis (RAS)\n\narterial spin labeling (ASL)\n\natherosclerotic disease\n\nbalanced fast gradient echo\n\nCEMRA\n\nclinical manifestation\n\ncomputed tomography angiography (CTA)\n\ncontrast-enhanced MR angiography (CEMRA)\n\nfibromuscular dysplasia\n\ngamma-variate function\n\nMR perfusion imaging\n\nmultislice computed tomography (MSCT)\n\nPC technique\n\nperfusion technique\n\nphase-contrast (PC) technique\n\nrenal blood flow measurement\n\nRenal transplants\n\narterial stenosis\n\nCEMRA\n\nchronic stenosis\n\ncontrast-enhanced MRA (CEMRA) techniques\n\ncontrast media\n\ndiagnostic imaging\n\ndonor renal artery stenosis\n\nimaging\n\nMR angiography study technique\n\npre and postoperative evaluation\n\nsingle and double transplants\n\nvascular anatomy\n\nvascular complication\n\nvein diseases\n\nRetroperitoneal fibrosis\n\nclinical manifestation\n\nMRI imaging\n\nRetrospective gating approach\n\nS\n\nSegmented k-space fast GRE imaging\n\nShaded surface display (SSD)\n\nSingle-shot fast spin echo (SSFSE) sequences\n\nSmall particles of iron oxide (SPIOs)\n\n3D Spoiled gradient echo (SPGR)\n\nSteady state free precession (SSFP) technique\n\nSteno-occlusive arterial disease\n\nasymptomatic and symptomatic\n\nbypass grafts\n\nCE-MRA\n\nDSA\n\nLeriche's syndrome\n\nPAOD\n\nsubclavian steal syndrome\n\nTOF angiography\n\nStenting and bypass\n\nSubclavian steal syndrome\n\nT\n\nT2-based MR angiography\n\nTakayasu's arteritis\n\nclinical manifestation\n\ndiagnosis\n\nsymptoms\n\nThoracic aorta\n\nanatomy\n\naortic aneurysm\n\naortic dissection\n\narterial circle of Willis\n\nascending aorta\n\nbasilar artery\n\nblack blood techniques\n\nbright blood techniques\n\ncommon carotid arteries\n\ncontrast dose and administration\n\ncontrast-enhanced magnetic resonance angiography (CE-MRA)\n\ncontrast injection synchronization\n\ncoronary artery\n\ndisease prevalence and spectrum\n\nexternal carotid artery\n\nfundamental sequences\n\nimage processing\n\ninnominate artery\n\ninternal carotid artery\n\ninternal mammary artery\n\nintramural hematoma\n\nparietal branches\n\npatient positioning\n\nposterior cerebral artery\n\npost EVAR evaluation\n\nsubclavian artery\n\nthoracic descending aorta\n\nthyrocervical trunk\n\ntrauma\n\nvascular thoracic outlet syndrome\n\nvertebral artery\n\nvisceral branches\n\nThoracic outlet syndrome (TOS)\n\nTime-of-flight (TOF) angiography\n\nperipheral vessels\n\nthoracic aorta\n\nTime-resolved MRA\n\nCE-MRA\n\npulmonary vessel\n\nthoracic aorta\n\nU\n\nUltrasmall particles of iron oxides (USPIOs)\n\nV\n\nVariable sampling in time (VAST) technique\n\nVascular imaging\n\narteries\n\nSee(see Arteries)\n\nparamagnetic gadolinium agents\n\nsuperparamagnetic USPIOs\n\nveins\n\nSeesee Veins)\n\nVascular stents\n\nVascular thoracic outlet syndrome\n\nVascular thrombosis\n\nVasospastic disease\n\nVasovist®\n\nVeins\n\nabdomen and pelvis\n\nSee also(see also Abdomen and pelvic veins)\n\nheart\n\nlimbs\n\npulmonary veins\n\nsuperior vena cava\n\nVertebral arteries\n\natherosclerosis\n\ndissection\n\nVirtual endoscopy (VE)\n\nVolume rendering (VR)\n\nW\n\nWhole heart CMRA\n" ]

{ "pile_set_name": "Books3" }

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[ "package pflag\n\nimport (\n\t\"fmt\"\n\t\"strconv\"\n\t\"strings\"\n)\n\n// -- float64Slice Value\ntype float64SliceValue struct {\n\tvalue *[]float64\n\tchanged bool\n}\n\nfunc newFloat64SliceValue(val []float64, p *[]float64) *float64SliceValue {\n\tisv := new(float64SliceValue)\n\tisv.value = p\n\t*isv.value = val\n\treturn isv\n}\n\nfunc (s *float64SliceValue) Set(val string) error {\n\tss := strings.", "Split(val, \",\")\n\tout := make([]float64, len(ss))\n\tfor i, d := range ss {\n\t\tvar err error\n\t\tout[i], err = strconv.", "ParseFloat(d, 64)\n\t\tif err !", "= nil {\n\t\t\treturn err\n\t\t}\n\n\t}\n\tif !", "s.changed {\n\t\t*s.value = out\n\t} else {\n\t\t*s.value = append(*s.value, out...)\n\t}\n\ts.changed = true\n\treturn nil\n}\n\nfunc (s *float64SliceValue) Type() string {\n\treturn \"float64Slice\"\n}\n\nfunc (s *float64SliceValue) String() string {\n\tout := make([]string, len(*s.value))\n\tfor i, d := range *s.value {\n\t\tout[i] = fmt.", "Sprintf(\"%f\", d)\n\t}\n\treturn \"[\" + strings.", "Join(out, \",\") + \"]\"\n}\n\nfunc (s *float64SliceValue) fromString(val string) (float64, error) {\n\treturn strconv.", "ParseFloat(val, 64)\n}\n\nfunc (s *float64SliceValue) toString(val float64) string {\n\treturn fmt.", "Sprintf(\"%f\", val)\n}\n\nfunc (s *float64SliceValue) Append(val string) error {\n\ti, err := s.fromString(val)\n\tif err !", "= nil {\n\t\treturn err\n\t}\n\t*s.value = append(*s.value, i)\n\treturn nil\n}\n\nfunc (s *float64SliceValue) Replace(val []string) error {\n\tout := make([]float64, len(val))\n\tfor i, d := range val {\n\t\tvar err error\n\t\tout[i], err = s.fromString(d)\n\t\tif err !", "= nil {\n\t\t\treturn err\n\t\t}\n\t}\n\t*s.value = out\n\treturn nil\n}\n\nfunc (s *float64SliceValue) GetSlice() []string {\n\tout := make([]string, len(*s.value))\n\tfor i, d := range *s.value {\n\t\tout[i] = s.toString(d)\n\t}\n\treturn out\n}\n\nfunc float64SliceConv(val string) (interface{}, error) {\n\tval = strings.", "Trim(val, \"[]\")\n\t// Empty string would cause a slice with one (empty) entry\n\tif len(val) == 0 {\n\t\treturn []float64{}, nil\n\t}\n\tss := strings.", "Split(val, \",\")\n\tout := make([]float64, len(ss))\n\tfor i, d := range ss {\n\t\tvar err error\n\t\tout[i], err = strconv.", "ParseFloat(d, 64)\n\t\tif err !", "= nil {\n\t\t\treturn nil, err\n\t\t}\n\n\t}\n\treturn out, nil\n}\n\n// GetFloat64Slice return the []float64 value of a flag with the given name\nfunc (f *FlagSet) GetFloat64Slice(name string) ([]float64, error) {\n\tval, err := f.getFlagType(name, \"float64Slice\", float64SliceConv)\n\tif err !", "= nil {\n\t\treturn []float64{}, err\n\t}\n\treturn val.([]float64), nil\n}\n\n// Float64SliceVar defines a float64Slice flag with specified name, default value, and usage string.", "\n// The argument p points to a []float64 variable in which to store the value of the flag.", "\nfunc (f *FlagSet) Float64SliceVar(p *[]float64, name string, value []float64, usage string) {\n\tf.VarP(newFloat64SliceValue(value, p), name, \"\", usage)\n}\n\n// Float64SliceVarP is like Float64SliceVar, but accepts a shorthand letter that can be used after a single dash.", "\nfunc (f *FlagSet) Float64SliceVarP(p *[]float64, name, shorthand string, value []float64, usage string) {\n\tf.VarP(newFloat64SliceValue(value, p), name, shorthand, usage)\n}\n\n// Float64SliceVar defines a float64[] flag with specified name, default value, and usage string.", "\n// The argument p points to a float64[] variable in which to store the value of the flag.", "\nfunc Float64SliceVar(p *[]float64, name string, value []float64, usage string) {\n\tCommandLine.", "VarP(newFloat64SliceValue(value, p), name, \"\", usage)\n}\n\n// Float64SliceVarP is like Float64SliceVar, but accepts a shorthand letter that can be used after a single dash.", "\nfunc Float64SliceVarP(p *[]float64, name, shorthand string, value []float64, usage string) {\n\tCommandLine.", "VarP(newFloat64SliceValue(value, p), name, shorthand, usage)\n}\n\n// Float64Slice defines a []float64 flag with specified name, default value, and usage string.", "\n// The return value is the address of a []float64 variable that stores the value of the flag.", "\nfunc (f *FlagSet) Float64Slice(name string, value []float64, usage string) *[]float64 {\n\tp := []float64{}\n\tf.Float64SliceVarP(&p, name, \"\", value, usage)\n\treturn &p\n}\n\n// Float64SliceP is like Float64Slice, but accepts a shorthand letter that can be used after a single dash.", "\nfunc (f *FlagSet) Float64SliceP(name, shorthand string, value []float64, usage string) *[]float64 {\n\tp := []float64{}\n\tf.Float64SliceVarP(&p, name, shorthand, value, usage)\n\treturn &p\n}\n\n// Float64Slice defines a []float64 flag with specified name, default value, and usage string.", "\n// The return value is the address of a []float64 variable that stores the value of the flag.", "\nfunc Float64Slice(name string, value []float64, usage string) *[]float64 {\n\treturn CommandLine.", "Float64SliceP(name, \"\", value, usage)\n}\n\n// Float64SliceP is like Float64Slice, but accepts a shorthand letter that can be used after a single dash.", "\nfunc Float64SliceP(name, shorthand string, value []float64, usage string) *[]float64 {\n\treturn CommandLine.", "Float64SliceP(name, shorthand, value, usage)\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Olympian speaks to students during Mental Health Awareness Week\n\nDuring the Hope Squad's Mental Health Awareness Week (February 20 -24), Kate Hansen, Olympic Luger, spoke to a select group of health and PE students on Thursday, February 23.", "\n\nHansen loves speaking to students about maintaining good physical and emotional health. ", "Hansen became famous during the Olympics because she dances to warm up. ", "Check her out on YouTube at: https://www.youtube.com/watch?v=93nvbFacVRE" ]

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[ "Two Black Fridays ago – on November 25, 2016 – Cuban dictator Fidel Castro finally died. ", "Two years later, the pro-democracy activists at the forefront of the fight for freedom lament that little in Cuba has changed for them, and what has changed has worsened.", "\n\nIn the immediate aftermath of current dictator Raúl Castro’s November 26 announcement of the death of his brother, the Cuban exile community celebrated with a global sigh of relief; geopolitical experts identified an opportunity for a new era in the island’s history.", "\n\n“With Fidel’s death, the political and economic situation will probably open up,” Michael Shifter, president of the Inter-American Dialogue group, told PRI at the time, expressing the general sentiment among pro-corporation optimists. ", "An analysis by the Aspen Institute warned the United States not to “bully” the repressive Castro regime in the immediate aftermath, proclaiming, “there is no counter-revolution in Cuba. ", "It’s not as if the Castro family has been suppressing thousands of anti-socialist Cubans.”", "\n\nSpeaking to Breitbart News, leaders of the Cuban counter-revolution – which, contrary to the Aspen Institute analysis, does exist – lament that any opportunity to ease the repression of dissident voices in the country appears to have passed without incident. ", "Both Fidel Castro’s death and the substitution of Raúl Castro as the Revolution’s international envoy with loyalist Miguel Díaz-Canel in April have done little for political freedom in the country, they agree.", "\n\n“The situation in Cuba for dissidents remains very similar to that which we had during Fidel Castro’s life, and in some ways is even worse,” José Daniel Ferrer, the General Coordinator of one of Cuba’s largest dissident groups, the Patriotic Union of Cuba (UNPACU),” told Breitbart News. “", "The current dictator, Miguel Díaz-Canel … takes orders directly from Raúl Castro [and] leaves clear who truly wields power.”", "\n\n“Following the death of Fidel, the repressive system remains intact,” Carlos Payá of Cuba’s Christian Liberation Movement (MCL) told Breitbart News. “", "Arrests continue, sometimes for a few days and sometimes prolonged [arrests] like that of Eduardo Cardet.”", "\n\nEduardo Cardet, the head of the MCL, was arrested shortly after Castro’s death for allegedly refusing to sign a government-mandated condolence book for the late dictator during the state’s forced nine-day mourning period. ", "The government convicted Cardet of allegedly attacking Cuban state security officers despite no witnesses corroborating the claim.", "\n\nOn the contrary, Cardet’s wife and children, who witnessed the arrest, said police brutally beat him in public after suspecting him of criticizing the condolence books. ", "The court did not accept their testimony. ", "Cardet is currently serving a three-year prison sentence, deprived of medical attention despite suffering from chronic asthma.", "\n\nPayá told Breitbart News that the government’s “harassment against his [Cardet’s] family is constant. ", "He has already earned a provisional release according to Cuba’s own laws and, on the contrary, they take increasingly coercive measures against him [in prison.”", "\n\n“He is more than a prisoner, he is a hostage of the regime,” Payá concluded.", "\n\nAs the head of one of Cuba’s largest dissident groups – and one of two prominent dissidents suffering an extended arrest for not mourning hard enough in the aftermath of Fidel’s death, the other being visual artist Danilo Maldonado Machado, known as “El Sexto” – Cardet’s case has become a rallying cry for freedom on the international stage. ", "Yet his is far from the only example of such continued repression.", "\n\nThe arbitrary arrest of dissidents remained a common harassment tactic throughout 2018. ", "These arrests, unlike the Cardet case, often last for only days or hours. ", "Police will brutally beat dissidents, often in public, and “disappear” them for hours before releasing them hours from their home with no way of getting back. ", "In October, the NGO Cuban Commission for Human Rights and National Reconciliation (CCDHRN) documented over 200 arbitrary arrests, most targeting groups like UNPACU, MCL, and the Ladies in White, a dissident group whose sole act of protest is attending Catholic Mass on Sundays. ", "Nearly every Sunday, police arrest and beat their leader, Berta Soler, in public.", "\n\n“We have on the island over 120 political prisoners, among them about 50 activists with UNPACU; arbitrary detentions continue, often violently; political prisoners are tortured and beaten; our homes continue to be attacked and robbed by the repressive forces of the tyranny,” Ferrer told Breitbart News.", "\n\nActivists within the Cuban exile community who use sources on the island to document human rights abuses and demand an international response agree that dissidents remain under assault in post-Fidel Castro Cuba.", "\n\n“There have not been any significant changes in Cuba in terms of economic and political freedom after Fidel Castro’s death … because we have to understand that Fidel Castro installed a system, not just a government,” Orlando Gutiérrez-Boronat, national secretary of the Assembly of Cuban Resistance, which operates out of Florida, told Breitbart News. “", "Many of the key people who helped him install it are still in power, starting with Raúl Castro, who as First Secretary of the Communist Party still runs the country.”", "\n\n“As long as the system remains in place through the absolute hold on power of the intelligence and security services, the Armed Forces and the Communist Party, there will not be any change in Cuba or in any of the Latin American countries, such as Venezuela, occupied by that heinous regime,” Gutiérrez-Boronat warned.", "\n\nJust as the situation has changed little, so too has the Cuban regime’s response to pressure to change. ", "Last week, the Cuban government issued a stern rebuke of the European Parliament’s call to release Cardet. ", "In Cuba, they claimed, “there are no raids, arbitrary detentions, acts of harassment or intimidation, there are no ‘disappeared’ [people], no tortured, and no political prisoners.”", "\n\nShortly before Fidel Castro’s death, Raúl Castro made a remarkably similar statement during a press conference with then-President Barack Obama. ", "Responding to Cuban-American journalist Jim Acosta’s question on whether Castro would free political prisoners as part of a failed attempt by the White House to thaw relations between the two countries, Castro simply replied, “what political prisoners?”", "\n\nThe chronic refusal to acknowledge its crimes against humanity has triggered a global effort to bring the Castros to justice. ", "UNPACU’s members continue to engage in peaceful acts of resistance, like hunger strikes, to call attention to the nature of the regime. ", "On Wednesday, the group launched a campaign to bring the Castro family and its lackeys before the International Criminal Court (ICC), which has jurisdiction over war crimes, genocide, and crimes against humanity.", "\n\nThe Assembly of Cuban Resistance has similarly worked for much of the year on collecting signatures within the exile community to bring the Castros before the ICC or any other international tribunal. ", "MCL continues to fight for justice not only for Cardet, but for his predecessor, the founder of the group, Oswaldo Payá. ", "Payá died in a car “accident” in 2012 after Cuban government agents rammed his car off a dark road.", "\n\nPayá’s death and that of fellow activist Harold Cepero in the crash are two of an estimated 11,000 deaths attributable to the Cuban Revolution, not counting soldiers killed in dubious military activities in places like Angola or the untold number of balseros, or “rafters,” who drowned attempting to escape to the United States. ", "Some estimates put the latter number as high as 78,000 people.", "\n\n“Change in Cuba is not just a political issue, it’s a matter of life and death for Cuba,” Gutiérrez-Boronat argues. “", "Under Communism, Cuba has become the only Latin American country with a negative birth rate, with the highest suicide and abortion rates in the Hemisphere, with the highest alcoholism rates in the region, with a youth population that wants desperately to emigrate in order to get away from the country’s shipwreck.”", "\n\n“The regime doesn’t even have the most minimal will to change towards democracy and knows that, before the growing demands of the dissidents and an ever increasing number of disaffected citizens, the only formula that has been effective for them has been repression and the fear that it generates,” Ferrer posits. “", "The regime knows that, when it stops repressing, it will lose the control it has over its people who desire to live in freedom with rights.”", "\n\nJust as the regime has changed little since Fidel’s rise, so too will the resistance fail to buckle under the pressure, Ferrer tells Breitbart News: “Amid this complex and difficult situation, we continue to inform, equip, and train more and more citizens to use non-violent struggle to conquer the rights and freedoms currently trampled.”", "\n\nFollow Frances Martel on Facebook and Twitter." ]

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[ "Two new antibiotics, A-218 and K-41. ", "Isolation and characterization.", "\nTwo new antibiotics, A-218 and K-41, were isolated from strains identified as Streptomyces hygroscopicus. ", "The antibiotics are characterized as polycyclic polyether compounds and are active against gram-positive bacteria." ]

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[ "There is one story that illustrates Chelsea’s recruitment strategy in the Frank Lampard era. ", "It comes from the agent of one of Europe’s brightest young players, who had been made aware that his client was first choice to be Chelsea’s long-term solution in his position.", "\n\n\n\nChelsea’s interest in the player dated back several years and it was clear they were serious. ", "Scott McLachlan, the club’s head of international scouting, kept in contact, letting the agent know when they were coming to watch and compile further information on his client. ", "The agent was keen to do a deal and optimistic the player’s club could be persuaded to sell.", "\n\n\n\nBut then, this season, the situation suddenly changed. ", "Lampard brought through an academy graduate in the player’s position, giving him regular first-team minutes and the opportunity to prove that he was every bit as promising. ", "The academy graduate, having been handed a new long-term contract, went from..." ]

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[ "<?", "php\n/**\n * Copyright © Magento, Inc. All rights reserved.", "\n * See COPYING.txt for license details.", "\n */\nnamespace Magento\\Sales\\Api;\n\nuse Magento\\Framework\\Api\\FilterBuilder;\nuse Magento\\Framework\\Api\\SearchCriteriaBuilder;\nuse Magento\\Framework\\Api\\SortOrder;\nuse Magento\\Framework\\Api\\SortOrderBuilder;\nuse Magento\\Sales\\Api\\Data\\CreditmemoCommentInterface;\nuse Magento\\TestFramework\\Helper\\Bootstrap;\n\nclass CreditmemoCommentRepositoryInterfaceTest extends \\PHPUnit\\Framework\\TestCase\n{\n /**\n * @var CreditmemoCommentRepositoryInterface\n */\n private $repository;\n\n protected function setUp()\n {\n $this->repository = Bootstrap::getObjectManager()->create(CreditmemoCommentRepositoryInterface::class);\n }\n\n /**\n * @magentoDataFixture Magento/Sales/_files/creditmemo_comments_for_search.php\n */\n public function testGetList()\n {\n /** @var FilterBuilder $filterBuilder */\n $filterBuilder = Bootstrap::getObjectManager()->create(FilterBuilder::class);\n\n $filter1 = $filterBuilder->setField(CreditmemoCommentInterface::COMMENT)\n ->setValue('comment 2')\n ->create();\n $filter2 = $filterBuilder->setField(CreditmemoCommentInterface::COMMENT)\n ->setValue('comment 3')\n ->create();\n $filter3 = $filterBuilder->setField(CreditmemoCommentInterface::COMMENT)\n ->setValue('comment 4')\n ->create();\n $filter4 = $filterBuilder->setField(CreditmemoCommentInterface::COMMENT)\n ->setValue('comment 5')\n ->create();\n $filter5 = $filterBuilder->setField(CreditmemoCommentInterface::IS_VISIBLE_ON_FRONT)\n ->setValue(1)\n ->create();\n\n /**@var SortOrderBuilder $sortOrderBuilder */\n $sortOrderBuilder = Bootstrap::getObjectManager()->create(SortOrderBuilder::class);\n\n /** @var SortOrder $sortOrder */\n $sortOrder = $sortOrderBuilder->setField(CreditmemoCommentInterface::COMMENT)\n ->setDirection(SortOrder::SORT_DESC)\n ->create();\n\n /** @var SearchCriteriaBuilder $searchCriteriaBuilder */\n $searchCriteriaBuilder = Bootstrap::getObjectManager()->create(SearchCriteriaBuilder::class);\n\n $searchCriteriaBuilder->addFilters([$filter1, $filter2, $filter3, $filter4]);\n $searchCriteriaBuilder->addFilters([$filter5]);\n $searchCriteriaBuilder->setSortOrders([$sortOrder]);\n\n $searchCriteriaBuilder->setPageSize(2);\n $searchCriteriaBuilder->setCurrentPage(2);\n\n $searchCriteria = $searchCriteriaBuilder->create();\n\n $searchResult = $this->repository->getList($searchCriteria);\n\n $items = array_values($searchResult->getItems());\n $this->assertEquals(1, count($items));\n $this->assertEquals('comment 2', $items[0][CreditmemoCommentInterface::COMMENT]);\n }\n}\n" ]

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[ "Comparison of urodynamic investigations before and after posterior sagittal anorectoplasty for anorectal malformations.", "\nThe authors evaluated 21 patients (10 boys, 11 girls) who had anorectal malformations (ARM). ", "Ten of them had infralevator (low-group I) and 11 of them had supralevator (high-group II) type ARM. ", "All of the patients underwent urodynamic investigation before and after posterior sagittal anorectoplasty (PSARP) operation. ", "Sacral and spinal anomalies were found in 54% (6 of 11) patients who had supralevator type ARM. ", "None of the patients with infralevator type ARM had additional sacral or spinal anomalies. ", "Before PSARP operation urodynamic investigations of all infralevator type ARM patients were within normal limits, whereas 82% (9 of 11) of patients with supralevator type ARM showed neurovesical dysfunction (NVD). ", "There was no significant difference between the preoperative and postoperative urodynamic findings. ", "The possibility of additional sacral or spinal anomalies and NVD in supralevator type ARM was high. ", "After PSARP operation no additional lower urinary tract dysfunction was detected in the urodynamic evaluation of ARM patients." ]

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[ "Q:\n\nStore multiple checkbox inputs in local storage\n\nI have multiple checkbox inputs that look like this:\n<input type=\"checkbox\" id=\"box-1\">\n<input type=\"checkbox\" id=\"box-2\">\n<input type=\"checkbox\" id=\"box-3\">\n\nI want to store their values (checked or unchecked) in the browser's local store.", "\nThe javascript that I'm using to do this is:\nfunction onClickBox() {\n let checked = $(\"#box-1\").is(\":checked\");\n let checked = $(\"#box-2\").is(\":checked\");\n let checked = $(\"#box-3\").is(\":checked\");\n localStorage.setItem(\"checked\", checked);\n}\n\nfunction onReady() {\n let checked = \"true\" == localStorage.getItem(\"checked\");\n $(\"#box-1\").prop('checked', checked);\n $(\"#box-2\").prop('checked', checked);\n $(\"#box-3\").prop('checked', checked);\n\n $(\"#box-1\").click(onClickBox);\n $(\"#box-2\").click(onClickBox);\n $(\"#box-3\").click(onClickBox);\n}\n\n$(document).ready(onReady);\n\nThe first part saves the checkbox's state on the click and the second part loads it when the page refreshes.", "\nThis works well if the lines for box 2 and 3 are removed, but I need it to work with all the checkboxes.", "\n\nA:\n\nYour main issue here is that you're only storing a single value in localStorage, checked, which will be overwritten every time you check a different box. ", "You instead need to store the state of all boxes. ", "An array is ideal for this, however localStorage can only hold strings, so you will need to serialise/deserialise the data when you attempt to read or save it.", "\nYou can also simplify the logic which retrieves the values of the boxes by putting a common class on them and using map() to build the aforementioned array. ", "Try this:\n<input type=\"checkbox\" id=\"box-1\" class=\"box\" />\n<input type=\"checkbox\" id=\"box-2\" class=\"box\" />\n<input type=\"checkbox\" id=\"box-3\" class=\"box\" />\n\njQuery($ => {\n var arr = JSON.parse(localStorage.getItem('checked')) || [];\n arr.forEach((c, i) => $('.box').eq(i).prop('checked', c));\n\n $(\".box\").click(() => { \n var arr = $('.box').map((i, el) => el.checked).get();\n localStorage.setItem(\"checked\", JSON.stringify(arr));\n });\n});\n\nWorking example\n\n" ]

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[ "1. ", "Introduction {#sec1-foods-07-00030}\n===============\n\nThe pumpkin (*Cucurbita* spp.), ", "one of the most popular vegetables consumed in the world, has been recently recognized as a functional food \\[[@B1-foods-07-00030],[@B2-foods-07-00030],[@B3-foods-07-00030]\\]. ", "Pumpkin seeds, generally considered agro-industrial waste, are an extraordinarily rich source of bioactive compounds with interesting nutraceutical properties \\[[@B4-foods-07-00030]\\]. ", "In recent years, several studies \\[[@B5-foods-07-00030],[@B6-foods-07-00030],[@B7-foods-07-00030]\\] have highlighted the health properties of pumpkin seed oil against many diseases, including hypertension, diabetes, and cancer. ", "It also shows antibacterial, antioxidant, and anti-inflammatory properties \\[[@B8-foods-07-00030],[@B9-foods-07-00030]\\]. ", "Due to the presence of interesting natural bioactive compounds, such as carotenoids, tocopherols, and sterols, pumpkin-derived products have a wide spectrum of biological activity, proven by in vivo experiments \\[[@B10-foods-07-00030]\\].", "\n\nBecause of the positive health effects, research has been focused particularly on the content and composition of fatty acids (FA) and tocopherols in pumpkin seed oil, while, to a lesser extent, other lipid components, such as sterols, alcohols, and phenol acids, have been studied, as is done with other food matrices to identify specific markers characteristic of the plant varieties \\[[@B11-foods-07-00030]\\]. ", "Among the relevant aspects to be considered when dealing with this vegetable, the beneficial effects of using environmentally friendly natural herbicides \\[[@B12-foods-07-00030]\\] must be mentioned, since the content of bioactive compounds could be affected, and there could be possible contamination of this vegetable due to the presence of *Fusarium* spp. ", "microfungi and their secondary metabolites \\[[@B13-foods-07-00030]\\], affecting the content of beneficial compounds of the vegetable itself.", "\n\nStevenson et al. ", "\\[[@B14-foods-07-00030]\\] summarized FA composition and reported significant differences among various cultivars of pumpkin seed oil extracted from various pumpkin sources. ", "Rezig et al. ", "\\[[@B15-foods-07-00030]\\] studied the chemical composition and oil properties of seeds of a Tunisian variety of pumpkin, Béjaoui (*C. maxima*). ", "They found that the major FA were oleic, linoleic, and palmitic acids and that the seed oil was rich in δ-tocopherol, while the sterol marker was β-sitosterol and the predominant phenolic acid was syringic acid. ", "Siano et al. ", "\\[[@B16-foods-07-00030]\\] highlighted that saturated FA (SFA) and monounsaturated FA (MUFA) of *C. maxima* produced in southern Italy showed similar values (25.20% and 25.54%, respectively), while the polyunsaturated FA (PUFA) content was 48.14%. ", "Habib et al. ", "\\[[@B17-foods-07-00030]\\] determined the proximate composition of powdered seed and the lipid composition of the oil of *C. maxima* collected in Bangladesh. ", "They affirmed that the high degree of unsaturation makes the oil suitable for use as valuable drying agent, and lower free FA content indicates suitability of the oil for consumption as food.", "\n\nOther researchers studied the chemical composition of pumpkin seed oils from *C. pepo* \\[[@B5-foods-07-00030],[@B18-foods-07-00030],[@B19-foods-07-00030],[@B20-foods-07-00030],[@B21-foods-07-00030]\\]. ", "Due to the differences among the species and/or varieties of *Cucurbita* spp. ", "grown in different areas of the world, the present study focused on characterizing a native Italian cultivar (*C. maxima*, var. ", "Berrettina, locally known as \"priest's hat\"), paying attention to the lipid composition of the seed oil. ", "Since there is little information about the lipid structure, the present research deepens understanding of the total FA content and intrapositional composition of Berrettina pumpkin by using stereospecific analysis, and pays attention to other minor lipid components such as sterols, alcohols, and carotenoids. ", "Butinar et al. ", "\\[[@B22-foods-07-00030]\\] proposed high-performance liquid chromatography (HPLC) analysis of triacylglycerol (TAG) as a useful technique to evaluate the genuineness of pumpkin seed oils produced in Slovenia, but to the best of our knowledge, there are no data in the literature dealing with stereospecific analysis of pumpkin seed TAG.", "\n\n2. ", "Materials and Methods {#sec2-foods-07-00030}\n========================\n\n2.1. ", "Materials and Chemicals {#sec2dot1-foods-07-00030}\n----------------------------\n\nMethanol (MeOH), diethyl ether, petroleum ether, formic acid, hydrochloric acid, and acetone were purchased from J.T. Baker B.V. (Deventer, the Netherlands). ", "Hexane, ethanol (EtOH), chloroform (CHCl~3~), anhydrous sodium sulfate (Na~2~SO~4~), and potassium hydroxide (KOH) were bought from Carlo Erba Reagents (Milan, Italy). ", "Deionized water (\\>18 MΩ cm resistivity) was obtained from a Milli-Q SP Reagent Water System (Millipore, Bedford, MA, USA). ", "Supelco™ 37 Component FAME Mix, containing the methyl esters of 37 fatty acids (Supelco, Bellefonte, PA, USA; catalog No. ", "47885-U), was used. ", "Lipase from porcine pancreas (EC 3.1.1.3), *sn*-1,2-diacylglycerol kinase from *Escherichia coli* (DAGK; EC 2.7.1.107), cholesterol (≥99%), ergosterol (≥95%), stigmasterol (\\~95%), β-sitosterol (≥95%), 5-α-cholestane (≥97%), γ-linolenic acid (≥99%), 2′,7′-dichlorofluorescein, *N*,*O*-bis(trimethylsilyl)trifluoroacetamide (BSTFA), 1-octadecanol (99%), 1-docosanol (98%), 1-octacosanol (≥99%), lutein (≥97%), and β-carotene (≥97%) were purchased from Sigma-Aldrich (St. Louis, MO, USA).", "\n\n2.2. ", "Collection of Pumpkin Samples {#sec2dot2-foods-07-00030}\n----------------------------------\n\nPumpkin belongs to the family *Cucurbitaceae*. ", "The samples (*C. maxima* L., var. ", "Berrettina) were taxonomically identified by Luigi Frassineti (Tuder Green Service, Todi, Italy). ", "It is a leafy green vegetable with medium-large flattish fruits with green-gray, moderately hard knobby skin, edible yellow/orange flesh, and a central cavity with numerous plump, whitish-yellow seeds. ", "Three pumpkins cultivated in central Italy (Todi) and collected in autumn 2016 were selected for their uniformity of shape, weight, and color. ", "The fresh pumpkin samples were weighed (about 2.5 kg each), peeled, and, after manual removal of seeds, cut into small pieces (1.5 cm × 1.5 cm × 1.5 cm) and analyzed. ", "The seeds were cleaned to remove impurities and dried at 60 °C for 24 h in a hot-air fan oven. ", "After that, the seeds were reweighed until the weight was constant. ", "The samples were stored in a dry place in the dark at room temperature.", "\n\n2.3. ", "Determination of Pumpkin Chemical Composition {#sec2dot3-foods-07-00030}\n--------------------------------------------------\n\nCrude fat, protein, moisture, and ash contents of pumpkin samples were determined according to the procedures described in the Association of Official Analytical Chemists (AOAC) method \\[[@B23-foods-07-00030]\\].", "\n\n2.4. ", "Seed Lipid Extraction {#sec2dot4-foods-07-00030}\n--------------------------\n\nDried pumpkin seed samples were ground using a kitchen grinder (Oster, model 869-50R, Lakewood, CA, USA). ", "Extraction of lipid fraction of the pumpkin seeds was performed using petroleum ether as a solvent in a Soxhlet extractor, according to AOAC procedure \\[[@B23-foods-07-00030]\\]. ", "The extract was dried over Na~2~SO~4~, and then the solvent was evaporated under reduced pressure using a rotary evaporator (Büchi Rotavapor B-480, Essen, Germany) at 40 °C. ", "Finally, the residue was weighed and dissolved in hexane. ", "The recovered oil was stored at 4 °C until use.", "\n\n2.5. ", "Isolation of TAG Fraction from Oil Samples {#sec2dot5-foods-07-00030}\n-----------------------------------------------\n\nThe TAG fraction was isolated by thin layer chromatography (TLC), according to the method described by Cossignani et al. ", "\\[[@B24-foods-07-00030]\\], from total fat of pumpkin seed samples using silica gel plates (SIL G-25, 0.25 mm, 20 cm × 20 cm; Macherey-Nagel, Germany) and petroleum ether/diethyl ether/formic acid (70:30:1, *v/v/v*) as a developing solvent. ", "The TAG fraction was scraped off, extracted with hexane/diethyl ether (1:1, *v/v*), subjected to transesterification, and analyzed by high-resolution gas chromatography (HRGC) as reported in [Section 2.6](#sec2dot6-foods-07-00030){ref-type=\"sec\"} to obtain the constituent fatty acid methyl esters (FAME). ", "The obtained data represent the total composition of FA esterified in all 3 *sn*-positions of TAG, named A~t~.\n\n### 2.5.1. ", "Stereospecific Analysis of TAG {#sec2dot5dot1-foods-07-00030}\n\nThe stereospecific analysis procedure \\[[@B25-foods-07-00030]\\] carried out on TAG of pumpkin seed oil isolated as reported in the previous paragraph involved the following steps:The pancreatic lipase procedure ([Section 2.5.2](#sec2dot5dot2-foods-07-00030){ref-type=\"sec\"}) to obtain the FA% intrapositional composition of *sn*-2 position of glycerol backbone of TAG, named A~2~;Preparation of *sn*-1,3/*sn*-1,2(2,3)-diacylglycerol (DAG), followed by the DAGK enzymatic procedure ([Section 2.5.3](#sec2dot5dot3-foods-07-00030){ref-type=\"sec\"}), to obtain the FA% intrapositional composition of *sn*-1 and *sn*-2 positions of glycerol backbone of TAG, named A~1,2~.\n\n### 2.5.2. ", "Pancreatic Lipase Procedure {#sec2dot5dot2-foods-07-00030}\n\nHydrolysis of TAG was carried out according to the method provided by the Italian fat and derivate control standards (Norme Italiane per il Controllo dei Grassi e Derivati (NGD) method) \\[[@B26-foods-07-00030]\\]. ", "Tris-HCl buffer (pH 8.08), bile salts, CaCl~2~, and pancreatic lipase were added to an aliquot of TAG. ", "The mixture was incubated under magnetic stirring in a water bath at 40 °C for 5 min, and then 6 M HCl and diethyl ether were added and the mixture was centrifuged. ", "Diethyl ether was dried by anhydrous Na~2~SO~4~ and evaporated under nitrogen flow to small volume. ", "The hydrolytic products were separated on TLC plates, and the developing solvent system was petroleum ether/diethyl ether/formic acid (70:30:1, *v/v/v*). ", "The band corresponding to *sn*-2-monoacylglycerols (*sn*-2-MAG), visualized with 2′,7′-dichlorofluorescein spray, was scraped off, methylated, and analyzed by HRGC as reported in [Section 2.6](#sec2dot6-foods-07-00030){ref-type=\"sec\"} to obtain the constituent FAME. ", "The obtained data represent the intrapositional composition of FA esterified in *sn*-2 position, named A~2~.\n\n### 2.5.3. *", "sn*-1,3/*sn*-1,2(2,3)-Diacylglycerol (DAG) Preparation {#sec2dot5dot3-foods-07-00030}\n\nAn aliquot of TAG was dissolved in anhydrous diethyl ether, and freshly prepared ethyl magnesium bromide in anhydrous diethyl ether was added. ", "The mixture was shaken, and then pentane (0.1% acetic acid) and water were added. ", "The solution was vortexed and centrifuged (ALC 4218 centrifuge, Thermo Scientific, Waltham, MA, USA). ", "The water was removed and the organic phase was dried over anhydrous Na~2~SO~4~ and concentrated with solvent removal under nitrogen stream. ", "The DAG mixture was applied to TLC plates previously treated with 5% boric acid solution (methanol/water, 80:20, *v/v*) and then activated for 1 h at 120 °C. ", "The developing system was hexane/diethyl ether (60:40, *v/v*). ", "The band containing the *sn*-1,2(2,3)-DAG fraction (Rf ≈ 0.30; Rf of the *sn*-1,3-DAG band ≈ 0.35), located by iodine vapor exposition, was scraped off and extracted with diethyl ether.", "\n\n### 2.5.4. ", "DAGK Enzymatic Procedure {#sec2dot5dot4-foods-07-00030}\n\nThe *sn*-1,2(2,3)-DAG ethereal solution was concentrated under nitrogen stream, then cardiolipin solution, buffered *sn*-1,2-DAGK, buffer, and Na~2~ATP were added, mixing each time. ", "After incubation at 40 °C for 90 min under constant stirring, chloroform/methanol (2:1, *v/v*) was added to the mixture to stop the reaction and extract the products of interest. ", "The combined extracts were concentrated, treated with anhydrous Na~2~SO~4~, and applied to TLC plates. ", "The developing system was chloroform/methanol/25% ammonia (65:25:5, *v/v/v*). ", "The band of the *sn*-1,2-phosphatidic acids (*sn*-1,2-PA), visualized with 2′,7′-dichlorofluorescein spray (Rf ≈ 0.1), was scraped off, methylated, and analyzed by HRGC with flame ionization detection (FID) as reported in the following paragraph to obtain the constituent FAME. ", "The obtained data represent the intrapositional composition of FA esterified in *sn*-1,2 positions, named A~1,2~.\n\nThe FA composition at the *sn*-1- and *sn*-3-positions was obtained applying the following formulas: where A~1~ = % intrapositional composition of FA esterified in *sn*-1 position; A~1,2~ = % intrapositional composition of FA esterified in *sn*-1 and *sn*-2 positions; A~2~ = % intrapositional composition of FA esterified in *sn*-2 position; A~t~ = % total composition of FA esterified in all 3 *sn*-positions of TAG; A~3~ = % intrapositional composition of FA esterified in *sn*-3 position.", "\n\n2.6. ", "Preparation of FAME and HRGC-FID Analysis {#sec2dot6-foods-07-00030}\n----------------------------------------------\n\nThe FAME of TAG, *sn*-2-MAG, and *sn*-1,2-PA fractions were prepared by transesterification. ", "Hexane and 2 N methanolic KOH were added to the fraction and stirred for 3 min, then water was added. ", "The organic phase (upper) containing the FAME was dried over anhydrous Na~2~SO~4~, then analyzed by HRGC. ", "A DANI GC1000 DPC gas chromatograph (Norwalk, CT, USA) equipped with a split-splitless injector and a flame ionization detector (FID) was used. ", "Separation was obtained using the CP-Select CB for FAME fused silica capillary column (50 m × 0.25 mm i.d., ", "0.25 μm f.t.; ", "Varian, Superchrom, Milan, Italy). ", "Chromatograms were acquired and processed using Clarity integration software (DataApex Ltd., Prague, Czech Republic). ", "The injector and detector temperature was 250 °C. ", "The oven temperature was held at 180 °C for 6 min, and raised to 250 °C at 3 °C/min; the final temperature was held for 10 min. ", "Carrier gas (He) flow rate was 1 mL/min; the injection volume was 1 µL with a split ratio of 1:70. ", "A standard solution containing 37 FAME was used to identify the individual FA. ", "The percentage of each FA was calculated using the peak area of the samples. ", "The data were normalized considering only the main reported FA (% mol mean values ≥0.1).", "\n\n2.7. ", "Alkaline Hydrolysis of Pumpkin Seed Oil {#sec2dot7-foods-07-00030}\n--------------------------------------------\n\nAlkaline hydrolysis of pumpkin seed oil was carried out according to the method reported by Cossignani et al. ", "\\[[@B27-foods-07-00030]\\]. ", "Prior to alkaline hydrolysis, 0.2% 5-α-cholestane in CHCl~3~ and 1% 1-octacosanol (used as internal standards) were added to the oil samples, then the American Oil Chemists' Society (AOCS) method (Ch 6--91) was used \\[[@B28-foods-07-00030]\\]. ", "The products obtained after alkaline reaction were applied to TLC silica gel plates previously treated with 0.2 N KOH in MeOH, then activated for 1 h at 100 °C. ", "The developing system was hexane/diethyl ether (65:35, *v/v*). ", "The band containing the sterols, visualized with 2′,7′-dichlorofluorescein spray, was scraped off and extracted with CHCl~3~. Then the solvent was evaporated and removed under nitrogen stream.", "\n\n2.8. ", "Preparation of Trimethylsilyl Ether Derivatives and HRGC-FID Analysis {#sec2dot8-foods-07-00030}\n--------------------------------------------------------------------------\n\nThe silylation reaction was carried out as described by Lombardi et al. ", "\\[[@B29-foods-07-00030]\\] with slight modifications. ", "In brief, BSTFA and acetone were added to the sterol fraction and the reaction was carried out at 40 °C for 20 min to obtain trimethylsilyl ether (TMSE) derivatives. ", "Sterols and alcohols, as TMSE derivatives, were analyzed using a DANI GC1000 DPC gas chromatograph equipped with a split-splitless injector and FID.", "\n\nSeparation of TMSE sterols and alcohols was obtained using the AT-1701 fused silica capillary column (25 m × 0.25 mm i.d., ", "0.2 μm f.t.; ", "Alltech, Milan, Italy).", "\n\nFor analysis of TMSE sterols, the following chromatographic conditions were used: injector and detector temperature was 300 °C; oven temperature of 260 °C was held for 4 min, then increased to 300 °C at 1.5 °C/min, and the final temperature was held for 30 min; carrier gas (He) flow rate was 1.2 mL/min.", "\n\nFor analysis of TMSE alcohols, the following chromatographic conditions were used: injector and detector temperature was 290 °C; oven temperature was held at 180 °C for 3 min, raised to 260 °C at 6 °C/min for 15 min, then raised to 280 °C at 2 °C/min for 30 min.", "\n\nChromatograms were acquired and processed using Clarity integration software. ", "The percentage of each sterol was calculated by using the peak area of the samples corrected with the correction factor equal to 1 as reported by Laakso \\[[@B30-foods-07-00030]\\]. ", "TMSE sterols were also analyzed by HRGC coupled with mass spectrometry (MS) detector as described in [Section 2.9](#sec2dot9-foods-07-00030){ref-type=\"sec\"}.", "\n\n2.9. ", "HRGC-MS Analysis {#sec2dot9-foods-07-00030}\n---------------------\n\nA Shimadzu GCMS-QP2010 gas chromatograph equipped with a quadrupole mass spectrometer (Shimadzu, Milan, Italy) and split-splitless injector maintained at 300 °C was used. ", "The following MS parameters were used: interface temperature 270 °C; MS ionization mode electron ionization; detector voltage 0.9 kV; acquisition mass range 50--500 u; scan speed 1000 u/s; acquisition mode full scan; scan interval 0.5 s; solvent delay 6 min. ", "Data were collected by GC-MS Solution software (Shimadzu). ", "The column and the chromatographic conditions were the same as those reported in [Section 2.8](#sec2dot8-foods-07-00030){ref-type=\"sec\"}.", "\n\nTMSE sterols and alcohols were identified by comparing retention times and mass spectra to those of authentic TMSE-derivatized compounds. ", "Confirmation of these structures was achieved by HRGC-MS using the National Institute of Standards and Technology (NIST; Gaithersburg, MD, USA) 2008 library to match mass spectral peaks of phytosterol standards to those found in pumpkin seed oil samples. ", "Comparisons of parent molecular ion (M+) and fragmentation ions/patterns were employed to assist in elucidating the identities of the phytosterols. ", "In addition to the presence of specific ion fragments, the relative intensity of the ion fragments was considered. ", "Some compounds, for which commercial standards are not available, were tentatively identified by comparison of relative retention times, M+ values, and fragmentation patterns with data obtained from olive oil analysis or from MS spectra reported in the literature.", "\n\n2.10. ", "Carotenoid Analysis {#sec2dot10-foods-07-00030}\n-------------------------\n\nThe seed oil carotenoids were analyzed by HPLC with diode-array and mass spectrometry detection systems (DAD-MS). ", "To perform this determination, a seed oil sample was diluted fourfold and injected into the HPLC system. ", "Quali-quantitative determination of carotenoids was carried out using the HPLC-DAD-MS validated method described in Blasi et al. ", "\\[[@B31-foods-07-00030]\\].", "\n\n2.11. ", "Statistical Analysis {#sec2dot11-foods-07-00030}\n--------------------------\n\nFA, sterol, alcohol, and carotenoid composition data are reported as mean values and standard deviation (SD). ", "HRGC analyses were carried out in duplicate. ", "Data were processed and edited with Microsoft Excel 2016 (Microsoft, Redmond, MA, USA).", "\n\n3. ", "Results and Discussion {#sec3-foods-07-00030}\n=========================\n\n3.1. ", "Nutritional Composition and Caloric Value {#sec3dot1-foods-07-00030}\n----------------------------------------------\n\nData on nutritional composition and caloric value of pumpkin (*C. maxima*, var. ", "Berrettina) are reported in [Table 1](#foods-07-00030-t001){ref-type=\"table\"}. ", "The samples had a high content of water (82.50%); in fact, a variety of vegetables have water composition in the range of 80--90%. ", "The flesh is characterized by a low fat content. ", "Simple sugars and ash showed similar values (0.82% and 0.84%, respectively), while the protein content was higher (1.28%). ", "Data relative to moisture, ash, and protein are in good agreement with those reported by Kim et al. ", "\\[[@B32-foods-07-00030]\\] for Korean pumpkin (*C. maxima*) flesh. ", "Generally, the proximate composition is extremely variable \\[[@B32-foods-07-00030],[@B33-foods-07-00030],[@B34-foods-07-00030]\\], due to the differences among the species and/or varieties of *Cucurbita* spp. ", "grown in different areas of the world. ", "The low caloric value of pumpkin (*C. maxima*, var. ", "Berrettina) is 25.35 kcal/100 g, according to data in the literature \\[[@B35-foods-07-00030],[@B36-foods-07-00030]\\].", "\n\n3.2. ", "Fatty Acid Composition of Seed Oils and Nutritional Quality Index {#sec3dot2-foods-07-00030}\n----------------------------------------------------------------------\n\nTotal FA% compositions, corresponding to each FA component of oil and TAG fraction, are reported in [Table 2](#foods-07-00030-t002){ref-type=\"table\"}. ", "SFA with carbon chains shorter than 14 carbon atoms, called short- and medium-chain FA, was not found in pumpkin seed oil, as confirmed in other papers \\[[@B14-foods-07-00030],[@B20-foods-07-00030],[@B37-foods-07-00030],[@B38-foods-07-00030]\\]. ", "SFA was represented especially by palmitic (C16:0) and stearic (C18:0) acids, at 14.2% and 5.8%, respectively. ", "It is reported that oils rich in myristic (C14:0) and palmitic acids affect the ratio of total to high-density lipoprotein (HDL) cholesterol only a little, and stearic acid slightly reduces this ratio \\[[@B35-foods-07-00030]\\]. ", "PUFA and MUFA fractions were the most abundant (37.2% and 41.7%, respectively, for oil; 37.8% and 43.0%, respectively, for TAG); in fact, the main FA were oleic (C18:1*n*-9) and linoleic (C18:2*n*-6) acids. ", "Berrettina pumpkin seed oil showed a higher content of oleic acid than linoleic acid (41.4% vs. 37.0% for oil); on the contrary, Procida et al. ", "\\[[@B20-foods-07-00030]\\] reported a higher content of linoleic acid (44.30--51.58%) than oleic acid (34.16--42.59%) for three Italian samples of pumpkin (Crudigno, Pepo, and Winter). ", "It has been reported by some authors \\[[@B14-foods-07-00030]\\] that oleic acid is the predominant FA (41--46%), followed by linoleic acid (33.4--34.3%), in pumpkin seed oil from Italy and Libya. ", "Siano et al. ", "\\[[@B16-foods-07-00030]\\] found that the main FA of southern Italian pumpkin (*C. maxima*) seed oil were linoleic acid (47.45%), followed by oleic (25.54%) and palmitic (17.58%) acids. ", "Habib et al. ", "\\[[@B17-foods-07-00030]\\] found that pumpkin (*C. maxima*, known as \"Misti Kumra\") seed oil contained a high amount of oleic acid, 40.58%, while linoleic acid was 14.97%.", "\n\nIt was reported by Orsavova et al. ", "\\[[@B38-foods-07-00030]\\] that MUFA may reduce low-density lipoprotein (LDL) cholesterol, while it may possibly increase HDL cholesterol, and that oleic acid (C18:1*n*-9) may promote insulin resistance contrary to PUFA, with protection against insulin resistance. ", "The high content of linoleic acid is an important nutritional aspect, because it is an essential FA (EFA), together with linolenic acid (C18:3*n*-3), and a lack of either of the two leads to ill health and causes deficiency symptoms. ", "In addition, several studies \\[[@B39-foods-07-00030]\\] have positively correlated EFA intake with reduction of numerous disorders (cardiovascular, neurological, visual, and cancerous).", "\n\nMinor FA (contents lower than 0.5%) of Berrettina pumpkin seed oil were myristic, palmitoleic (C16:1*n*-7), margaric (C17:0), heptadecenoic (C17:1*n*-7), arachidic (C20:0), behenic (C22:0), and lignoceric (C24:0) acids. ", "These data are in good agreement with similar studies \\[[@B14-foods-07-00030],[@B20-foods-07-00030],[@B37-foods-07-00030],[@B38-foods-07-00030]\\].", "\n\nThe extreme variability of FA composition of pumpkin seeds, and consequently of the corresponding pumpkin seed oils, is affected not only by the variety of the cultivar, but also by the growth conditions and degree of ripeness \\[[@B40-foods-07-00030]\\].", "\n\nIn addition, the nutritional quality of pumpkin (*C. maxima,* var. ", "Berrettina) cultivated in central Italy was evaluated, using different indices, based on the FA composition of the oils. ", "It is known that some FA can help to prevent or promote coronary thrombosis and atherosclerosis based on their effects on LDL concentration and serum cholesterol \\[[@B41-foods-07-00030]\\]. ", "The equations proposed by Ulbricht and Southgate \\[[@B41-foods-07-00030]\\] for the atherogenic index (AI) and thrombogenic index (TI) showed that C12:0, C14:0, and C16:0 FA are atherogenic, while C14:0, C16:0, and C18:0 are thrombogenic. ", "PUFA *n*-3, PUFA *n*-6, and MUFA are antiatherogenic and antithrombogenic. ", "Atherogenic indices have been described as powerful indicators of the risk of cardiovascular disease; the higher the value, the higher the risk of developing the disease, and vice versa. ", "The AI of pumpkin (*C. maxima*) seed oil was lower than that reported by Siano et al. ", "\\[[@B16-foods-07-00030]\\] (0.19 for Berrettina vs. 0.34), while the TI was comparable (0.50 for Berrettina vs. 0.65).", "\n\n3.3. ", "Stereospecific Analysis Data {#sec3dot3-foods-07-00030}\n---------------------------------\n\nThe indirect method of analyzing TAG was based on a chemical--enzymatic--instrumental (stereospecific analysis) procedure and allowed us to carry out qualitative and quantitative analysis of all molecular TAG species, including enantiomeric ones. ", "In fact, it is known that in TAG molecules the positions esterified by FA are numbered relative to their stereospecific numbering (*sn*) as *sn*-1, *sn*-2, and *sn*-3. ", "The procedure allowed us to evaluate the FA % composition of each of the three *sn*-positions of TAG (% intrapositional composition). ", "These data could be used to obtain the distribution of FA among the three *sn*-positions of TAG \\[[@B24-foods-07-00030],[@B25-foods-07-00030],[@B42-foods-07-00030],[@B43-foods-07-00030]\\].", "\n\nInitially, the lipid fraction was isolated by Soxhlet extraction, and then the TAG fraction was purified by TLC. ", "As shown in [Figure 1](#foods-07-00030-f001){ref-type=\"fig\"}, several steps were carried out. ", "Initially, the total FA% composition (A~t~) was determined by HRGC. [", "Figure 2](#foods-07-00030-f002){ref-type=\"fig\"}a shows the characteristic HRGC profile of the FAME of the TAG fraction of pumpkin samples. ", "Then, enzymatic hydrolysis of TAG with pancreatic lipase was used to obtain *sn*-2-MAG, and finally, after HRGC analysis of the FAME ([Figure 2](#foods-07-00030-f002){ref-type=\"fig\"}b), the acidic composition of *sn*-2-position (A~2~) of the glycerol backbone of TAG was obtained. ", "TAG was also subjected to chemical hydrolysis with Grignard reagent, then separation of enantiomeric *sn*-1,2(2,3)-DAG, realized by enzymatic synthesis of *sn*-1,2-PA, allowed us to obtain the acidic composition of the *sn*-1,2-positions (A~1,2~) of the glycerol backbone of TAG, after HRGC analysis of the FAME ([Figure 2](#foods-07-00030-f002){ref-type=\"fig\"}c).", "\n\nThe stereospecific analysis represents a potent analytical-investigative procedure to give the fingerprint of TAG fraction for each botanical variety or animal species. ", "The results of the stereospecific analysis procedure are shown in [Table 2](#foods-07-00030-t002){ref-type=\"table\"}. ", "It was observed that Berrettina pumpkin seed oil had a high percentage of UFA (98.5%) in *sn*-2 position, represented by MUFA (36.2%) and PUFA (62.4%). ", "In *sn*-2 position, the main FA was linoleic acid (62.1%), followed by oleic acid (36.0%). ", "SFA are preferentially esterified in *sn*-1 position (44.7%), represented essentially by palmitic and stearic acids (28.6% and 13.7%, respectively). ", "Regarding the two primary positions, oleic acid was equally distributed between the *sn*-1 and *sn*-3 positions, while linoleic acid prefers the *sn*-3 position (42.2%).", "\n\n3.4. ", "Unsaponifiable Fraction {#sec3dot4-foods-07-00030}\n----------------------------\n\nAnother part of the research was analyzing the main components of unsaponifiable fractions, i.e., sterols and alcohols. ", "Alkaline hydrolysis was carried out on pumpkin seed oils to obtain data relative to the qualitative composition of sterol and alcohol fractions. ", "Phytosterols have been studied for their role in lowering cholesterol levels. ", "In addition to this property, plant sterols have antiatherogenic, anti-inflammatory, anticancer, and antioxidation activities \\[[@B44-foods-07-00030]\\]. ", "Together with the high content of linoleic acid, sterols can help in the treatment of lipid-associated disorders such as atherosclerosis.", "\n\nIn contrast to the other vegetable oils with Δ^5^-sterols (β-sitosterol, campesterol, and stigmasterol) as the major components, Wenzl et al. ", "\\[[@B45-foods-07-00030]\\] showed that pumpkin seed oil contains specific Δ^7^-phytosterols, typical of only a few plant families (e.g., *Cucurbitaceae*), that provide a fingerprint for detection of adulteration. ", "These Δ^7^-sterols are supposed to give the pumpkin seed oil a beneficial effect in the treatment and prophylaxis of disorders of the prostate gland and the urinary bladder \\[[@B46-foods-07-00030]\\].", "\n\nIn this paper, sterol identification was carried out by HRGC-MS. ", "Each peak was analyzed via detection of the parent molecular ion and the fragmentation pattern of the TMSE derivative. ", "In addition to the presence of specific ion fragments, the relative intensity of the ion fragments was considered. ", "Some TMSE sterols were identified by comparison with the NIST mass spectra library; typical fragmentation is reported in [Table 3](#foods-07-00030-t003){ref-type=\"table\"}, together with sterol composition (% and mg/100 g). ", "TMSE sterols give a molecular ion that is not abundant, while the first significant ion observed in the high mass range was usually equivalent to \\[M-15\\]^+^, due to the loss of the methyl terminal group. ", "Other main fragment ions useful for identifying the single sterol compounds are \\[M-90\\]^+^, \\[M-105\\]^+^, and \\[M-129\\]^+^. They correspond to the loss of the trimethylsilanol, methyl group with trimethylsilanol, and fragmentation of the 1,2-cyclopenthanophenanthrene structure, respectively. ", "The predominant sterols of Berrettina pumpkin seed oil are Δ^7^-sterols, in particular Δ^7,22,25^-stigmastatrienol, Δ^7,25^-stigmastadienol, and spinasterol, which accounted for about 76.8% of the total sterols, followed by Δ^7^-avenasterol and Δ^7^-stigmastenol. ", "The Δ^5^-sterols were represented by campesterol, stigmasterol, and only a little cholesterol, as in other foodstuff \\[[@B47-foods-07-00030]\\]. ", "Differences between the contents of Δ^5^- and Δ^7^-sterols could be attributed to the maturity stage of seeds or to the solvent used in the extraction procedure \\[[@B15-foods-07-00030]\\]. ", "A total sterol content of 295 mg/100 g oil was measured in *C. maxima* seed oil; 15.7 mg/100 g was represented by Δ^5^-sterols and 279.3 mg/100 g by Δ^7^-sterols. ", "The total content was in agreement with other studies \\[[@B9-foods-07-00030],[@B48-foods-07-00030]\\], even if a wide range of variability is reported \\[[@B9-foods-07-00030]\\]. ", "Hence, more detailed examinations of the composition of the sterol fraction of this oil could be of special interest. ", "For example, analysis of a more extensive sampling is required for better characterization of pumpkin seed oils and for their authentication.", "\n\nThe alcoholic fraction (aliphatic and triterpenic classes) was also studied, after derivatization as TMSE and analysis by HRGC-MS; the typical fragmentation is reported in [Table 4](#foods-07-00030-t004){ref-type=\"table\"}, together with the alcohol composition (% and mg/100 g). ", "Some aliphatic alcohols (from C16 to C25 members of the 1-alkanol homologous series) with odd and even numbers of carbon atoms of the aliphatic chain were identified. ", "The TMSE alcohols were identified by comparison with the NIST mass spectra library. ", "TMSE alcohols give a molecular ion that is not abundant, while the first significant ion observed in the high mass range was equivalent to \\[M-15\\]^+^, due to the loss of the methyl terminal group, and \\[M-117\\]^+^, equivalent to the loss of \\[(CH3)~3~-Si-O\\]^+^, i.e., the OTMSi group. ", "Moreover, HRGC-MS analysis of alcohols after BSTFA derivatization resulted in various peaks with MS fragments *m/z* 73, 75, 103, and 117 characteristics for OTMSi groups. ", "The peak at *m*/*z* 129, corresponding to \\[(CH3)~3~-Si-O^+^=CH-CH=CH~2~\\]^+^, has been identified as the fragment originating from the breakdown of ring A along with the TMS moiety. ", "Four main triterpenic alcohols were identified: butyrospermol, obtusifoliol, β-amyrine, and cycloartenol. ", "The key fragmentation ions were molecular ion \\[M\\]^+^, \\[M-15\\]^+^, \\[M-90\\]^+^, and \\[M-105\\]^+^. Aliphatic alcohol content was 36.8%, of which hexadecanol and octadecanol were the most abundant (each about 4.4 mg/100 g oil), while triterpenic alcohol content was around 63.2%, of which obtusifoliol was the most abundant (11.9 mg/100 g oil).", "\n\nThese minor compounds are also important constituents of edible oils and could be useful in distinguishing different pumpkin oil varieties.", "\n\n3.5. ", "Carotenoid Analysis {#sec3dot5-foods-07-00030}\n------------------------\n\nHPLC-DAD-MS analysis, performed directly on seed oils, detected two important carotenoids: lutein and β-carotene. ", "Quantitative analysis showed a lutein concentration of 8 mg/L seed oil, while β-carotene concentration was 2.5 mg/L seed oil.", "\n\nCarotenoids such as lycopene, lutein, β-carotene, and zeaxanthin have been studied by many researchers both analytically and biologically \\[[@B49-foods-07-00030],[@B50-foods-07-00030],[@B51-foods-07-00030]\\]. ", "Carotenoids represent a significant added value for food: various health properties have been associated with these compounds, including antioxidant and anticancer activity, photoprotection, protection against cardiovascular diseases, and anti-inflammatory activity \\[[@B52-foods-07-00030],[@B53-foods-07-00030],[@B54-foods-07-00030]\\].", "\n\n4. ", "Conclusions {#sec4-foods-07-00030}\n==============\n\nThe results reported in this study confirm that pumpkin seed oils are interesting vegetable oils with important nutritional value, related to the presence of MUFA, PUFA, phytosterols, and carotenoids. ", "A more extensive sampling for a better characterization of pumpkin seed oils and for authentication purposes is necessary. ", "To the best of our knowledge, this is the first time stereospecific analysis data of pumpkin seed oil have been reported. ", "Information obtained from this research could help to assess the potential of seed oil from this pumpkin cultivar to be commercially exploited for nutraceutical application, and incorporated into food formulations to benefit human health.", "\n\nEach author contributed equally to the manuscript setting up and preparation.", "\n\nThe authors declare no conflict of interest.", "\n\n{#foods-07-00030-f001}\n\n{#foods-07-00030-f002}\n\nfoods-07-00030-t001_Table 1\n\n###### \n\nNutritional composition (g/100 g edible part) of pumpkin (*C. maxima*, var. ", "Berrettina) (mean value ± standard deviation (SD), *n* = 3).", "\n\n Component Mean Value ± SD\n --------------------- -----------------\n Energy (kcal/100 g) 25.35\n Moisture 82.50 ± 0.37\n Dry matter 17.50 ± 0.14\n Total ash 0.84 ± 0.04\n Crude protein 1.28 ± 0.03\n Crude oil 0.08 ± 0.01\n Total sugars 4.90 ± 0.09\n Starch 4.10 ± 0.05\n Simple sugars 0.82 ± 0.03\n\nfoods-07-00030-t002_Table 2\n\n###### \n\nTotal and intrapositional % fatty acid composition (% mol, mean value ± SD, *n* = 3) of oil and triacylglycerol (TAG) fraction of pumpkin (*C. maxima*, var. ", "Berrettina) seed oil.", "\n\n Total Lipids TAG *sn*-1- *sn*-2- *sn*-3-\n ------------------------------------ ------------ -------------- ------------ ------------ ------------ ------------\n Yield (%) 29.0 ± 0.9 \n Saturated fatty acids (SFA) \n Mystiric acid C14:0 0.2 ± 0.0 0.1 ± 0.0 0.5 ± 0.0 -- --\n Palmitic acid C16:0 14.2 ± 0.4 12.2 ± 0.4 28.5 ± 0.0 1.0 ± 0.0 7.1 ± 0.0\n Margaric acid C17:0 0.2 ± 0.0 0.1 ± 0.0 0.5 ± 0.0 -- --\n Stearic acid C18:0 5.8 ± 0.2 6.2 ± 0.2 13.7 ± 0.0 0.4 ± 0.0 4.4 ± 0.0\n Arachidic acid C20:0 0.5 ± 0.0 0.4 ± 0.0 -- -- 1.1 ± 0.0\n Behenic acid C22:0 0.1 ± 0.0 0.2 ± 0.0 1.5 ± 0.0 -- --\n Lignoceric acid C24:0 0.1± 0.0 -- -- -- --\n Total SFA 21.1 19.2 44.7 1.5 11.6\n Monounsaturated fatty acids (MUFA) \n Palmitoleic acid C16:1*n*-7 0.2 ± 0.0 0.2 ± 0.0 -- 0.1 ± 0.0 0.4 ± 0.0\n Heptadecenoic acid C17:1*n*-7 0.1 ± 0.0 0.1 ± 0.0 -- 0.1 ± 0.0 0.3 ± 0.0\n Oleic acid C18:1*n*-9 41.4 ± 0.7 42.7 ± 0.7 46.5 ± 0.0 36.0 ± 0.0 44.6 ± 0.0\n Eicosenoic acid C20:1*n*-9 0.1 ± 0.0 -- -- -- --\n Total MUFA 41.7 43.0 46.4 36.2 46.3\n Polyunsaturated fatty acids (PUFA) \n Linoleic acid C18:2*n*-6 37.0 ± 0.5 37.4 ± 0.5 7.7 ± 0.0 62.1 ± 0.0 42.0 ± 0.0\n Linolenic acid C18:3*n*-3 0.2 ± 0.0 0.4 ± 0.0 1.1 ± 0.0 0.3± 0.0 0.1 ± 0.0\n Total PUFA 37.2 37.8 8.8 62.4 24.1\n Index \n UFA/SFA 3.7 4.2 1.2 65.7 6.1\n MUFA/SFA 2.0 2.2 1.0 24.1 4.0\n PUFA/SFA 1.8 2.0 0.2 41.6 2.1\n PUFA*n*-6/PUFA*n*-3 185 93.5 7.0 207 420\n UI 116.3 118.9 65.2 161.3 129.6\n AI 0.19 0.16 0.55 0.01 0.10\n TI 0.50 0.44 1.38 0.03 0.32\n\n--: \\<0.1%; UI: unsaturation index: Σ(mol % of each FA) × (number of double bonds of each FA); AI: atherogenic index (C12:0 + 4 × C14:0 + C16:0)/(MUFA + PUFA*n*-6 + PUFA*n*-3); TI: thrombogenic index (C14:0 + C16:0 + C18:0)/(0.5 × MUFA + 0.5 × PUFA*n*-6 + 3 × PUFA*n*-3 + (PUFA *n*-3/PUFA*n*-6)).", "\n\nfoods-07-00030-t003_Table 3\n\n###### \n\nFragmentation ions used for identification of trimethylsilyl ether (TMSE) sterols of pumpkin (*C. maxima*, var. ", "Berrettina) seed oil and sterol composition (% and mg/100 g oil; mean value ± SD, *n* = 3).", "\n\n Sterol \\[M\\]^+^ \\[M-15\\]^+^ \\[M-90\\]^+^ \\[M-105\\]^+^ \\[M-129\\]^+^ \\% mg/100 g\n ----------------------------- ---------- ------------- ------------- -------------- -------------- ------------ ------------\n Cholesterol 458 443 368 353 329 0.3 ± 0.1 0.9 ± 0.1\n Campesterol 472 457 382 367 343 3.3 ± 1.0 10.3 ± 1.0\n Stigmasterol 484 469 394 379 355 1.6 ± 0.4 4.5 ± 0.8\n Spinasterol 484 469 394 379 -- 20.5 ± 1.9 61.8 ± 4.2\n Δ^7,25^-Stigmastadienol 484 469 394 379 -- 26.4 ± 2.3 78.4 ± 5.5\n Δ^7,22,25^-Stigmastatrienol 482 467 392 377 -- 29.9 ± 2.5 91.2 ± 6.8\n Δ^7^-Stigmastenol 486 471 396 381 -- 5.7 ± 1.0 15.1 ± 1.5\n Δ^7^-Avenasterol 484 469 394 379 -- 12.3 ± 0.9 32.8 ± 2.8\n Δ^5^-Sterol (total) 5.2 15.7\n Δ^7^-Sterol (total) 94.8 279.3\n\n\\[M\\]^+^ indicates molecular ion. ", "\\[M-15\\]^+^, \\[M-90\\]^+^, \\[M-105\\]^+^, and \\[M-129\\]^+^ correspond to loss of the methyl group, trimethylsilanol, methyl group with trimethylsilanol, and to fragmentation of the 1,2-cyclopenthanophenanthrene structure, respectively.", "\n\nfoods-07-00030-t004_Table 4\n\n###### \n\nFragmentation ions used for identification of TMSE alcohols of pumpkin (*C. maxima*, var. ", "Berrettina) seed oil and alcohol composition (% and mg/100 g oil; average value ± SD, *n* = 3).", "\n\n -------------------------- -------------- ----------------- ----------------- ------------------ ------------ --------------\n **Aliphatic Alcohols** **\\[M\\]^+^** **\\[M-15\\]^+^** **\\[M-90\\]^+^** **\\[M-117\\]^+^** **%** **mg/100 g**\n Hexadecanol 314 299 224 195 7.4 ± 2.0 4.3 ± 1.0\n Heptadecanol 328 313 238 209 3.1 ± 0.9 1.9 ± 0.3\n Octadecanol 342 327 252 223 7.5 ± 1.3 4.4 ± 0.9\n Nonadecanol 356 341 266 237 3.4 ± 0.8 2.9 ± 1.5\n Eicosanol 370 355 280 251 4.9 ± 1.0 2.0 ± 0.8\n Docosanol 398 383 308 279 3.1 ± 0.9 2.2 ± 0.3\n Tricosanol 412 397 322 293 1.8 ± 0.5 1.3 ± 0.3\n Tetracosanol 426 411 336 307 3.6 ± 0.5 1.2 ± 0.2\n Pentacosanol 440 425 350 321 2.3 ± 0.7 1.5 ± 0.9\n Total 36.8 21.7\n **Triterpenic Alcohols** **\\[M\\]^+^** **\\[M-15\\]^+^** **\\[M-90\\]^+^** **\\[M-105\\]^+^** \n Butyrospermol 498 483 408 393 13.7 ± 1.2 8.1 ± 2.1\n Obtusifoliol 484 469 394 379 20.2 ± 1.5 11.9 ± 1.1\n β-Amyrine 498 483 408 393 16.1 ± 1.1 9.5 ± 1.8\n Cycloartenol 498 483 408 393 13.3 ± 1.0 7.8 ± 1.5\n Total 63.2 37.3\n -------------------------- -------------- ----------------- ----------------- ------------------ ------------ --------------\n\n\\[M\\]^+^ indicates molecular ion. ", "For aliphatic alcohols: \\[M-15\\]^+^, \\[M-90\\]^+^, and \\[M-117\\]^+^ correspond to loss of the methyl group \\[-CH~3~\\], trimethylsilanol \\[-OSi(CH~3~)~3~\\], and ethyl trimethylsilanol \\[-CH~3~CH~2~-OSi(CH~3~)~3~\\]. ", "For triterpenic alcohols: \\[M-15\\]^+^, \\[M-90\\]^+^, and \\[M-105\\]^+^ correspond to loss of the methyl group \\[-CH~3~\\], trimethylsilanol \\[-OSi(CH~3~)~3~\\], and methyl group with trimethylsilanol \\[-CH~3~OSi(CH~3~)~3~\\].", "\n\n[^1]: These authors contributed equally to this work.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Three suburban residents - including a mother and son - are charged with violating trademarks, after the companies whose merchandise was fraudulently produced agreed to press charges.", "\n\nBaosong Sun, 38, of the 2500 block of Greenwood Avenue, Highland Park, was arrested May 15th. ", "Officers from the Sheriff’s Police Special Operations Unit received information that Sun was selling fake Nike gym shoes. ", "The investigation led officers to a storage facility where Sun was renting lockers. ", "Search of those lockers resulted in the seizure of more than 3,390 pairs of gym shoes bearing a counterfeit Nike logo, along with nearly 1,000 items with fake Chanel and Louis Vuitton labels. ", "If authentic, the items confiscated in this seizure would have an approximate retail value of more than $682,000.", "\n\nIn a separate raid five days later, more than 4,660 items, bearing various fake designer labels such as Ed Hardy, Chanel and Louis Vuitton, as well as NBA, MLB and NFL logos were seized from P & L Fashions, located at 1750 W. 47th Street in Chicago. ", "The estimated retail value of these items, if authentic, is $916,000.", "\n\nShao Hua Li, 46, and Jia Hao Pan, 22, both of the 5200 block of west 110th Street in Oak Lawn were arrested on May 20th. ", "Li and Pan, who are mother and son, had been selling the fake designer merchandise for approximately four months from their store in Chicago.", "\n\nLi and Pan each posted $25,000 bond and are scheduled to appear in court on May 27th. ", "Sun, whose next court date is pending, posted $100 bond." ]

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[ "SAFER barrier\n\nThe Steel and Foam Energy Reduction Barrier (SAFER Barrier), sometimes generically referred to as a soft wall, is a technology found on oval automobile race tracks and high speed sections of road and street tracks, intended to absorb and reduce kinetic energy during the impact of a high speed crash, and thus, lessen injuries sustained to drivers and spectators. ", "It was designed by a team of engineers led by Dean Sicking at the Midwest Roadside Safety Facility at the University of Nebraska-Lincoln. ", "It was developed from 1998–2002, and first installed at the Indianapolis Motor Speedway in May 2002.", "\n\nThe SAFER barrier consists of structural steel tubes welded together in a flush mounting, strapped in place to the existing concrete retaining wall. ", "Behind these tubes are bundles of closed-cell polystyrene foam, placed between the barrier and wall. ", "The theory behind the design is that the barrier absorbs a portion of the kinetic energy released when a race car makes contact with the wall. ", "This energy is dissipated along a longer portion of the wall. ", "The impact energy to the car and driver are reduced, and the car is likewise not propelled back into traffic on the racing surface.", "\n\nThe SAFER barrier also lessens damage to the car itself, thereby reducing repair costs. ", "After its introduction in 2002, nearly every oval track on the IndyCar and NASCAR circuits had the device installed by 2005. ", "Road and street tracks apply SAFER barriers on high speed cornering sections where space is limited.", "\n\nThe SAFER Barrier and its developers have won several awards within the racing and engineering community, including the Louis Schwitzer Award, Pocono Raceway Bill France, Sr. ", "Award of Excellence, NASCAR Bill France, Jr. Award of Excellence, R&D 100 Award, SEMA Motorsports Engineering Award, GM Racing Pioneer Award, Autosport Pioneering and Innovation Award. ", "Sicking also received the National Science and Technology Medal from President George W. Bush, in part due to his work on the SAFER Barrier and on other roadside safety devices.", "\n\nHistory\nThroughout the decades of organized professional automobile racing, track owners and sanctioning bodies were constantly developing and attempting to utilize various devices to protect drivers and spectators in the event of a crash. ", "Tire barriers, water and sand barrels, Styrofoam blocks, gravel traps, guardrails, earth embankments, and other various low-cost devices were implemented, with a varying level of success and usefulness. ", "In most cases, the devices were practical for road and street courses, but impractical, or particularly inappropriate for oval tracks. ", "\n\nOval tracks typically were constructed with reinforced concrete walls around the entire perimeter of the track (and along all or parts of the inside perimeters). ", "The high speeds of oval track racing required strong walls to prevent cars from leaving the racing surface and protect spectators alike, primarily due to centrifugal force. ", "Early years saw metal guardrails on the outside perimeters at some oval tracks, but their limitations and troublesome results saw them completely phased out by the late 1980s. ", "The concrete walls generally showed favorable protection for spectators, and even against large NASCAR stock cars, routinely held up nearly unscathed during crashes. ", "However, the hard surface and unforgiving nature of the walls were prone to cause injury to the drivers in a crash. ", " \n\nIn the later years of the 20th century, sharply increasing speeds and several high-profile fatal accidents accelerated the need and public outcry for safety improvements at the track level. ", "The undesirable results or outright failures of existing safety devices required the need for a full-scale research and development of a new device.", "\n\nThroughout the 1970s–1990s, Indycar constructors, for instance, had attempted to address the issue of impact dissipation through car design. ", "Pieces of the car (wheel assemblies, wings, bodywork, etc.) ", "were designed to breakaway after impact, absorbing kinetic energy. ", "Crumple zones were also created. ", "While it typically yielded positive results, it also had drawbacks. ", "The debris field created new hazards for cars approaching the crash scene, and if cars hit pieces of the debris, it could be propelled into the spectator areas. ", "In two high-profile incidents multiple spectators were fatally injured when sheared off wheel assemblies were punted into the grandstands.", "\n\nPEDS Barrier\nThe precursor to the SAFER Barrier was developed in 1998. ", "The Polyethylene Energy Dissipating System (or PEDS Barrier) was developed by the Indy Racing League and retired GM engineer John Pierce at Wayne State University. ", "The device consisted of PE cylinders mounted upright along the concrete wall, covered with plates of the same material, overlapping each other in the direction of travel. ", "The plates mounting pattern resembled scales on a fish.", "\n\nThe PEDS barrier was installed on a trial basis at the Indianapolis Motor Speedway in time for the 1998 Indianapolis 500. ", "It was installed along the inside wall near the entrance to the pits. ", "However, it was not impacted during the race. ", "About two months later, the barrier received its first full-scale test. ", "During the 1998 IROC at Indy race, Arie Luyendyk spun and impacted the barrier broadside with his IROC stock car. ", "The violent impact ripped many of the PEDS Barrier components from the wall, threw them high into the air, and littered the track with huge amounts of debris. ", "Luyendyk's car bounced off the wall, across the track and back into oncoming traffic. ", "The car was narrowly missed by another car approaching at high speed.", "\n\nThough the barrier was credited with saving Luyendyk from serious injury, it was deemed mostly a failure due to the flaws that were exposed with the design. ", "A slightly updated version (PEDS-2) was installed for a trial basis for the 1999 Indianapolis 500, but after driver Hideshi Matsuda impacted it, another major flaw (the tendency to \"catch and pivot\") was exposed. ", "The barrier was removed soon after.", "\n\nSAFER Barrier\n\nAfter the mixed results with the PEDS Barrier, the Indianapolis Motor Speedway contacted engineers at the University of Nebraska-Lincoln starting in the fall of 1998, in order to spearhead development of a new barrier. ", "Dean Sicking at the Midwest Roadside Safety Facility led the project, sponsored and bankrolled by the Indy Racing League, with some support from NASCAR.", "\n\nWith the primary goal of reducing driver impact, the project also had the following objectives:\nA device that would have a flush surface – to prevent \"catch and pivot\" or \"wrapping\" scenarios.", "\nA device that would be able to be retro-fitted to the existing concrete walls at the multitude of speedways across the country, which each had varying existing conditions.", "\nPrevent the car from bouncing back to the racing surface and into oncoming traffic.", "\nBe able to withstand both open wheel Indy cars and heavy NASCAR stock cars (since many tracks hosted both series)\nA device that could easily be repaired after impact – preventing lengthy delays during an event.", "\nCost-effectiveness \n\nThe SAFER Barrier development was completed in the spring of 2002, and was first installed at the Indianapolis Motor Speedway in May 2002, in time for the 2002 Indianapolis 500. ", "It was first \"tested\" by Robby McGehee in a crash during the first day of practice. ", "\n\nAfter successful usage at Indianapolis, the system began to be installed at several other tracks nationwide. ", "By 2006, every oval facility that hosted an IRL IndyCar Series or NASCAR Sprint Cup Series event included the SAFER barrier. ", "In 2006, Iowa Speedway became the first racetrack to install a purpose-built, self-standing SAFER barrier that extends around the entire outer circumference of the track. ", "All previous installations had been the retrofit style to an existing concrete wall only in the turns. ", "Most oval speedways more than a mile in length in the United States have since installed the system. ", "Several tracks that had SAFER barriers initially installed in the turns in the early/mid-2000s have extended their barriers to more than just the turns, some to the entire perimeter. ", "Many have added additional barriers along the inside walls. ", "\n\nAn interesting challenge was presented with Dover International Speedway. ", "When officials came to install the barrier, they found the wall, which was made of steel and not concrete, would not support the system. ", "Officials were able to install the system on the inside concrete wall successfully. ", "After a re-design and further testing, the system was installed a year and a half later.", "\n\nThe barrier received its first road course usage when Watkins Glen International adopted the SAFER barrier for key sections of the circuit, most notably in the bus stop chicane and Turn 11 for 2010. ", "International road and street track adoption for the SAFER barrier has progressed gradually. ", "Typically they are installed on high speed cornering sections, where space for runoff areas or gravel traps is limited and side impacts are of concern. ", "Notable uses include:\n Circuit de la Sarthe: Porsche Curves (2016)\n Autódromo José Carlos Pace: Turn 14 (2010)\n Baku City Circuit: Turns 13, 19 (2016)\n Circuit Gilles Villeneuve: Turn 5 (2017)\n Road America: Turn 11 (2019)\n\nOther forms of \"soft walls\"\n Cellofoam – This is an encapsulated polystyrene barrier—a block of plastic foam encased in polyethylene.", "\n Impact Protection System (IPS) – This inner piece of the wall is then wrapped in a rubber casing. ", "Holes are drilled in the concrete wall and cables are used to tie the segments to it.", "\n Compression barriers – This idea is to place cushioning materials, such as tires, water barrels, or sand barrels, against the concrete wall, and then cover those cushions with a smooth surface that would give when impacted, and then pop back out to its previous shape once the impact is over.", "\n\nReferences\n\nExternal links\n\n Midwest Roadside Safety Facility – designers of the SAFER Barrier\n IndyCar.com – The official site of the IRL\n Eldora meets guidelines without SAFER barriers\n \n\nCategory:Auto racing equipment" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Muhammad al-Arabi al-Darqawi\n\nAbu Abdullah Muhammad al-Arabi al-Darqawi (1760–1823) was a Moroccan Sufi leader of the Shadhili tariqa and the author of letters concerning the dhikr he preached and instructions for daily life. ", "He stressed noninvolvement in worldly affairs (Dunya) and spoke against other Sufi orders exploiting claims of barakah (blessings). ", "He was imprisoned by the Moroccan ruler Mulay Slimane (r. 1792–1822) for supporting revolts against the throne, but was released by Abderrahmane (r. 1822–1859). ", "\n\nA branch of the Shadhili order, the Darqawa, was organized around his teachings after his death, with members coming from a wide range of social groups. ", "Though the Darqawa was once the most important tariqah in Morocco, its power waned as it spread throughout North Africa.", "\nAl-Darqawi was descended from a Hasanid/Idrissid sherif family that lived among the Beni Zerwal Berbers, in the hills to the north-east of Fez. ", "His tomb is in the Zawiya Bou Brih also in the Rif.", "\n\nHis Letters\n\nAlmost all of the letters concern the method based on the central techniques of invocation or dhikr, not usually discussed openly by Sufi masters. ", "The letters were compiled by al-`Arabi al-Darqawi himself, copied by his disciples and printed many times in Fez, in lithographed script. ", "Titus Burckhardt has made this translation on the basis of two nineteenth-century manuscripts as well as the lithographed edition.", "\n\nShaykh Ibn 'Abbas, Sayyidi Ahmad ibn Muhammad az-Zagari al-Hasani, known as Ibn al-Khayyat, wrote concerning Sayyidna Moulay al-Arabi ad-Darqawi, as a way of introduction to Moulay al-Arabi's Risala:\n\nIn the Name of Allah, the most Beneficent the most Merciful\n\nSalutations and peace upon our master Muhammad and his family. ", "Praise be to Allah who placed in every age one who calls to Allah and is a guide to the treatment of the sicknesses of the nafus (i.e. ego) and to the path of putting hearts right. ", "Whoever answers his call is happy. ", "Whoever is arrogant or shy continues with the hobbling-cord of his sickness. ", "SubhannAllah (Glory be to God, Allah)! ", "He purifies the hearts of whomever He wills of His slaves and makes them Imams in the path of guided conduct. ", "They travel on the Path to Allah and they recognize its states. ", "They have insight into the machinations of the nafs. ", "They know its actions. ", "Their Master has guided them to His Path after much striving. ", "Their selves have been put to rest after struggle and suffering. ", "They have drawn near to their Master with sincere intention and their Master has drawn near to them as befits the sublime essence.", "\n\nThese are the letters of the Sheikh, the Imam, the Ghawth (spiritual axis, pole) who benefits the elite and the common, the famous wali (saint) and great siddiq (truthful one), the perfect realized gnostic, the one who has arrived, who is drowned in the sea of Tawhid (oneness of Allah), utterly crushed and annihilated in the immensity of the sublime essence, who is firmly established and firmly rooted, the lofty mountain that joins the shari'at of our master Muhammad (peace and blessings of Allah upon him) and the haqqiqa (spiritual tasting), bewildered in every station of his realization, the Cave of mankind and the shelter of the elite and common. ", "He is the sign, ayyat, of the Merciful and the rarity of the age, the word of Allah from His direct presence, and the shelter of His resplendent tajalli-manifestation. ", "He is the Sharif ad-Darqawi al-Hasani, the teacher, endowed with noble qualities, our lord and master al-Arabi, may Allah give us the benefit of his baraka and send back some of his fragrant breeze to us. ", "He is loved by those from who the veils have been lifted\nand from whom others are distant. ", "The cosmos is crushed and annihilated in their eyes since they see He is One, the Conqueror. ", "What contemplation it is! ", "How sweet it is! ", "What a station it has! ", "How high they are!", "\n\nRegarding his letters, it is a drink that is clear and pure for the thirsty. ", "All examinations agree that the knowledge of their author is an overflowing sea. ", "In them are the commands and words of the shari'at of Muhammad, and the sunnah and actions of the tariqa, and the secrets and states of the reality, Haqqiqa.", "\n\nO brother (and sister)! ", "Grab on to them and act according to them. ", "Take on their character. ", "All that there is in them is the shari'at of the master of the Messengers, peace and blessings of Allah upon him and his family, the path of the wayfarers, indications of the realized gnostics who have arrived, and the estasies of the beloved lovers. ", "They, like their author, are well-known and famous in every land. ", "They are spread out as this Darqawi Tariqa is spread out, the group of the dutifully obedient, may Allah have mercy upon all of them (those of the past, the future, and the current brotherhood) .", "\n\nI said: Moulay al-Arabi ad-Darqawi, the author of these letters, may Allah be well pleased with him, was the answer for this world in the heart of the sources. ", "How many people who had blind eyes, heedless hearts, and ears deaf to perception of the divine presence were opened by Allah at his hand, and the hand of his companions and heirs after him! ", "They were not aware and now their hearts have found a nest and their spirits a residence, may Allah profit us by their baraka.", "\n\nMoulay al-Arabi ad-Darqawi rvitalized the Shadhili Tariqa and filled North Africa with tassawuf, having trained and authorized thousands of others who were qualified to take seekers by the hand, by the permission of Allah, glorified is He; his tariqa spread primarily via Sheikh Ahmad ibn Mustapha 'Alawi of Mostaganem, Algeria and Sheikh Muhammad ibn Habib of Meknes, Morocco to Syria, Jordan, Palestine, the US, Canada, Europe. ", "Sheikh Nuh Ha Mim Keller, Sheikh Abdelqadir As Sufi, Sheikh Muhammad Yaqubi, and Ahmad Salah As Sufi, India and Pakistan and others have later further spread the tariqa to Western lands by the grace of the Beneficent.", "\n\nSee also\nMuhammad Abul-Huda al-Yaqoubi\n\nReferences\n\n Al 'Arbi Al Darqawi, Majmu'at Rasa'il (Letters from Al Darqawi to his disciples), Casablanca, 1999\n The Darqawi Way (The Letters of Al-Arabi al-Darqawi translated by Aisha Bewley), Diwan Press, Norwich UK, 1980, \n Letters of a Sufi Master, The Shaykh ad-Darqawi, Shaykh al-'Arabi ad-Darqawi, Translated by Titus Burckhardt, Preface by Martin Lings, Fons Vitae (1998) \n\nCategory:Moroccan Sufi writers\nCategory:Moroccan letter writers\nCategory:1760 births\nCategory:1823 deaths\nCategory:18th-century Moroccan people\nCategory:19th-century Moroccan people\nCategory:Moroccan religious leaders\nCategory:People from Fez, Morocco" ]

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[ "Consider the humble video game cartridge. ", "It’s a small, durable plastic box that imparts the most immediate, user-friendly software experience ever created. ", "Just plug it in, and you’re playing a game in seconds.", "\n\nadvertisement\n\nadvertisement\n\nIf you’ve ever used one, you have two men to thank: Wallace Kirschner and Lawrence Haskel, who invented the game cartridge 40 years ago while working at an obscure company and rebounding from a business failure. ", "Once the pair’s programmable system had been streamlined and turned into a commercial product–the Channel F console–by a team at pioneering electronics company Fairchild, it changed the fundamental business model of home video games forever. ", "By injecting flexibility into a new technology, it paved the way for massive industry growth and the birth of a new creative medium. ", "Almost two decades ago, cheaper means of distributing game software–first optical media, then the Internet–began to supplant cartridge technology. ", "Even so, the business model created by Kirschner, Haskel, and engineers at Fairchild still remains as relevant as ever. ", "Until now, their amazing story has never been told. ", "Fairchild’s Channel F, the first game console with cartridges The unwritten history of video game cartridges begins in an unlikely place: American Machine and Foundry (AMF), a manufacturer best known for its bowling alley equipment. ", "In the 1960s, AMF ran an R&D department in Stamford, Connecticut that originated many of its bowling technology innovations. ", "Among them was an automated scoring system, devised in 1968, that kept track of individual player scores and displayed them on a video display mounted near the ceiling of a bowling alley. ", "Around 1969, AMF decided to move its R&D department from Stamford to North Carolina. ", "Facing a difficult move, a handful of AMF R&D engineers led by a man named Norman Alpert decided to leave AMF and form their own company. ", "Alpex Computer Corporation was born, named after Alpert himself. ", "At first, Alpex worked on an electronic cash register in partnership with mailing-equipment giant Pitney Bowes. ", "But due to intense competition from IBM and NCR, the joint venture ended acrimoniously in late 1973.", "\n\nadvertisement\n\nMagnavox’s Odyssey console Photo: Magnavox Left dangling with no product to sell, Alpex Computer Corporation sought a new market for its talents. ", "With a drastically pared-down work force of three employees (all refugees from an amusement supply company), the firm could afford to take risks. ", "According to Wallace Kirschner, one of the ex-AMF engineers who followed Norm Alpert to Alpex, the company immediately considered entering the emerging video game market. ", "Video games had exploded onto the scene less than two years before, driven largely by the success of Atari’s Pong arcade machine and Magnavox’s Odyssey home console (both launched in 1972). ", "Up to that point, all commercial video game products had been based on discrete, dedicated logic circuitry to generate on-screen gameplay. ", "None in commercial production used a computer as the heart of its architecture. ", "The Odyssey, developed by a team of engineers at defense contractor Sanders Associates, utilized mid-1960s technology that precluded the used of a computer. ", "Likewise, the founders of Atari had originally sought to run games as computer software on minicomputers around 1969, but the high cost of the systems involved made that dream impractical. ", "The status quo changed in 1971, when Intel announced its 4004 microprocessor. ", "On a single chip the size of a pinky fingernail, it contained the computing functionality of what would have once required multiple circuit boards full of electronics. ", "The 4004 was followed by the 8008 in 1972 and the 8080 in 1974, each one adding dramatic leaps in capability over its predecessor. ", "Competing semiconductor firms like Fairchild, National Semiconductor, and RCA began work on their own microprocessors, while engineers around the world applied Intel’s new chips to just about every field imaginable. ", "It was in that climate that Wallace Kirschner realized that considerably more sophisticated video games could be generated using software running on a microcomputer with a bitmapped display rather than using dedicated hardware. ", "Lawrence Haskel in the 1970s In early 1974, Kirschner got the go-ahead from Alpert to pursue his video game idea, but the firm realized it was racing the clock to develop this idea before competitors did. ", "With that in mind, Alpex hired Lawrence Haskel, an engineer well versed in software who had worked alongside Kirschner at both AMF and Pitney Bowes-Alpex. ", "The plan was set: Kirschner would create the hardware, and Haskel, a big fan of games himself, would program the software. ", "Their target? ", "A home video game console which would let users switch games at will.", "\n\nadvertisement\n\nBy 1974, the only home console the U.S. market had seen was the Magnavox Odyssey. ", "It had been built primarily to play a game of video ping-pong, but could be expanded by using a series of jumper cards that turned on and off certain electronics inside the console. ", "In tandem with taped-on-screen plastic overlays and physical board and card game paraphernalia, the Odyssey could provide new gameplay experiences. ", "Even so, there are only so many truly fun games you can play by moving a couple of dots around on a TV screen. ", "Kirschner and Haskel began development on their game console in early 1974. ", "The pair christened their new project “RAVEN,” for “Remote Access Video Entertainment.” ", "At the heart of the system, the pair initially chose the Intel 8008, an 8-bit CPU. ", "Around that, Kirschner built a device that could generate a 128-by-64 black-and-white display that used a pricey eight kilobits of RAM to store the image of the bitmap (the state of the screen’s pixels). ", "Intel’s 8008 chip Photo: Wikipedia “At the time, memory was very, very expensive,” recalls Haskel. “", "I mean, a penny a bit, or something like that.” ", "That limited both the graphical capability of the system and the complexity of the software. ", "Each game had to be less than two kilobits (or 256 bytes) in size. ", "For comparison, this paragraph of text alone takes about 384 bytes to store electronically in its simplest form. ", "Reaching for inspiration, Haskel based his first program on the prevailing trend in the video game market: sporty, ping-pong type games popularized by the Odyssey and Atari’s Pong arcade machine. ", "The games made a big impact on Haskel, who vividly recalls the first time he saw the Odyssey in action during a visit to a department store. “", "I was going to see the furniture department, and there was a little kid playing Odyssey,” recalls Haskel. “", "I sat down and played with him for probably an hour. ", "It was the coolest thing I’d ever seen. ", "I couldn’t get that out of my mind.” ", "So for his first game program at Alpex, Haskel reinterpreted video ping-pong to reflect a cultural stalwart in the American northeast: hockey, which his family played every winter on a frozen pond behind his Connecticut house.", "\n\nadvertisement\n\nTo this day, I still think that is the most challenging game that I’ve played. ", "Haskel’s electronic version of the popular sport looked Pong-like at first glance, with an overhead view of a hockey rink, two paddles, and a ball. ", "Then he expanded on the Odyssey ping-pong model with on-screen scoring (a la Atari’s Pong) and a game clock, and by allowing the player paddles (two white vertical lines on the screen) to rotate to deflect the ball in various directions. ", "The main player paddle could also move forward and back across the rink. ", "In a crowning touch, Haskel added a goalie paddle that could be independently controlled by each player. “", "You had your hands really flying around with this,” says Haskel of the game controls. ", "The player could move a paddle up, down, left, or right; rotate it clockwise or counterclockwise; and move a goalie paddle up or down. ", "There was a button for each movement. “", "To this day, I still think that is the most challenging game that I’ve played,” says Kirschner. ", "Haskel followed Hockey with Tic-Tac-Toe, a simple on-screen version of the game; Shooting Gallery, which allowed a player to rotate a “gun” and fire a bullet to hit a moving target; and Doodle, a primitive art program which let the player draw or erase white lines on the TV screen. ", "Needed: Switchable Software As the game library expanded, it made sense to devise a way to interchange Haskel’s programs, allowing players to easily switch between them inexpensively while using only one relatively expensive computerized console at the heart of the system. ", "That way, the consumer would only buy the expensive part once and reuse it with a wide variety of software.", "\n\nadvertisement\n\nHP’s HP-9810 calculator Photo: HPMuseum.net The Calculator With Cartridges Alpex’s memory module invention was not without precedent. ", "The earliest such modules made their commercial appearance in 1971 when Hewlett-Packard released its HP-9810A desktop calculator. ", "More a computer than a calculator, the HP-9810A could be programmed by inserting plastic-encased ROM modules. ", "For example, one such module, entitled “Mathematics,” would add a range of built-in mathematical functions to the machine’s repertoire. ", "None of those HP cartridges contained games. ", "And no one interviewed for this article from Alpex, Fairchild, Atari, or RCA say they were aware of HP’s memory modules at the time of their work on video game cartridges. ", "So it appears that the HP memory module’s influence on the video game industry was slim or non-existent. ", "General purpose computers at the time approached interchangeable software with an array of removable storage options–often paper tape, magnetic tape, or packages of spinning magnetic disks–that required far too much expensive hardware to be practical in a consumer product. ", "Kirschner and Haskel found a better solution right front of them, as a natural part of the development process. ", "Intel’s 8080 development kit encouraged the use of EPROM (Erasable-Programmable Read Only Memory) chips–a form of ROM chip that allowed the programmer to write and erase a program multiple times to speed up the development process. ", "Typically, once an EPROM was programmed, a hardware designer would either solder the chip directly to a printed circuit board or insert it into a delicate socket soldered onto such a board. ", "It became obvious to Kirschner almost immediately that if consumers were going to use their console, they needed a way to change out those ROMs in a user-friendly fashion. ", "So Alpex’s engineers decided to mount the fragile ROM chip to a circuit board and, in turn, connect the chip’s pins to a more durable connector that could withstand repeated insertion and removal. ", "That’s how the first prototype video game cartridge was born. “", "We went to RadioShack and bought these little plastic boxes,” recalls Kirschner. “", "And we were able to plug the little box into the console with a connector we put on it.” ", "Kirschner remembers RAVEN’s cartridge enclosures as being about five inches wide by three inches high by a couple of inches deep. ", "Each black plastic box encased a circuit board with a memory chip containing video game code mounted on it. ", "Alpex needed a business partner with deep pockets.", "\n\nadvertisement\n\nThese memory modules interfaced with the RAVEN console via a 25-pin connector protruding from the wide dimension of the cartridge box. ", "Such a connector could withstand far more insertions than a delicate memory socket, but its 25 small pins were not suitable for consumer use. ", "Alpex punted that problem down the road, setting the stage for a second round of video game cartridge innovation that took place at an entirely different company. ", "With all the key components of their RAVEN console in place, Kirschner and Haskel demonstrated their creation to Norm Alpert and Alpex’s board of directors. ", "Alpert knew that his small company did not have the money to market and manufacture the game console itself. ", "It needed a business partner with deep pockets. ", "From its inception, Alpex had designed RAVEN to work with a common home television set as its display device. ", "So Alpert first targeted American television set manufacturers as potential partners. ", "In early 1975, his company approached Sylvania, Zenith, RCA, and Motorola (which once made TV sets), with Kirschner and Alpert giving demonstrations of the console under strict non-disclosure agreements. “", "None of them were interested,” recalls Kirschner. “", "They had their heads in the sand, just coming out of the vacuum tube age, and they didn’t do transistorized electronic designs themselves. ", "That’s why they later disappeared.” ", "Enter Fairchild Indeed, it took significant imagination to realize that Alpex’s console, which existed then as a roughly 16-by-16-by-5 inch metal box filled with circuit boards, a handful of bulbous game modules, and an overly complex keyboard for input, could be streamlined into an attractive consumer product. ", "Doing so would take major creativity, electronic design know-how, and marketing finesse. ", "With that in mind, Alpex shifted gears and approached semiconductor manufacturers, who were just then beginning to launch their own consumer electronics products. ", "Among these gadgets were the first electronic clocks, the first pocket calculators, and early digital wristwatches.", "\n\nadvertisement\n\nVideo games seemed like the next logical venue for Fairchild’s chips. ", "In Alpex’s early point-of-sale terminal days, a Fairchild parts rep named Shawn Fogarty had frequently supplied them with components. ", "In early 1975, Fogarty received a very vague phone call from Alpert asking him to visit Alpex. ", "Curious about what Alpert and his crew were up to, Fogarty agreed to visit the Alpex office for a demonstration. “", "These guys were smarter than shit,” he remembers. “", "They were very capable and could put out real products.” ", "Fogarty liked what he saw and sent news of it back Fairchild’s vice president of Consumer Products, Greg Reyes, in California. ", "The console made a positive impression on Reyes, who got the ball rolling with the CEO of Fairchild, Wilf Corrigan. ", "Video games seemed like the next logical venue for the company’s chips. ", "Corrigan tapped Gene Landrum, the former head of National Semiconductor’s consumer products arm, to be part of a team to evaluate the technology and write a feasibility report on the Alpex console from a marketing and business perspective. ", "Landrum recalls the assignment: “Corrigan says, ‘I want you to go to Connecticut, and I am going to send this engineer with you–this guy Lawson–and I want you to look at this thing and decide if we will buy it.” ", "Fairchild engineer Jerry Lawson, in a photograph from the 1980s That “Lawson” was Jerry Lawson (1940-2011), an electronics whiz from Queens, New York who happened to be one of the Valley’s few African-American electronics engineers. ", "By 1975, Lawson had already extensively experimented with video games himself, having created his own video arcade game in his garage around 1973. ", "Knowing Lawson’s affinity for video games, Reyes decided that Lawson would be an appropriate engineer to spearhead a new video game project within Fairchild. “", "I had a secret assignment,” Lawson told me during an interview in 2009. “", "Even the boss that I worked for wasn’t to know what I was doing. ", "I was directly reporting to a vice president at Fairchild with a budget.”", "\n\nadvertisement\n\nThe Alpex prototype used Intel’s 8080 CPU–a chip from Fairchild’s competitor (the pair had upgraded from the 8008 around the release of the 8080 in the spring of 1974). ", "Ultimately, Kirschner and Haskel, with assistance from Lawson, had to convert their prototype into a version that worked with Fairchild’s F8 chip before the company would license the technology. ", "Lawson also worked on taming RAVEN’s awkward keyboard control scheme into a fairly complicated joystick that could work with Haskel’s Hockey game. ", "An industrial designer named Nicholas Talesfore created artist’s concepts for the potential game console and hand controller, adding dramatic visual impact to Landrum’s presentation. ", "Jerry Lawson’s controller prototype On November 26, 1975, Gene Landrum completed his report, “Business Opportunity Analysis: Alpex Video Game,” for Greg Reyes. ", "Accompanying the report was a schematic sketch of Lawson’s controller prototype as well as Talesfore’s initial designs for the production hand controller and game console. ", "The project had picked up a new code name as well: “STRATOS”. ", "A portion of the write-up read: “This is an electronic video game aimed at the consumer home TV aftermarket. ", "It is designed to eliminate the possibility of game obsolescence through the use of a ‘unique’ (and hopefully patentable) cartridge technique for adding additional games.” ", "Among numerous statistics, Landrum projected that the STRATOS console could sell 5.5 million units by 1978, capturing 22% market share with a gross retail revenue of $220 million. ", "They turned out to be highly optimistic numbers that never came to pass. ", "However, they told Fairchild executives what they wanted to hear, and Corrigan gave the go-ahead for Fairchild to enter the video game business. ", "The new console would be called the Fairchild Video Entertainment System, or VES for short (a name change would later re-christen it the “Channel F”). ", "Bad Winner Early on, as Fairchild’s engineers hacked away at the hardware for the new console, Alpex’s Lawrence Haskel found himself tasked with translating his early games written for the Intel 8080 into software that would run on Fairchild’s CPU. ", "One of these games, Hockey (along with Tennis, a Pong clone), shipped built into the system, while the remaining three—Tic-Tac-Toe, Shooting Gallery, and Doodle—became the basis of Videocart-1. ", "Within one of those games, Haskel programmed the world’s first video game inside joke. ", "In Tic-Tac-Toe, whenever the player loses to the computer, the words “You Lose Turkey” appear on the screen. ", "Haskel programmed that in as a playful reference to Lawson, whose favorite silly insult epithet was the word “turkey.” ", "To the programmer’s surprise, Lawson did not encounter the message until some time later. ", "But when he did, Lawson reportedly found it quite amusing. ", "With Lawson in charge of electronic engineering and software for the project and Talesfore as head of industrial design, the group began work miniaturizing Alpex’s unwieldy prototype into a size that would fit within a box that could sit comfortably atop a living room TV set. ", "Before long, they realized that implementing the actual removable game software module would take special expertise. ", "Talesfore knew just the guy to do the job: Ron Smith, a mechanical engineer he had worked with at National Semiconductor. ", "Only one year prior, while working at National Semiconductor, Smith mechanically engineered the world’s first pocket calculator prototype with a removable memory module, the Novus 7100. ", "But before the 7100 made it to market, National Semiconductor changed direction, eventually closing its consumer products division altogether. ", "As perhaps the only person on Earth who had previous experience designing consumer-oriented ROM memory modules, Smith was a qualified choice for the job, and Fairchild hired him as head of mechanical engineering on the project in early 1976.", "\n\nadvertisement\n\n“They had already started the tooling for the console,” recalls Smith (referring to the process of making the metal mold that will later form the console’s plastic shell), “and they were going to mold this box with no cartridge in it, then figure it out later.” ", "Smith cancelled the tooling and hired additional engineers to make sure the fundamental internal mechanisms of the console were in place before the industrial design was finalized. “", "I said, ‘Guys, you design from the inside out, not the outside in,'” recalls Smith. ", "After all, a key piece of the system was still missing: the cartridge itself. ", "Cartridge mechanism designer Ron Smith in the 1980s Alpex’s prototype had always included a way to exchange games via plug-in modules. ", "But the modules were fragile and awkward. ", "Fairchild had to envision a consumer-friendly way to package them, a job that fell primarily to industrial designer Nick Talesfore. ", "Inserting and removing socketed electronic assemblies had, until then, been an activity reserved for trained technicians, engineers, and military personnel. ", "Taking a sensitive circuit board and putting it into the hands of a consumer–who might be prone to stepping on it, dunking it in the toilet, or leaving it baking in the sun–posed a considerable design challenge. ", "Obviously, the board needed a protective shell of some kind. ", "8-Track Inspiration Talesfore zeroed in immediately on the familiar form of the 8-track tape cartridge, an audio recording format which gained significant traction in the 1970s through its use in car audio systems. ", "Relatively rugged, easy to insert and remove with one hand, and vibration-resistant, the 8-track tape proliferated where the comparatively delicate vinyl record feared to tread. ", "He chose a shape and size for his new game cartridge enclosure that closely matched the 8-track tape standard. ", "Then he added ribbing around the edges for improved grip, and selected a bright yellow plastic color to make a statement. ", "Cartridges were the true star of the show, he figured, so they deserved to stand out.", "\n\nadvertisement\n\nChannel F cartridge (left) vs. 8-track cartridge (right) Talesfore hired an artist he had previously met at National Semiconductor named Tom Kamifuji to design the labels. ", "His illustrations depicted scenes that were often dramatically exaggerated (or confusingly abstract) compared to the actual on-screen graphics, setting a precedent that other companies would follow for years to come. ", "What Does a Console Look Like? ", "In 1976, with the release of America’s first mainstream home VCRs still a year away, and previous game consoles containing only fixed selections of games, Nick Talesfore found himself with few precedents to draw from while designing the world’s first programmable video game player. ", "Instead, he took design cues from other gadgets of the day–such as 8-track tape players and desktop digital clocks- giving the Channel F a faux woodgrain finish and ample amounts of smoky Plexiglas. ", "As a finishing touch, he added a compartment on top where players could store the game controllers when not in use: “My mother always told me to pick up my toys, so I thought it would be cool if the kid had an easy way to put the controllers away,” he explains. ", "The result was an efficient, compact unit with a footprint similar to a small 8-track tape player that did what it needed to do. “", "Could it have been more creative? ", "Probably,” says Talesfore. “", "But I didn’t have time to do a bunch of studies and models. ", "I just had one spin at it.” ", "Each game package also came prominently numbered, starting with Videocart-1. ", "This provided an easy way to refer to cartridges which contained multiple games of varying genres (Fairchild ultimately made it up to Videocart-26). ", "In retrospect, the numbering system reflects a time when no one had any idea how many cartridges were enough for a system, how long a system like the Channel F could last on the market, or about the later appearance of third-party game publishers which could quickly balloon the number of games available into the hundreds, if not thousands. (", "Anyone up for a game of Videocart-963?) ", "As Talesfore worked on the graphic design for the system literature and the industrial design of the cartridges and the console itself, mechanical engineer Ron Smith tackled the real guts of the cartridge problem: how to physically attach and detach the cartridge from the console. ", "In an interview with Lawson I conducted in 2009, he touched upon the fears the Channel F team had in designing cartridge circuitry durable enough to withstand physical shock, thousands of insertions without breakage, and worst of all, electrostatic discharge. ", "A stray zap of static electricity can easily fry an unprotected semiconductor chip. “", "We were afraid–we didn’t have statistics on multiple insertion and what it would do, and how we would do it, because it wasn’t done,” said Lawson. “", "I mean, think about it: Nobody had the capability of plugging in memory devices in mass quantity like in a consumer product. ", "Nobody.” ", "To protect from accidental damage, Ron Smith’s cartridge design contained a spring-loaded plastic door that protected a row of 22 gold-plated contacts inside the plastic housing while not in use. ", "Once inserted into the console, a cam would open the door, exposing the contacts. ", "Then a special connector with flexible metal pins inside the console would rotate up to meet the cartridge and make electrical contact–while simultaneously sweeping them to break through any corrosion that had built up on the fingers.", "\n\nadvertisement\n\nAs he worked, Smith took notes–including these pages dealing with the chute which the console used to hold the cartridge while in use:\n\nFinally, a separate mechanism would lock the cartridge into place so that it would not jostle loose while active; it could be released with an eject button located in front of the cartridge chute. ", "This frictionless, zero-force experience ensured that the consumer would never struggle with inserting or removing a cartridge from the system. ", "As with an 8-track tape, you could do so using one hand if necessary. ", "Smith and Talesfore later received a patent for their work on the Channel F console and cartridge, providing a basic template for cartridge-and-console design that many game systems would follow for years to come. ", "Here are drawings from some of the patents associated with the Channel F project:\n\nadvertisement\n\nThe Debut The Channel F made its first public appearance in June of 1976 at the Summer Consumer Electronics Show in Chicago. ", "However, the company only displayed a non-working empty shell, so the system did not attract much press attention. ", "A few weeks later, the Channel F made a much bigger debut nationwide as part of a July 6, 1976 article in Businessweek called “The Smart Machine Revolution.” ", "The multi-page feature touted the Channel F alongside cars, watches, and scales as a product that demonstrated the enormous potential of microprocessors in everyday consumer products. ", "Patent drawings of Fairchild’s controller Creating the Controller Cartridges aside, Smith had another tricky engineering problem on his hands: how to take Lawson’s complex controller design and make it practical, durable, and most importantly, mass producible. ", "To assist with the task, Smith hired Rich Rhodes. ", "The pair clarified Lawson’s design into the first digital home-game joystick in the industry, which stood out a time when most video games were played with knobs not too unlike that you’d find on your home stereo. ", "Talesfore handled the aesthetic stylings of the device, with ridges along its handle for the fingers and a tri-lobed top to improve grip. ", "When finalized, the Channel F’s hand controller possessed more degrees of movement than any bundled console joystick before or since. ", "Despite the unique design, the controllers (which initially came wired into the system and were non-interchangeable) won little praise from consumers and critics. ", "But it did the job fairly well for the simple games available at the time. ", "Following the article, excitement for the concept behind Fairchild’s new system rippled through the home video game industry, which faced a glut of dedicated systems by that time–almost all of which played a copy of Atari’s Pong. ", "The new razor/razor blade business model embodied in the console/cartridge system represented a welcome change, with video game revenue forecasts from then on projecting massive growth of the industry due to sales of high-profit cartridge-based software that played on low-profit consoles. ", "Most importantly, the debut of the Channel F served as a wake-up call to those companies who, by 1976, also had cartridge-based consoles in the works. ", "RCA was one of them with its Studio II, which was developed concurrently with the Channel F. William Bachman, one of the co-inventors of the Studio II’s cartridge mechanism, confirmed in an interview that the system was in the works at least by May of 1976–before Fairchild went public with its console. ", "Atari, which had also been working on a programmable console concept, received physical cartridge design inspiration from a familiar place. ", "In 1976, Ron Smith had hired a contract engineer named Doug Hardy to assist him with designing the Channel F cartridge mechanism. ", "Before completing the project, Hardy quit the job and joined up with Atari. ", "One year later, Hardy co-designed the cartridge shell and mechanism for the Atari VCS (later known as the Atari 2600), which would debut in October 1977. ", "While the 2600 cartridge bore a different internal construction to avoid patent trouble, the basic cartridge metaphor pioneered by Fairchild had already made its mark. ", "A brochure for the Channel F Shortly before launch of its console, Fairchild changed the name of the console from the Video Entertainment System (VES) to the Channel F–short for “Channel Fun.” ", "Unfortunately for Fairchild, the slight first-to-market lead for the Channel F did not confer any particular advantage to the console in the long run. ", "With titles like Math Quiz, Video Blackjack, Mind Reader, Maze, and Acey-Deucey, Fairchild’s games tended to be light on action. “", "We learned at Atari that if you weren’t pounding someone and shooting someone and blowing someone up, people didn’t like your game that much,” says John Ellis, former VP of consumer engineering at Atari. “", "Not to say that I agree with that philosophy, but that’s the way it was.” ", "Photo by Flickr user Kreg Steppe Cartridges Bring Doom Only a few years after the Atari 2600’s massive success, the cartridge-based business model almost destroyed the home video game industry. ", "Because of the patented technologies involved, console makers like Atari assumed they would always be the sole suppliers of the cartridges for their own systems. ", "What Atari didn’t count on was that others might want to publish games that worked on its console as well. ", "A group of Atari programmers who wanted more credit for their work formed the first of those companies, Activision, in 1979. ", "Seeking a way to publish its own games on Atari’s console without violating patents, the company called in the two men who invented the commercial video game cartridge to begin with: Ron Smith, and later, Nick Talesfore. ", "Smith designed an elegant, legal solution. ", "Activison produced many high-quality games that quickly became hits. ", "Hundreds of other publishers jumped into the market, each making their own array of Atari 2600-compatible cartridges with no particular regard to quality. ", "They glutted the market, causing the average price of video game cartridges to plummet. ", "The crash killed video game companies by the dozens and left the U.S. game industry looking like a post-apocalyptic war zone until Nintendo’s NES revived it. ", "RCA also learned the hard way that taking the intellectual path was often bad for business. ", "Its almost comically primitive Studio II system (which launched a mere two months after the Channel F in February 1977) relied heavily on simplistic educational titles and slow sports like bowling (arguably its best game). ", "It tanked within a year of its launch in great part due to the fact that its titles were arguably more boring than watching paint dry–although with black and white graphics at 64-by-32 pixel resolution, there wasn’t much room for anything more exciting on the screen. ", "The Channel F sold fairly well compared to its dedicated console predecessors during its first year on the market, but the Atari 2600, with its library of vibrant action titles and home versions of popular arcade games, soon overtook it, then completely engulfed it. ", "Still hanging on, in 1978, Fairchild redesigned the Channel F to give the console a fighting chance against the 2600. ", "The Channel F System II came with a sleek new look and new detachable hand controllers which included bona fide action buttons. ", "But it was too little too late for Fairchild, and the revised model only saw limited release before the firm decided to pull the plug on the system altogether, selling the technology to Zircon International in 1979. ", "Under Fairchild’s stewardship, the Channel F sold only around 350,000 units total. ", "During that same period, Atari moved millions of units of the 2600 and millions more software cartridges. ", "Here are images of some of the Channel F’s games, taken from an advertising brochure:\n\nGame Company Beats Chip Companies Why did Atari beat Fairchild and RCA? ", "It specialized in games. ", "It wanted to entertain, and it wanted to do so vividly, bombastically, viscerally. ", "Its experience developing midway-style arcade titles had given it a taste for what attracted and what pleased, and its laid-back management style had fostered innovation at an elemental level that fed its explosive growth through the 1970s. ", "Contrast that with Fairchild and RCA, which only operated their consumer divisions as vehicles for their semiconductor chip businesses. ", "For upper management, fun was almost beside the point. ", "To that end, the Channel F suffered badly from internal corporate maneuvering. ", "100% of the chips in the Channel F came from Fairchild Semiconductor, which forced its sister division Exetron (the consumer division responsible for the Channel F) to buy the chips at a fixed price (which was sometimes higher than the price it offered to competitors), gaining a profit from each sale. ", "Meanwhile, Atari could pick and choose the lowest market prices for its chips from a wide variety of vendors. ", "With no semiconductor overlord to please, Atari was fast on its feet, allowing the company to reduce the cost of its console as much as possible to undercut the competition. ", "Ultimately, the games-as-software model allowed the possibility of selling a base console on a slim margin (or even a loss) to achieve as high a market penetration as possible, then making up the loss from sizable profits of relatively inexpensive-to-duplicate software. ", "This same business model is what drives the video game industry today, almost 40 years later. ", "Today, the creators of the first cartridge-based video game system have little to do with the video game industry. ", "But their contributions ushered in a new era. ", "Making games interchangeable allowed consoles to transcend their hardwired origins, giving birth to the video game as a creative medium with endless potential. ", "In that sense, the cartridge was as much as cultural revolution as a technological one." ]

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[ "Aktuella rättsfall\n\nPublicerad: 2018-08-30 15:50\n\n\n\nFoto: Gorm Kallestad/TT\n\nNär mannen stoppades av polisen var han påverkad av cannabis och åtalades för ringa narkotikabrott och drograttfylleri. ", "Mannen hävdar dock att han blivit bjuden på en födelsedagstårta med cannabis - och att han därför saknade uppsåt. ", "Åklagaren kunde inte motbevisa detta och han frias därför av tingsrätten." ]

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[ "Legit vs. fake organizations are difficult to identify for the public. ", "One \"master\" I encountered actually used the name of one of his students because it was Japanese to set up his organization so it sound more official." ]

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[ "Q:\n\nwhy does the code > if 3 == 1 or 2: print('A') else: print('B') < print A but not B\n\nI recently started learning my first programming language and i couldn't understand why this code gave me A as the answer and not B\nif 3 == 1 or 2:\n print('A')\nelse:\n print('B')\n\nA:\n\nYou check for the two conditions 3==2 and 2. ", "2 evaluates to true, so you get A as output.", "\nIf you want to check 3 for beeing 1 or 2, you have to do it like this:\nif 3 == 1 or 3 == 2: print('A') else: print('B')\n\nSee e.g. Do not understand why if condition evaluates to True when variable is integer for details why 2 is true, especially this answer.", "\n\n" ]

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[ "Q:\n\nFind the number of unique paths, given a fixed set, that produce a given output.", "\n\nI'm looking to find the probability of selecting a given number M given a set of N numbers in a bounded range (or potentially in several differently bounded ranges, but I'm starting simple). ", "I'm trying to come up with the probability of a number of dice rolls, so as an example, given that I roll 3 six-sided die, what is the probability of a 10? ", "Or, given five 20-sided die, what is the probability of a 64? ", "\nI know that in the case of the 3 six-sided die, the chance of an 18 or a 3 are both (1/6)^3, or 1/216, because only a single combination of values can produce either 3 or 18. ", "But what about a number like 10? ", "It has multiple combinations that can produce it, like 3+3+4, or 6+2+2. ", "I know that there are 216 unique paths available given the three six-sided die, and that the end probability of rolling any number M will then be the number of unique paths that produce a number times 1/216, which should work even given a number outside the summable range (Since the number of unique paths that could equal that number would be 0). ", "\nSo I guess my question really boils down to: how can I determine the number of unique paths or combinations that will sum to any given number? ", "\n\nA:\n\nSay you want $N$ dice with $s$ sides each to add up to $M$. This corresponds to distributing $M$ balls into $N$ non-empty bins with capacity $s$, or equivalently distributing $M-N$ balls into (possibly empty) bins with capacity $s-1$. The number of ways of doing this can be calculated using inclusion-exclusion, and the result is given at Balls In Bins With Limited Capacity (which also covers the case of different capacities that you're potentially interested in). ", "For the above dice throw, the result is\n$$\n\\sum_{t=0}^N(-1)^t\\binom Nt\\binom{M-st-1}{N-1}\\;,\n$$\nwhere, contrary to convention, the binomial coefficient is taken to be $0$ if the upper index is negative. ", "This needs to be divided by $s^N$, the total number of possible throws.", "\nIn your first example, $N=3$, $s=6$ and $M=10$, which gives the probability\n\\begin{align}\n&\\frac1{6^3}\\sum_{t=0}^3(-1)^t\\binom 3t\\binom{10-6t-1}{3-1}\\\\\n={}&\\frac{\\binom92-3\\binom32}{6^3}\\\\\n={}&\\frac{36-9}{6^3}&\\\\\n={}&\\frac18\\;.", "\n\\end{align}\nIn your second example, $N=5$, $s=20$ and $M=64$, which gives the probability\n\\begin{align}\n&\\frac1{20^5}\\sum_{t=0}^5(-1)^t\\binom 5t\\binom{64-20t-1}{5-1}\\\\\n={}&\\frac{\\binom{63}4-5\\binom{43}4+10\\binom{23}4}{20^5}\\\\\n={}&\\frac{595665-617050+88550}{20^5}\\\\\n={}&\\frac{67165}{20^5}\\\\\n={}&\\frac{13433}{640000}\\\\\n\\approx{}&0.021\\;.", "\n\\end{align}\n\n" ]

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[ "\n448 N.W.2d 892 (1989)\nIn re the Marriage of Constance Lee NOLDEN, Petitioner, Appellant,\nv.\nCurtis Lee NOLDEN, Respondent.", "\nNo. ", "C8-89-842.", "\nCourt of Appeals of Minnesota.", "\nDecember 12, 1989.", "\n*893 Michael J. Froelich, Minneapolis, for appellant.", "\nThomas A. Lennon, Edina, for respondent.", "\nHeard, considered and decided by WOZNIAK, C.J., and PARKER and CRIPPEN, JJ.", "\n\nOPINION\nCRIPPEN, Judge.", "\nAppellant challenges the trial court's determination of her nonmarital interest in proceeds of a home sale; we reverse and remand on this issue. ", "Respondent challenges the finding that the downpayment on the home was nonmarital property; we affirm on this issue.", "\n\nFACTS\nThe 1980 marriage of the parties was dissolved in February 1989. ", "During the summer of 1983, appellant's parents delivered a $10,000 check payable to appellant, representing proceeds of a family relative's estate. ", "Appellant testified that her parents gave the money to her \"only\" and that they used the word \"only\" when making the gift. ", "The parties put the money in a joint account and used it as a downpayment on a contract to purchase their home. ", "Appellant conceded that her parents suggested this use of the money. ", "Appellant also testified her parents knew at least one bank had refused to give the parties a home loan. ", "Appellant's mother testified that she knew that the parties would buy a home before she gave them the money, but that the money was not a loan and that she had no intent that respondent share in the gift.", "\nThe trial court found that the $10,000 was given \"to petitioner\" and concluded that appellant was entitled to a portion of the proceeds of the sale of the home representing \"her nonmarital property.\" ", "The court determined that she was entitled to a 10/45ths interest ($10,000 towards a purchase price of $45,000) but provided that this percentage would be calculated after payment of the amount due on the contract for deed, payment of $1100 to respondent for improvements (evidently nonmarital improvements), and payment of $6100 to appellant's parents to repay a personal loan.", "\n\nISSUES\n1. ", "Is there sufficient evidence to support the trial court's finding that appellant received a $10,000 nonmarital gift?", "\n2. ", "Did the trial court err in computing the nonmarital share of an asset by proportionally dividing the net equity value?", "\n\nANALYSIS\n\n1. ", "Nonmarital investment.", "\nAll property acquired by either spouse after marriage and before court valuation is presumed to be marital. ", "Minn. Stat. § ", "518.54, subd. ", "5 (1988). ", "The presumption is overcome by showing, inter alia, that the acquisition is a gift \"by a third party to one but not to the other spouse.\" ", "Id. Here the trial court found that the $10,000 was given to appellant *894 such that it constituted nonmarital property. ", "Because appellant's testimony, if believed by the trial court, demonstrates that the gift was given expressly to her \"only,\" we cannot hold that the finding of nonmarital property is clearly erroneous. ", "See Minn.R.Civ.", "P. 52.01.", "\n\n2. ", "Present nonmarital interest.", "\nAppellant used her nonmarital gift to invest in real estate for the benefit of both parties. ", "A nonmarital investment used in the purchase of real estate entitles the person, upon dissolution, to\nthe proportion the * * * contribution at the time of acquisition bore to the value of the property at the time of the purchase multiplied by the value of the property at the time of separation.", "\nBrown v. Brown, 316 N.W.2d 552, 553 (Minn.1982) quoted in Nardini v. Nardini, 414 N.W.2d 184, 191 (Minn.1987). ", "The nonmarital share must be calculated on the basis of the value of the property at the time of dissolution, not on amount of net ownership equity in the property. ", "Stroh v. Stroh, 383 N.W.2d 402, 406 (Minn.Ct.", "App. ", "1986). ", "Here, the trial court made its calculation based on net equity, subtracting from value the amount due on a contract before apportioning appellant's nonmarital interest. ", "We must remand for the trial court's recalculation of the amount of the nonmarital interest.[1]\nAlthough the trial court's action appears to be founded on a calculation error, appellant characterizes the judgment as an improper invasion of her nonmarital interest without a necessary finding that respondent would suffer unfair hardship if he were not awarded a portion of her nonmarital property. ", "Minn.Stat. § ", "518.58, subd. ", "2 (1988). ", "The trial court made no hardship finding. ", "Respondent suggests that we can affirm the trial court's distribution because there is enough evidence in the record to find unfair hardship.", "\nRespondent bases his argument on Faus v. Faus, 319 N.W.2d 408 (Minn.1982). ", "His reliance is misplaced. ", "In Faus, the trial court did not make specific findings based on the relevant factors set out in Minn. Stat. § ", "518.58, subd. ", "2, yet the trial court did make a finding of unfair hardship. ", "Faus, 319 N.W.2d at 412-13. ", "We cannot affirm where there is no evidence the trial court premised its order on a theory of unfair hardship. ", "Furthermore, Faus was decided before Moylan v. Moylan, 384 N.W.2d 859 (Minn.1986). ", "In Moylan, the supreme court, in reviewing a child support modification, required express trial court findings on statutory factors, even if those factors were adequately shown in the record. ", "Moylan, 384 N.W.2d at 863-65. ", "On remand, the trial court will have occasion to determine whether there must be a division of nonmarital property to avoid unfair hardship.", "\n\n3. ", "Amount of debt.", "\nRespondent further challenges a portion of the trial court's finding that appellant's parents are owed $6100 by the parties. ", "There is no clear error in light of testimony of appellant's mother that all the money was a loan to the parties.", "\n\n4. ", "Reimbursement claim.", "\nRespondent also claims he is entitled to $7500 spent on contract for deed payments, insurance, and telephone. ", "Indeed, the trial court found that these expenditures were made but did not provide for reimbursement. ", "Respondent is not entitled to any reimbursement for payments made out of marital income. ", "The record shows, however, that these expenditures include at least $2400 that came from a personal loan for which respondent remains solely responsible. ", "The distribution of this debt was not included in the court's division of marital property. ", "On remand, the *895 court should determine whether adjustment of the property division is needed in light of evidence that respondent remains obligated to pay the debt. ", "See, e.g., Swendson v. Swendson, 256 Minn. 445, 98 N.W.2d 665 (1959).", "\n\nDECISION\nThere is adequate evidence to sustain the trial court's finding on a nonmarital gift. ", "The resulting present interest of respondent in a home was erroneously calculated.", "\nAffirmed in part, reversed in part and remanded.", "\nNOTES\n[1] The nonmarital investment was $10,000, the purchase price was $45,000 and the property has a $60,000 fair market value. ", "We do not have evidence before us as to the net value after anticipated sale costs. ", "In addition, under Nardini, 414 N.W.2d at 193, the purchase price of the property used as the denominator in calculating appellant's share of the value must be increased by any additions to value not attributable to general market appreciation. ", "Because of the trial court's finding of an $1100 improvement, this sum must be added to the denominator.", "\n" ]

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[ "version: '2'\nservices:\n zookeeper:\n image: zookeeper:3.4.10\n\n kafka:\n image: wurstmeister/kafka:0.10.2.1\n environment:\n KAFKA_ADVERTISED_HOST_NAME: kafka\n KAFKA_ADVERTISED_PORT: 9092\n KAFKA_ZOOKEEPER_CONNECT: zookeeper:2181\n KAFKA_GROUP_INITIAL_REBALANCE_DELAY_MS: 10\n KAFKA_OFFSETS_RETENTION_MINUTES: 20160\n KAFKA_OFFSETS_TOPIC_NUM_PARTITIONS: 4\n links:\n - zookeeper\n volumes:\n - /var/run/docker.sock:/var/run/docker.sock\n\n tests:\n build:\n context: jenkins-slave-kafka\n dockerfile: Dockerfile\n volumes:\n - $WORKSPACE:$WORKSPACE\n - /var/run/docker.sock:/var/run/docker.sock:rw\n links:\n - kafka\n - zookeeper\n environment:\n KAFKA_ADVERTISED_HOST_NAME: kafka\n KAFKA_ADVERTISED_PORT: 9092\n KAFKA_ZOOKEEPER_CONNECT: zookeeper:2181\n command: /sbin/my_init -- su - jenkins -c \"$TESTS_COMMAND\"\n" ]

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[ "Besarta Leci\n\nBesarta Leci (born 14 October 1993) is a Kosovar footballer who plays as a goalkeeper and has appeared for the Kosovo women's national team.", "\n\nCareer\nLeci has been capped for the Kosovo national team, appearing for the team during the UEFA Women's Euro 2021 qualifying cycle.", "\n\nReferences\n\nExternal links\n \n \n \n\nCategory:1993 births\nCategory:Living people\nCategory:Kosovan women's footballers\nCategory:Kosovo women's international footballers\nCategory:Women's association football goalkeepers" ]

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[ "Manson and Chris Harris, who competed in the double at the Rio Olympics in 2016, went on to win the premiere M2x by four seconds over Storey and Cameron Crampton. ", "Harris was Storey’s doubles partner in Sarasota and Crampton sculled in the NZL M4x at Sarasota. ", "Harris has said that although he has been spending a lot of time in the single, he recently got back in the double with Storey and they intend to compete together in the European World Cups.", "\n\nManson also won the M4x with Chris Harris and two sweep oar rowers from the NZL M8+, Brook Robertson and Joe Wright. ", "However, Manson had to settle for a bronze in the premier M8+ when his Central RPC crew was beaten by Waikato RPC." ]

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[ "Cemal Gürsel\n\nCemal Gürsel (; 13 October 1895 – 14 September 1966) was a Turkish army officer, and the fourth President of Turkey.", "\n\nEarly life \nHe was born in the city of Erzurum as the son of an Ottoman Army officer, Abidin Bey, and the grandson of Ibrahim (1820–1895) and the great-grandson of Haci Ahmad (1790–1860). ", "After the elementary school in Ordu and the military middle school in Erzincan, he graduated from the Kuleli military high school in Istanbul. ", "He was a popular figure and was therefore nicknamed \"Cemal Ağa\" (big brother Cemal) since his childhood school years and onwards all his life. ", "\nGürsel served in the Army for 45 years. ", "During World War I, he participated in the Battle of Çanakkale in Dardanelles, Gallipoli as a lieutenant with the First Battery of the 12th Artillery Regiment in 1915 and received the War Medal. ", "He later fought at the Palestine and Syria fronts in 1917 and became a prisoner of war by the British while suffering malaria during his command of the 5th Battery of the 41st Regiment on 19 September 1918. ", "Gürsel was kept as a prisoner of war in Egypt until 6 October 1920. ", "During his presidency much later, when interviewed by the foreign press as to why he had not learned English during his captivity, he somewhat regretfully recalled that he was so frustrated to be a captive, he protested and studied French in the British camp instead.", "\n\nAfter his release, Cemal Gürsel returned to Anatolia to re-join Mustafa Kemal subsequent to Erzurum Congress and took part in all the western front campaigns in the Turkish War of Independence between 1920–1923. ", "He was promoted for gallantry in the First Division excelling in the battles of Second Inönü, Eskişehir and Sakarya, and was later awarded the Medal of Independence by the first Parliament for his combat service in the Final Offensive.", "\n\nGürsel was married, in 1927, to Melahat, the daughter of the chief engineer on the Ottoman cruiser Hamidiye. ", "From this marriage, a son Özdemir was born. ", "The couple adopted a daughter Türkan.", "\n\nMilitary career \nCemal Gürsel attended the Turkish Military College and graduated in 1929 as a staff officer. ", "He was promoted colonel in 1940. ", "He was made a brigadier general in 1946 and made commander of the 65th Division. ", "He was later the commander of the 12th Division, the 18th Corps commander, and commander of the 2nd Interior Tasks District. ", "Made Lieutenant general in 1953, was general in 1957, being appointed Commander of 3rd Army. ", "Service included chief of intelligence, and he was appointed as the Commander of Land Forces in 1958 when he was commanding an army.", "\n\nGürsel, as an easy-going and fatherly figure with a fine sense of humor, was well liked both nationally and in NATO circles, and had earned the respect and confidence of both the nation and the armed forces with his professional knowledge and demeanor. ", "A patriotic memorandum he sent on 3 May 1960 to the Minister of Defense in an effort to establish checks and balances on ongoing affairs, reflecting his personal views in continuation of the chat they had the night before, expressing his support to the prime minister Adnan Menderes and belief that the Prime Minister should replace the President with immediate effect to bolster a much needed national unity, resulted in his suspension from his post, forcing early retirement instead of becoming the next Chief of the Turkish General Staff.", "\n\nA farewell letter by him, advocating and urging the army to stay out of politics, was forwarded to all units of the armed forces at the time of his departure on leave. ", "Cemal Gürsel's statement read: 'Always hold high the honor of the army and the uniform you wear. ", "Protect yourselves from the current ambitious and harmful political atmosphere in the country. ", "Stay away from the politics at all cost. ", "This is of utmost importance to your honor, the army's might and the future of the country.' ", "He went to İzmir where he became the president of the Anti-Communism Association of Turkey.", "\n\nHead of state \n\nA coup d'état organised and conducted by army officers at the rank of colonels and below took place without the participation or leadership of Cemal Gürsel on 27 May 1960 after continuing civilian and academia unrests throughout the country. ", "It is rumored that four-star general Ragıp Gümüşpala, the Commander of the Third Army based in Eastern Anatolia, gave an ultimatum to the rebelling officers that if they did not have a general appointed as their head, the Third Army would attack to take over the capital and the administration of the country, thereby forcing the rebel group to find a senior officer over them. ", "Because of his immense popularity among the public and military ranks, Gürsel was subsequently chosen by the revolutionaries overnight and brought into the chairmanship of the military coup and became, , the only leader in the world put into power by a military takeover who had previously had no role in its planning or execution. ", "He, while still in his pajamas, was escorted to Ankara in the military C-47 transport plane by a captain who was the youngest officer of the radical coup team who that by that time had already sent President Celal Bayar, Prime Minister Adnan Menderes, List of Chief of General Staff Rüştü Erdelhun and some other members of the ruling Demokratic Party to a military court on Yassıada in the Sea of Marmara, accusing them of violation of the constitution. ", "The day after the coup, four-star general Cemal Gürsel was declared the commander in chief, Head of state, Prime minister and Minister of Defense of the 24th government on 30 May 1960, in theory giving him more absolute powers than even Kemal Atatürk had ever had.", "\n\nGürsel freed 200 students and nine newsmen, and licensed 14 banned newspapers to start publishing again (Time, 6 June 1960). ", "He fetched ten law professors, namely Sıddık Sami Onar, Hıfzı Veldet Velidedeoğlu, Ragıp Sarıca, Naci Şensoy, Hüseyin Nail Kubalı, Tarık Zafer Tunaya, İsmet Giritli, İlhan Arsel, Bahri Savcı and Muammer Aksoy, accompanied by Erdoğan Teziç, a law postgraduate student as their assistant (currently Professor and the former Chairman of the Turkish Council of Higher Education), from Istanbul and Ankara Universities to help draft a new constitution on 27 May, right after he arrived in Ankara. ", "During their first meeting with General Cemal Gürsel on the same day, Prof. Onar declared on behalf of the group of law academicians that 'the circumstances of the day should not be interpreted as an ordinary and political coup d'état, implying the revolution being brought by the change process starting in the republic that day. ", "President Cemal Gürsel also formed a scientific council to guide the Ministry of Defence, later forming the Scientific and Technological Research Council of Turkey to advise the government more broadly. ", "\n\nHe appointed General Ragıp Gümüşpala, the commander of the Third Army, as the new Chief of the General Staff who, upon his retirement in two months, was succeeded by General Cevdet Sunay, and Gümüşpala was further directed by Gürsel to form the new Justice Party to bring together the former members of the Democratic Party. ", " A simple and conservative sort, Gürsel became Turkey's most popular figure, forbade display of his picture alongside Atatürk's in government offices, rode about in an open Jeep touring rural communities, talking to the peasants almost as if they were his children (Time, 6 January 1961). ", "He was successful with his personal interventions in reducing the number of execution verdicts from the Yassıada tribunals from 15 down to three. ", "Gürsel's plea for forgiveness and attempts along with several other world leaders for the reversal of the execution sentences and for the release of Adnan Menderes and two other ministers were rejected by the Junta. ", "A member of the National Unity Committee writes in his memoirs that, upon Cemal Gürsel's intervention on the prevention of Menderes' execution, the chief prosecutor of the tribunal, Altay Ömer Egesel, said: ‘Let us hurry! ", "They will save him (Menderes)!’, ", "also arranging a contingency plan for conducting the execution in a Navy Destroyer in the event of a forgiveness operation in Imrali Island to save Menderes while, at the same time, placing a press release questioning the legal ability of Gürsel for an intervention. ", "Senator Mehmet Feyyat, District Attorney of Istanbul at the time, recently declared: ‘They cut off our phone lines. ", "Adnan Menderes was hanged against the regulations. ", "I was supposed to oversee the execution. ", "The revolution tribunal's chief prosecutor Egesel conducted the execution despite not being authorized. ", "İsmet İnönü and Cemal Gürsel were already phoning for him (Menderes) not to be executed but the telecommunications' office cut off the lines and Egesel made use of the (communication) gap to conduct the execution.", "’Cemal Gürsel resisted pressure to continue military rule, was wounded as a result of a military assassination attempt on his life (forgave the colonel who shot him), thwarted subsequent multiple military coup attempts, appointed the organizers of the coup to overseas posts and played an important role in the preparation of a new constitution and return to the democratic order of the Kemalist vision.", "\n\nStatesman \n\nCemal Gürsel rescheduled and attended the previously cancelled Turkish and Scottish national football teams' game in Ankara on 8 June 1960 (Turkey 4, Scotland 2) which was followed by a National Football Tournament, the Cemal Gürsel Cup, that helped boost the national morale in the post-coup weeks with finals in Istanbul on 3 July (Fenerbahçe 1, Galatasaray 0). ", "He took an active role in extensive modernization of Turkish Armed Forces and the staunch defense of the free world and Europe during the cold war, in particular during the Cuban Missile Crisis. ", "The declaration of independence of Cyprus according to the prior agreements and the deployment of a Turkish military unit to Cyprus took place in August 1960. ", "He hosted the visit of Queen Elizabeth II to Ankara in early 1961 and the visit of the vice president Lyndon Johnson in 1962. ", "Gürsel obtained, with the coordinated work of Sir Bernard Burrows, and granted permission of the ruling military National Unity Committee (NUC) for British military combat aircraft to overfly Turkish airspace on their way to support Kuwait, which was under threat of invasion by Iraq in July 1961.", "\n\nWhen questioned by a German journalist regarding his intentions on becoming the next president upon proposal of the interim parliament, Cemal Gürsel responded that he was ready to serve only if asked by the nation, not by the interim house. ", "He neither put his own candidacy forward for the presidency nor lobbied for his election or against any other candidate in any way. ", "He offered his endorsement of candidacy of several high rank academicians in Medicine and Sciences in Ankara for both the interim prime minister and future president positions. ", "Gürsel placed a special emphasis on participatory democracy with the promotion of the full interests of the nation's minorities, appointing Turkish Citizen ethnic leaders Hermine Kalustyan of Armenian, Kaludi Laskari of Greek and Erol Dilek of Jewish origin as his \"Deputy Representatives of Head of State\" and the full members of the interim House of Representatives. ", "The editor of Shalom, Avram Leyon, accompanied him on his travels and foreign state functions. ", "He re-established the freedom of speech that was overwhelmingly taken away from the media organs and from the press by the previous cabinet.", "\n\nThe constitution, which brought for the first time a full text of civil and political rights under constitutional protection along with an improved system of checks and balances in Turkish history, was approved by a referendum held on 10 October 1961. ", "With the establishment of the first Constitutional Court that created a new paradigm shift by scrutinizing the parliamentary rulings as the \"checks\" organ in 1961 and the addition of a Senate to the parliament, the Turkish Grand National Assembly was re-opened after the general elections, nominated and voted him as the fourth president of Turkey. ", "Journalist Parliamentarian Cihat Baban claims in his book, The Gallery of Politics (Politika Galerisi) that Cemal Gürsel told him \"We may solve all troubles if Süleyman Demirel becomes the head of the Justice Party (Adalet Partisi). ", "I am working very hard for him become the party leader. ", "If I succeed in this, I will be happy..\" Demirel was elected Chairman at the second grand party convention on 28 November 1964. ", "The President of the Republic of Turkey Cemal Gürsel assigned the mandate to form and serve as the Prime Minister of the new government to İsmet İnönü in November 1961, June 1962 and December 1963, to Senator Suat Hayri Ürgüplü on February 1965 and, following the general elections, to Suleyman Demirel of Justice Party in October 1965.", "\n\nWith the reduction of tensions between the West and the Soviet bloc, Gürsel sought improved relations for his country's population of 27.8 million with the Soviet Union, such as the initiation of a telephone line agreement, as with the other members of the Western alliance while initiating new credit agreements with the US and the UK as well as bilateral technical and investment relations with Germany in 1960s.", "\n\nThe atomic reactor in Istanbul became operational in 1962 along with his establishment of the first Research and State Library of the government in two years after his administration started. ", "He promoted the grant of the freedom of and the legal rights to form unions and to go on strike in the country. ", "Turkish Universities gained autonomous independence by law for the first time upon the legislation he passed. ", "Cemal Gürsel granted a presidential pardon for the life sentences of the previous president Celal Bayar and the former chief of general staff Rustu Erdelhun whose prior execution sentence was also revoked by the National Unity Committee upon Gürsel's appeals. ", "He initiated the new era of planned economy in Turkey, formed a State Institute of Statistics, launched the State Planning Organization (DPT) that implemented \"The First 5-Years Development Plan\", arranged re-entry of the Turkish Republic in the United Nations Security Council in 1961 and moved Turkey, through his close and personal diplomatic dialogues with Charles de Gaulle and Konrad Adenauer, into the direction of European Union membership with the Ankara Agreement, signed with France, Belgium, Netherlands, Germany, Italy and Luxembourg in 1963, resulting in associate membership the following year and a large Turkish workforce migration to Germany and Western Europe to assist their postwar industrial development.", "\n\nWhen a Cypriot leader who was exiled out of the UK previously in 1956 on the basis of his struggle for Cypriot independence from the British rule, wanted in November 1963 to amend the basic articles of the 1960 constitution, communal violence ensued and Turkey, Great Britain and Greece, the guarantors of the agreements which had led to Cyprus' independence, wanted to send a NATO force to the island under the command of General Young. ", "Due to the continued ethnic violence between the Cypriot Turks and Cypriot Greeks, President Gürsel ordered warning flights and subsequent continuous air assaults by the Turkish Air Force against the island which continued between 7 and 10 August 1964, ending with the fulfilment of the military objectives of Turkey, and the invitation to calm by Nikita Khrushchev of USSR.", "\n\nCemal Gürsel reformed the \"Teskilat-i Mahsusa\", the \"Special Organization\" of clandestine security services to a modern National Intelligence Agency in response to and preparation against escalating international terrorism trends in 1963. ", "He paved the way to Middle Eastern countries and Pakistan to concentrate on economic and cultural matters of mutual interest and Ankara recognized Syria following the breakup of the short-lived United Arab Republic in 1961, further reestablishing diplomatic relations with Egypt in 1965. ", "In July 1964, Pakistani President Ayub Khan, Turkish President Cemal Gürsel, and Shah Mohammad Reza Pahlavi of Iran announced in Istanbul the establishment of the Regional Cooperation for Development (RCD) organization to promote transportation and joint economic projects also envisioning Afghanistan and possibly Indonesia joining at some time in the future. ", "He granted asylum to the political dissidents Ayatollah Khoumeini of Iran and Molla Barzani of Iraq.", "\n\nGürsel, 40 years after the foundation of the Republic, launched the first radio broadcasting station of Eastern Anatolia within the centrally located province of Erzurum, where Ankara and Istanbul radios’ transmissions were not received. ", "He brought the Microwave Telecommunications Network into operation increasing telephone and teletype capacity along with a High-Frequency Radio Link connecting London and Ankara with Rawalpindi, Karachi, Tehran and Istanbul. ", "He laid the foundations of the new agricultural and structural development plans for the south-eastern Anatolian regions in early 1960s for the first time. ", "With his directive, The Holy Relics from the Prophets Abraham, Moses, Joseph, David and Muhammad, including the oldest Qur'an in existence from the 7th Century were put on display from their storage rooms within the Topkapi Palace for public viewing for the first time on 31 August 1962. ", "Gürsel added the first Ministry of Culture and Tourism to the cabinet. ", "In a parallel effort of promoting the country's touristic popularity in the West, Topkapi), the movie version of the book by Eric Ambler that had been commissioned for the same purpose, was shot in Paris and Istanbul and was introduced with success. ", "Similarly, one of the favorite books of John F. Kennedy, Ian Fleming's From Russia with Love was shot in Istanbul as the second James Bond movie, to promote the touristic popularity of Turkey, with his keen interest. ", "The Directorate of Religious Affairs network of the country was founded with his directive and became operational on 22 June 1965. ", "He started the new procedure of returning the law proposals presented for the President's approval back to the Parliamentary re-discussions in 1963. ", "Cemal Gürsel founded The National Security Council (MGK) as well as the Scientific and Technological Research Council of Turkey (TUBITAK) in 1963, appointing Professor Cahit Arf as its first director, officially charging TUBITAK primarily with governmental advisory duty by legislation. ", "In addition to the foundation of the Turkish Radio and Television (TRT) organization as a government agency in 1964 that brought television broadcasting to Turkey for the first time under his administration, the opening of The School of Press and Broadcasting at the College of Political Sciences in Ankara followed in November 1965. ", "The country's new initiative of Planning of Population Growth Control was put in effect in 1965. ", "The production of the first domestic Turkish automobile, the Devrim (Revolution), took place with Cemal Gürsel's directive which sparked the initiation of an automotive industry in the republic in the following few years. ", "The first use of a computer in the country, iron and steel mass production growth, the thermic power plant and a petrol pipeline structuring took place during his presidency. ", "Cemal Gürsel refused remuneration for his Head of State and subsequent Presidential positions and made his and his family's living with his retired general's salary, meeting their own expenses during their life in the Presidential Palace in Çankaya, Ankara.", "\n\nIllness \nBecause of a paralysis that started in early 1961 and progressed quickly in 1966, on 2 February Cemal Gürsel was flown to the Walter Reed Army Medical Center in Washington, D.C. on the private airplane \"BlueBird\" sent by US President Lyndon B. Johnson. ", "One week later, he fell into a coma there after suffering a series of new paralytic strokes. ", "The government decided he return to Turkey on 24 March. ", "President Johnson travelled by helicopter from the White House to Andrews Air Force Base, Maryland, near Washington, D.C., to pay his respects to President Cemal Gürsel on his departure to home, In addition to issuing the following statement 'Our distinguished friend, President Cemal Gursel of Turkey, came to the United States on 2 February for medical treatment. ", "There was hope that new therapeutic procedures only recently developed in this country would be useful in treating his illness of several years. ", "We were initially encouraged by his progress at Walter Reed Hospital, only to be shocked by the news on 8 February that his health had suffered a grave new blow. ", "Our best talent, coupled with the skill of the eminent Turkish doctors who accompanied the President, was exerted to the utmost in the hope that the President might return to his home in fully restored health. ", "We are saddened that this hope was not to be realized. ", "We have been deeply honored to have President Gürsel come to our country to seek medical treatment. ", "As he returns to his homeland, our prayers go with him'. ", "With a report of a medical committee by Gülhane Military Hospital in Ankara, the parliament ruled on 28 March 1966 that his presidency be terminated due to ill health in accordance with the constitution. ", "He died of apoplexy at 6:45 pm on 14 September 1966 in Ankara. ", "He left behind no directives or last will. ", "He was laid to rest at the \"Freedom Martyrs Memorial\" section in the yard of the mausoleum of Atatürk. ", "His body was transferred on 27 August 1988 to a permanent burial place in the newly built Turkish State Cemetery.", "\n\nLegacy \nAmong all of his achievements and great modesty in his down-to-earth plain demeanor, he tried to place the most emphasis on the need for a well-educated youth and a hard-working population with high standards of ethics for a westernized democratic progress in Atatürk's tradition (commentary by Imran Oktem, Chief Supreme Court Justice – Yargitay, 1966). ", "His portrait as a statesman and soldier remained next to Atatürk's in most homes in Turkey for a long time. ", "Erzurum Cemal Gürsel Stadium, some schools and streets were named after him. ", "The developments during his term were described as the \"Turkish Revolution\" which was celebrated annually on 27 May as the Constitution Day until 1981. ", "In 2002, a commemorative coin was released for the same. ", "In 2008, the movie The Cars of Revolution was released in his memory.", "\n\nQuotes from him \n \"I took over the administration of the state to stop the tragic course of events.\" (", "Cemal Gürsel, radio address on the evening of 27 May 1960)\n \"The network was ready. ", "I personally did not want the army to intervene and had been stopping the attempts (of takeover) of my younger friends. ", "Things reached to such a state that despite my belief that the army should not interfere I let them free in their duties. ", "Now my only goal is to reinstate an administration built on the principles of justice and ethics.\" (", "Cemal Gürsel, An interview. ", "Cumhuriyet, 16 July 1960)\n \"Those who follow Atatürk will not be left behind.\" (", "Cemal Gürsel, from the address on the occasion of the 25th anniversary of Atatürk's death, 10 November 1963)\n\nQuotes about him \n\n \"General Gursel may be described as the father of the second Turkish Republic similar to Atatürk being the father of modern Turkey. ", "At a time of deep division, Gursel earned and maintained the respect of the Turkish Nation that regarded him as the symbol of national unity. ", "When he passed away, he had the identity of the trusted father of the nation.\" (", "Prof. Bernard Lewis, 15 September 1966)\n \"A few days before the coup, it was known that the coup was imminent but General Cemal Gursel was dismissed as a non-political general. ", "No leading role by General Cemal Gursel was determined despite the foreknowledge of the plot.\" (", "The CIA; The Inside Story by Andrew Tully, pages 51, 53. ", "Crest books, 1962)\n \"On 27 May, he (Cemal Gursel) was hurriedly requested to come (from his residence in İzmir) to the capital (Ankara) to assume the leadership of National Unity Committee.\" (", "The Turkish Revolution, Aspects of Military politics. ", "By Walter Weiker. ", "pages 121, 122. ", "The Brookings Institution, 1963)\n \"When 27 May revolt occurred, Cemal Gürsel was not a participant. ", "He was invited to become the head due to the circumstances and he willingly accepted.\" (", "Burhan Felek, Milliyet, Page 2, 18 September 1971)\n \"General Gürsel was brought into the NUC chairmanship by the revolution team when he was in retirement preparation. ", "In actuality he was in the position of a chairman found in last minute with a hurried search. ", "He never was the responsible leader for a true leader is not to be appointed but is self-appointed.\" (", "By a leading member of the NUC)\n \"One of the core players of the coup, Orhan Erkanli told that they revolted on 27 May without knowing what to do on 28 May. No one, including Cemal Gürsel knew who and how many would be forming the NUC. ", "In actuality, even Cemal Gürsel was brought in later.\" (", "Years of Ismet Pasha of our Democracy, 1960–61 by Metin Toker, page 25. ", "Bilgi. ", "1998)\n \"It is now known that the coup was the result of years of planning on the part of conspirators, a number of radical colonels and ranks below in their early forties. ", "He (Cemal Gürsel) was not involved in the details of the organization of the coup d'état. ", "When the coup had succeeded, he was brought to Ankara.\" (", "Turkey, A modern History by Erik Zurcher. ", "pages 253,254. ", "I.B. Tauris, 2003)\n \"We just see that a few very important lines in his letter (to the Minister of Defence) had been censored. ", "That means we are going without learning the true history, without knowing who knows what facts and what true pictures of turning points.\" (", "Çetin Altan, Author, Journalist, September 2006)\n \"An extremely important document that sheds light on the past has been revealed. ", "Testimony from eyewitnesses at the time helped make known that the letter had been modified after 27 May, but the location of the original letter was unknown. ", "This important document adds a new dimension to the 27 May revolution. ", "We have come face to face with a new document that changes our written history. ", "It was my greatest wish to obtain just such a document; not for my own satisfaction, but for my father, to prove this reality and obtain genuine evidence. ", "I was thrilled when I heard about this.\" (", "Mr Aydın Menderes, Author, the Son of Prime Minister Adnan Menderes, September 2006)\n \"They cut off our phone lines. ", "Adnan Menderes was hung against the regulations. ", "I was supposed to oversee the execution. ", "The revolution tribunal's chief prosecutor Altay Egesel conducted the execution despite not being authorized. ", "İsmet İnönü and Cemal Gürsel were already phoning for him (Adnan Menderes) not to be executed but the telecommunications' office cut off the lines and Egesel made use of the (communication) gap to conduct the execution.\" (", "Mehmet Feyyat, District Attorney General, Istanbul Province Prosecutor General 1961, The Administrator of the Imrali Prison, The Lawyer of the Year, Senator. ", " (Reported by Özkan GÜVEN, STAR Newspaper, 13 November 2006 with a summary in Turkish at Law in the Capitol)\n \"Where are we now and where are the nations such as Portugal, Greece and Spain with whom we departed for the competition of development in 1960s? ", "While we still crawl around $5000 per capita income, they have caught $20K pci a long while ago. ", "In one word, an embarrassment.\" (", "Hasan Cemal, Milliyet, October 2006)\n \"We built an automobile with the mentality of the West and we forgot to put gasoline in it with the mentality of the East.\" (", "Cemal Gürsel, President, on the Anniversary of the Turkish Republic, 29 October 1963)\n\nReferences \n\nSong of The Pharaohs — The Kings of the East and the West\nAnalysis of political scene on 26 May 1960, research article (in Turkish)\nGeneral Gursel hosting HRH Queen Elizabeth's first visit to Turkey, Ankara, 1961\n1960–1962 Landmarks of Turkish History\n1963–1966 Landmarks of Turkish History\nThe full translated text of Cemal Gursel's letter The research copy of the Turkish original\nCemal Gursel's Memorandum Revealed\nHis video and photographs at the President's Web Page\nCemal Gursel with Vice President Lyndon Johnson in Ankara, 1962 (Anatolian Agency Album)\n60's video montage\nU.S. Presidential Messages search Cemal Gursel\n Text of Ankara Agreement\nThe movie \"The Cars of Revolution\"\nHis photos in LIFE Magazine\nCyprus, 1964. ", "Video footage of massacres and offensives against Turkish Community\nCable from US Embassy reflecting collective efforts of Cemal Gursel, Ismet Inonu and his entire cabinet and Gen Cevdet Sunay to stop executions\n\nCategory:1895 births\nCategory:1966 deaths\nCategory:People from Erzurum\nCategory:Kuleli Military High School alumni\nCategory:Turkish Military Academy alumni\nCategory:Army War College (Turkey) alumni\nCategory:Turkish Army generals\nCategory:Commanders of the Turkish Land Forces\nCategory:Ministers of National Defence of Turkey\nCategory:Prime Ministers of Turkey\nCategory:Presidents of Turkey\nCategory:Burials at Turkish State Cemetery\nCategory:Recipients of the Medal of Independence with Red Ribbon (Turkey)\nCategory:Leaders who took power by coup\nCategory:Members of the 24th government of Turkey\nCategory:Members of the 25th government of Turkey" ]

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[ "ISLAMABAD, PAKISTAN - Authorities in Afghanistan confirmed Monday that the Taliban captured 58 government forces during recent fighting in a northwestern district bordering Turkmenistan.", "\n\nAnother 58 Afghan soldiers who had taken refuge in the neighboring Central Asian country after fleeing the insurgent offensive in Bala Murghab have returned home, the Defense Ministry said. ", "It added a search operation was underway in the border district to free the hostages.", "\n\nThe Afghan foreign ministry, in a separate statement, said it \"appreciates the warm welcome extended to the citizens of Afghanistan and health care provided to them\" by the Turkmenistan government.", "\n\nThe Taliban has kept the hotly contested Afghan district in the Badghis province under pressure for more than two weeks, killing dozens of government forces and reportedly capturing about 200 others.", "\n\nBala Murghab Afghanistan\n\nWhile many parts and key security outposts are said to have fallen to insurgents, Afghan officials insist government forces are still holding the Bala Murghab district center.", "\n\nThe Taliban on Sunday released pictures on social media of 72 captured Afghan security forces, saying they \"surrendered\" to the insurgents in the fighting in Bala Murghab. ", "It was not possible to independently verify the claims.", "\n\nA major Taliban attack a week ago in the district eliminated an entire Afghan National Army company.", "\n\nTrump, National Security Officials Discuss Afghanistan President Donald Trump and his national security team had an hourlong, classified meeting on Afghanistan on Friday, a day after a top Afghan official openly complained that the Trump administration was keeping his government in the dark about its negotiations with the Taliban. ", "The meeting at the Pentagon included Vice President Mike Pence, Secretary of State Mike Pompeo, CIA Director Gina Haspel and Trump's national security adviser, John Bolton, among others. ", "President Donald Trump and his national security team had an hourlong, classified meeting on Afghanistan on Friday, a day after a top Afghan official openly complained that the Trump administration was keeping his government in the dark about its negotiations with the Taliban. ", "The meeting at the Pentagon included Vice President Mike Pence, Secretary of State Mike Pompeo, CIA Director Gina Haspel and Trump's national security adviser, John Bolton, among others.", "\n\nThe insurgents claim they either control or have a strong presence in a majority of Badghis' six districts. ", "It was not possible to independently verify the insurgents' claims.", "\n\nThe Taliban is ramping up battlefield attacks against Afghan forces ahead of announcing its so-called \"spring offensive,\" due in coming weeks, when hostilities intensify.", "\n\nMeanwhile, the insurgent group is also engaged in direct talks with the United States to negotiate a political settlement to the 18-year-old war in Afghanistan.", "\n\nBoth sides noted at the end of their last round of discussions on March 12 that they have made significant progress toward ending the war. ", "The dialogue is seeking the withdrawal of U.S.-led foreign forces from Afghanistan in return for Taliban's guarantee to prevent Afghan territory from becoming a hub for international terrorists." ]

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[ "Typical graphical user interfaces for video playback are difficult to use when it comes to accessing video chapters, often providing users with few clues as to what content lies in a given chapter. ", "User interfaces for accessing or renewing licenses governing the use of videos commonly lack suitable integration with video playback tools. ", "Short comings with user interfaces for video playback and license renewal are especially apparent on devices having small displays such as portable media players and smart phones." ]

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[ "Free light chains of immunoglobulins in patients with systemic sclerosis: correlations with lung involvement and inflammatory milieu.", "\nHumoral immunity and B cells are thought to play an important role in the pathophysiology of the systemic sclerosis (SSc). ", "The production of free light chains (FLC) of immunoglobulins is abnormally high in several pathological autoimmune conditions and reflects B cell activation. ", "Furthermore, FLCs demonstrated different biological activities including their capability to modulate the immune system, proteolytic activity and complement cascade activation. ", "The aims of this study are to determine the FLC levels in patients with SSc compared with healthy controls (HC) and to study their possible association with organ involvement and disease characteristics. ", "Sixty-five patients with SSc and 20 HC were studied. ", "Clinical and immunological inflammatory characteristics were assessed for all the patients with SSc. ", "κ-FLC and λ-FLC, interleukin 6 (IL-6) and B cell activating factor levels were measured. ", "The mean serum κ-FLC levels and FLC ratio were significantly higher in patients with SSc compared with HC, while the serum λ-FLC levels were comparable.", "The levels of FLC were comparable in patients with diffuse skin disease and limited skin involvement, while κ-FLC levels were increased in patients with restrictive lung (forced vital capacity (FVC) <80%) disease (26.4±7.4 mg/L) when compared with patients with FVC ≥80% (19.6±7.3 mg/L, P=0.009). ", "In patients with SSc, the levels of serum κ-FLC level directly correlated with the IL-6 levels (R=0.3, P=0.001) and disease activity (R=0.4, P=0.003). ", "FLC levels are elevated in SSc and high levels are associated with lung involvement and with a higher degree of inflammation, supporting a possible role of B cell activation in the pathophysiology of the disease." ]

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[ "Sinfonia (disambiguation)\n\nA sinfonia is any of several musical instrumental forms. ", "\n\nSinfonia may also refer to:\n\n Sinfónía, a 2004 live album by Icelandic pop/rock band Todmobile with the Icelandic Symphony Orchestra\n Sinfonia (Berio), a 1968–69 composition by the Italian composer Luciano Berio\n Sinfonia (1968 Berio album), a 1968 recording of Berio conducting the premier of his \"Sinfonia\"\n ABC Sinfonia, the Australian Broadcasting Corporation's national training orchestra from 1967 to 1986\n\nSee also\n Sinfonia concertante\n Phi Mu Alpha Sinfonia, an American National Music Fraternity" ]

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[ "[Painless myocardial ischemia in patient with extensive constrictive atherosclerosis of coronary arteries].", "\nWe describe in this article a clinical case of a patient with arterial hypertension, painless myocardial ischemia and extensive constrictive atherosclerosis of coronary arteries. ", "Coronary heart disease (painless ischemia) was suspected basing on results of transesophageal electrostimulation coupled with stress echocardiography and was confirmed by coronary angiography. ", "This description is followed by discussion of possibilities of different instrumental methods in diagnostics of painless ischemia, classification of painless ischemia, treatment, and prognosis." ]

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[ "My favorite out of those is Obama, but after only 4 years in the Senate, I can't see him running.", "\n\nIt'd be between Richardson, Edwards and Warner. ", "Out of those Warner would probably be the best candidate in the general, but he might be a better VP. ", "I guess I'd go with Edwards/Warner if I could pick the whole ticket.", "\n\n“They cheated us again and again, made decisions behind our back, presenting us with completed facts. ", "That’s the way it was with the expansion of NATO in the East, with the deployment of military infrastructure at our borders. ", "They always told us the same thing: 'Well, this doesn't concern you.'\" ", "-Vladimir Putin" ]

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[ "Q:\n\nPythonic list slicing with variable step size?", "\n\nTo frame the question, let's assume I've got the following list in Python, where X is some arbitrarily large natural number:\nl = [1, 2, 3, 4, 5, 6, 7, ... X]\n\nAnd I want to slice it such that I take the first, second, third, fifth, eighth, etc. ", "elements of the list, abiding by the Fibonacci sequence. ", "E.g. an operation akin to:\nl_prime = [l[0], l[1], l[2], l[4], l[7], l[11], ...]\n\nI'm comfortable with Python indexing notation, of l[start:end:step_size], and I'm wondering if there's a way to index Python lists within this notational paradigm with a step size that varies after each index is added to my new sliced list. ", "Or, would I need to use some other technique to solve the prior problem I posed?", "\n\nA:\n\nIf you can use numpy this is really easy.", "\nl = np.array([1, 2, 3, 4, ..., X])\nfibs = np.array([0, 1, 2, 4, 7])\nprint(l[fibs])\n\n" ]

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[ "Overview\n\nPraying with Confidence: 31 Days of Powerful Moments with God\nby Jeff Leake\n\nIn Praying with Confidence, you’ll find an easy-to-follow guide to improving your prayer\ntime. ", "Over the course of 31 days, author Jeff Leake provides tips and patterns to help you\ndevelop a\nnew discipline of prayer. ", "Each day features a unique prayer pattern based on well-known prayers\nthroughout the Bible, as well as the six main elements of prayer:\n\nWorship\n\nAgreement\n\nThanksgiving\n\nSpecific Requests\n\nConfession\n\nWorship\n\nFollowing the structure provided in this book, you’ll be able to bring a renewed focus to your\nprayer life.", "\n\nProduct Details\n\nMeet the Author\n\nFor the past twenty-four years, Jeff Leake has served as the lead pastor of a\nmulti-campus church in the\ncity of Pittsburgh, PA. ", "He is the author of three books: God in Motion, The Question That\nChanged My Life, and\nLearning to Follow Jesus. ", "He and his wife, Melodie, reside in Allison Park, PA. ", "Jeff\nis\nalso the leader of a church\nplanting movement that has planted 50 churches over the past 20 years. ", "He leads a multiplying\nchurch\nand lives a multiplying\nlife." ]

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[ "Proud to Be in the Startup Hustle\n\nManatt Digital works with companies across all stages, but we certainly have a soft spot for our startup clients, many with whom we get to help in launching and accelerating their growth in the marketplace. ", "Whether it’s messaging and positioning, business planning and modeling, navigating fundraising strategies, securing strategic relationships, and/or negotiating content deals, we help our clients best position their businesses for entrance and success. ", "And not only do we get to roll up our sleeves and dive deep into the startup hustle with our clients, but we also get to learn firsthand from their successes. ", "However, the best part of the hustle is that we get to partner with some of the smartest founders in the business.", "\n\nWe are so proud to feature a few of our clients in our newsletter this month. ", "We are confident that these companies will soon be big names in their respective industries, and we encourage you to check them out. ", "It is my honor to introduce you to these impressive founders:\n\nm/f people—4 Questions\n\nOne of Manatt Digital’s most dynamic engagements to date has been its work with m/f people, a lifestyle brand and ecommerce startup based on the philosophy of minimalism that was founded by Greg Alterman. ", "m/f people engaged both our business and legal advisory teams to support the development and execution of their go-to-market strategy.", "\n\nm/f people launches in June 2017 with best-in-class products in apparel and skincare and will roll out additional products, including home and food, throughout the year. ", "Greg is a serial entrepreneur and no stranger to the process of brand building and launching a new business. ", "Prior to m/f people, Greg founded lifestyle apparel brand Alternative Apparel as well as the cold-pressed juice company Juice | Served Here. ", "We sat down with Greg recently to get his thoughts on his latest venture and what it takes to become a successful entrepreneur. ", "Make sure to visit www.mfpeople.com and sign up to receive information on the company’s launch, product updates, and special promotions and deals.", "\n\n1. ", "What problem are you trying to solve with m/f people?", "\n\nLife is stressful. ", "In our work lives and with the aid of technology, we are more productive than we have ever been before, yet we find ourselves rushing and stressed all the time. ", "m/f is going to try to get to the root of the hustle and bustle and exists to help people create “Zen” in their home environment, specifically bathrooms and closets, which are crucial to getting out of the house every day, so they can have MORE time to do the things that matter most. ", "The problem that we will try to solve has so many layers, but at our core, we are a lifestyle brand in the form of a management tool to help simplify your life and routine.", "\n\n2. ", "Who are your customers?", "\n\nJust as seen in our name, m/f is male and female. ", "Because we have not yet launched, it is difficult to say exactly who our customers are; but we are targeting the “expert aesthete” and calling them m/fers. ", "m/fers are those who value design, simplicity, attention to detail, brand loyalty, transparency, art and high-quality products.", "\n\n3. ", "How do you define success in your business?", "\n\nBesides the obvious ringing of the register, success can be achieved by creating super-impactful brand collateral that our customers can become familiar with, and efficient operations that they can learn to trust. ", "We hope to reach hundreds of millions of eyeballs this year, and success to us will be achieved when we start to resonate in the market as a real alternative or “anti-Amazon” for your daily essentials.", "\n\n4. ", "As a successful entrepreneur, what are the biggest lessons you’ve learned so far?", "\n\nEvolve or die! ", "As quickly as the digital landscape changes, we must stay nimble and make strategic decisions as we find our way. ", "I expect many challenges over the next few months, but if we stay true to our vision, we can evolve in a way that will feel authentic to our employees, stakeholders and customers. ", "Also, things take time! ", "We must remain patient. ", "We are a lifestyle brand first and foremost, and it is to be expected that it will take longer to build than a pure product-led company.", "\n\nPassionflix\n\nBy Jordan Pritchett\n\nThe OTT landscape continues to evolve at lightning speed. ", "New entrants thrive in this crowded space when they have a deep understanding of their audience, deliver niche or targeted content, and can build a community of passionate consumers. ", "Passionflix, a multiplatform SVOD startup launching later in 2017, embodies these strategic elements and plays an active role in defining OTT’s continued progression.", "\n\nPassionflix aims to be the online content destination for all things love, passion, romance and happy endings. ", "Passionflix was founded in 2016 by Tosca Musk, Jina Panebianco and Joany Kane, who have together made over 60 films and television series with credits spanning executive, producer, director and writer roles.", "\n\nThe concept for Passionflix was born from the recognition that the romance genre is categorically underserved. ", "While existing network, cable and digital channels pay a level of homage to the genre, they only scratch the surface in terms of the depth of their content offering. ", "Given that, the trio seized on the opportunity to corner the market by catering exclusively to the genre’s large and passionate following while also providing new avenues for enhanced content discovery and curation. ", "In addition to a curated library of romantic classics, Passionflix will offer original productions adapted from books by authors who already command a large and loyal fan base. ", "Subscribers to Passionflix will be granted access to the entire content catalog, in addition to the ability to purchase themed merchandise. ", "Founding Members (open to all) receive additional access to events and savings.", "\n\nThe founders of Passionflix know their market, are deeply connected to their target audience, and excited to fill a content gap to very underserved demographic of women, many who are household decision makers.", "\n\nPassionflix engaged Manatt Digital’s business and legal teams to advise on and support their content strategy and acquisition. ", "Visit https://www.passionflix.com to learn more about the service and pre-launch subscription promotions.", "\n\nEveryday Influencers and Press X\n\nThe eSports market is projected to generate $696 million in 2017, with brands contributing $516 million through a combination of advertising ($155 million), sponsorship ($266 million) and media rights ($95 million), according to Newzoo’s 2017 Global Esports Market Report.", "\n\nRecently, I have been working at the center of the eSports business in representing the talent management company Everyday Influencers (EI) and its sister marketing agency, Press X. EI represents many of the most influential streamers and casters in the industry, including Imaqtpie, Dyrus, Pokimane, Scarra and Seagull.", "\n\nRecently featured in Rolling Stone, 25-year-old Michael “Imaqtpie” Santana built a large and engaged community playing League of Legends as a star player of Team Dignitas, retired from the pro-gaming scene in 2014, and launched his career as a Twitch streamer—a career that banks him $2 million a year before factoring in any sponsorship money. ", "See “Meet the Retired Pro-Gamer Who Earns $2 Million a Year,” Rolling Stone.", "\n\nEI’s reach in the world of eSports is deep, as the talent (creators, casters and professionals) it manages have large and engaged followings on YouTube and Twitch. ", "Many are sought after by brands that need to reach the highly engaged gamer demographic. ", "Twitch has 100 million monthly viewers who spend an average of 106 minutes daily watching live gaming, creating a tightly knit and highly interactive network of personalities, players and spectators. ", "See the Twitch website here. ", "With over 40 clients and a combined reach of over 300 million, EI has become the leader in talent management for gaming and eSports creators and professionals.", "\n\nThe company’s CEO and co-founder, Damon Lau, is no stranger to building successful businesses in new and emerging markets. ", "He has over 15 years of global entrepreneurial experience spanning various industries, including gaming, sports, consumer products and automotive. ", "Damon, who runs the company with his wife (and company COO) Deb Lau, co-founded Esports Network, where he launched Canada’s largest gaming communities and viewing events for eSports in Toronto, Montreal and Hong Kong. “", "The concept of having representation among esports content creators and professional players isn’t top of mind for the great majority of personalities in the scene,” says Lau. “", "Everyday Influencers was created because we’re invested in keeping the interests of talent first.” ", "He is also the former CEO of Round 5, a consumer products company managing exclusive licenses for global entertainment properties such as the Ultimate Fighting Championship, spearheading property awareness and distribution among mass market retailers such as Walmart, Target, K-Mart, Toys R Us, Walgreens, CVS, GameStop and Best Buy.", "\n\nWith an extensive portfolio of creators and partnerships with top brands within and outside gaming, Damon was approached by brands looking for EI to develop creative and strategic campaigns in gaming and eSports. ", "This lead to the formation of Press X, EI’s sister company that consults for and manages campaigns for both endemic and nonendemic brands that want to reach this demographic. ", "The campaigns that the company creates often utilize influencers with a deep focus on authenticity. “", "For EI, our main goal is to facilitate the education process behind the development of personal brands and to create a tangible road map for aspirations so that talent can focus on what they do best. ", "On the brand side, there’s a huge disconnect when it comes to understanding the endemic culture. ", "Our technical experience in areas like new media, digital marketing and brand/business development, along with our being esports natives, naturally led us to form Press.”", "\n\nWith brand investment projected to double to $1.5 billion by 2020, EI and Press X are well-positioned to grow and take a leadership role in the standard for talent management in eSports, and in designing brand campaigns that resonate with their growing fan bases. ", "As Lau puts it, “We are the go-to agency for people interested in gaming.”", "\n\nPuptimize\n\nPuptimize digitizes dog training. ", "It is a free app that makes it easy to raise your dog through free professional training and expert-recommended products—all tailored to you and your dog. ", "Puptimize lets you teach what you want, when you want, in just minutes per day.", "\n\nWe all want to be great pet parents, but there are three clear barriers to that: knowledge, cost and time. ", "Puptimize removes all three of these by making it easy, fun and free to raise a great dog. ", "The app breaks lessons down into short activities and reminds you when it’s time to take action—at the time that you’ve chosen.", "\n\nMillions of dog owners are just guessing on training, guessing on products, even guessing which advice they can trust. ", "Puptimize’s mission is to end that guesswork—and in the process, help end the disturbingly high number of dogs that are given up and given away each year.", "\n\nPuptimize believes that by creating a world full of confident, educated pet parents raising happy, well-behaved dogs, it can accomplish that goal.", "\n\nCo-Founders Rob Steinberg and D.J. Todd spent their pre-Puptimize careers in leadership positions at companies like Shazam, Yahoo, HP and Intuit. ", "They brought that consumer, digital and mobile experience to Puptimize to bring the pet industry into the 21st century. ", "The app launched with the most important commands, but much more content will be rolling out soon.", "\n\nSo if you have a dog, download the free Puptimize iOS app and see how much easier it can be to raise a great dog.", "\n\nRelated Posts\n\nDISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.", "\n\n\"My best business intelligence, in one easy email…\"\n\n*By using the service, you signify your acceptance of JD Supra's Privacy Policy.", "\n\nPrivacy Policy (Updated: October 8, 2015):\n\nhide\n\nJD Supra provides users with access to its legal industry publishing services (the \"Service\") through its website (the \"Website\") as well as through other sources. ", "Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement (\"Policy\"). ", "By using the Service, you signify your acceptance of this Policy.", "\n\nThe information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. 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", "In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.", "\n\nSharing and Disclosure of Information JD Supra Collects\n\nExcept as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.", "\n\nIn the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.", "\n\nLinks to Other Websites\n\nThis Website and the Service may contain links to other websites. ", "The operator of such other websites may collect information about you, including through cookies or other technologies. ", "If you are using the Service through the Website and link to another site, you will leave the Website and this Policy will not apply to your use of and activity on those other sites. ", "We encourage you to read the legal notices posted on those sites, including their privacy policies. ", "We shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. ", "This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.", "\n\nChanges in Our Privacy Policy\n\nWe reserve the right to change this Policy at any time. ", "Please refer to the date at the top of this page to determine when this Policy was last revised. ", "Any changes to our privacy policy will become effective upon posting of the revised policy on the Website. ", "By continuing to use the Service or Website following such changes, you will be deemed to have agreed to such changes. ", "If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.", "\n\nContacting JD Supra\n\nIf you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at: info@jdsupra.com.", "\n\n- hide\n\n*With LinkedIn, you don't need to create a separate login to manage your free JD Supra account, and we can make suggestions based on your needs and interests. ", "We will not post anything on LinkedIn in your name. ", "Or, sign up using your email address." ]

{ "pile_set_name": "Pile-CC" }

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[ "[Clinical review of 3 cases of aspergillosis].", "\nThree cases of aspergillosis observed in Pavia Infectious Disease Clinic in 1983-85 are described. ", "The cases differed both in the site of the infection (lungs, bones and liver) and in the patients' basic immunological situation. ", "The importance of mycological investigations during diagnosis is emphasised, though they should of course be flanked by instrumental examinations and blood chemical assays. ", "The efficacy of specific treatment with amphotericin B combined with surgery and plasma exchange is also emphasised." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Oldsmobile Intrigue A/C Compressor\n\nYou enjoy taking care of your Intrigue.", "\n\nAuto enthusiasts know that good looks is built into each Oldsmobile, and understand that only the best replacement Intrigue parts will suffice when maintenance needs to be done. ", "When your Oldsmobile Intrigue left the factory, it was destined for a driver who wants long-lasting quality in their automobile. ", "It's not all the time that you realize that you have to buy a replacement A/C Compressor to repair your vehicle. ", "Make no mistake, you bought your Intrigue because you wanted to buy strength and a dash of luxury both impeccably combined into one automobile.", "\n\nWhat A/C Compressor does for your vehicle.", "\n\nEver since the 1950s, cars and trucks have been built with either standard or optional climate control systems. ", "On your Oldsmobile Intrigue, the main component of this system is the A/C compressor. ", "The air conditioning uses a refrigerant called R134a to fuel a thermal reaction that emits cold air, and the Oldsmobile Intrigue A/C compressor, as the name would suggest, compresses this refrigerant into a dense liquid. ", "Further down the line it gets expanded into a gas and then cooled before entering your cabin. ", "If your car or truck did not have a functioning A/C compressor, you would not be able to cool your vehicle on hot days.", "\n\nThe best parts are right around the corner.", "\n\nTrust in the value of the parts you get from carpartsdiscount.com and realize incredible savings on all your upcoming repairs. ", "Given all the hassles associated with installing a part to fix your car or truck, let www.carpartsdiscount.com be the most authoritative website you go to make buying it easy. ", "Bring your Intrigue back to life with the best replacement parts from the experts at Car Parts Discount. ", "Just choose your year from the list below to find the right Oldsmobile Intrigue A/C Compressor for your 2002, 2001, 2000, 1999, 1998 model." ]

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[ "LSD has largely been ignored while the world gushes over legal weed and decriminalized magic mushrooms. ", "But a new research project in New Zealand will assess whether the counterculture’s favorite psychedelic is just a hedonistic substance or a tried-and-true medical treatment .", "\n\nThe clinical trial, led by Dr. Suresh Muthukumaraswamy at the University of Auckland, will investigate whether LSD and psilocybin microdoses actually do anything , and if they do, whether those effects can translate to medical treatments.", "\n\n“The data looks promising, but it's not clear yet… whether the risk-benefit ratio is there, and we're not sure yet whether it might work over and above a good placebo,” Muthukumaraswamy told the NZ Herald .", "\n\nGallery — Bitchin' Blotter Papers:\n\nWhile you may have never heard of Muthukumaraswamy before, you’ve likely seen some of his research, especially if you’re a devoted acid head. ", "In 2016, he was part of the research group that performed brain imaging studies on people tripping from LSD . ", "The study discovered that LSD works by connecting all parts of the brain together at once. ", "The findings were so mind-blowing that Inverse awarded the study “Experiment of the Year” and noted that it would “fundamentally alter the future of an entire field.”", "\n\nLSD has made some serious strides over the decades, from Woodstock to modern medical clinics. ", "Otherwise known as acid, LSD is known for causing hallucinations and fuzzy, feel-good thoughts, but it could also treat everything from PTSD to drug addiction to clinical depression . ", "The same goes for psilocybin, the psychedelic component of “magic mushrooms.”", "\n\nIf the project receives government approval, Muthukumaraswamy and his team will conduct the world’s first randomized, controlled clinical trial for LSD and psilocybin microdosing.", "\n\nOf course, this wouldn’t be the first study delving into LSD’s secrets. ", "Last last year, researchers in the UK began the first placebo-controlled trial for microdosing LSD. ", "Over the past year, Dutch researchers began looking into the same thing, too, while American researchers published their LSD microdosing study results this summer. ", "These ongoing studies are different from the New Zealand trial because they’re not concerned with whether microdosing possesses medical efficacy, but rather whether microdosing generates real psychoactive effects or if it’s just placebo.", "\n\n“Drug tests in pharmaceutical companies usually involve hundreds of people in each study across multiple studies and multiple centers in order the get the data that you need to say it works, that we have a really good side-effect profile, and we know how to do this in the safest possible manner,” Muthukumaraswamy continued . “", "We're just not even close to there yet.”", "\n\nGallery — Edibles That Look Like Real Food Products:" ]

{ "pile_set_name": "OpenWebText2" }

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[ "Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. ", "FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). ", "A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. ", "Collapsing glomerulopathy can be classified as HIV-associated or idiopathic. ", "Many patients with podocyte diseases, including minimal change nephropathy (MCN), FSGS, and collapsing glomerulopathy are refractory to all conventional remittive therapy. ", "Current studies: * ritiuximab + cyclosporine: single center, open label * sparsentan: multicenter, placebo-controlled RCT, industry-sponsored (IRB submission pending) * MaNAc: phase 1B, single center, open label for pharmacokinetics and response (IRB approval pending, CRADA formerly with New Zealand Pharmaceuticals, now with Escala) We are carrying out studies of a dual-function molecule, cannabinoid receptor antagonist and AMPK agonist, in mouse models of FSGS, in collaboration with George Kunos, NIAAA" ]

{ "pile_set_name": "NIH ExPorter" }

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[ "Q:\n\nFace/Edge loop selection precision\n\nWhen I use face/edge loop selection,every now and then the selection goes off in the wrong direction. ", "See image below. ", "I was trying to select vertical face loops only, but a horizontal one got selected. ", "This causes me to Ctrl+Z every time this happens and retry and this ends up being very frustrating when doing precision work. ", "Any idea how to avoid this?", "\n\nA:\n\nIt all depends on where you click. ", "Click on the edge that is perpendicular to the direction you want to select. ", "As you can see, if you click closer to the middle of a face, Blender will go with whichever edge it is closer to, so you will get \"random\" directions.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "President McAleese hosts reception as GAA marks 125 years\n\nPresident Mary McAleese with the Artane Boys Band at a reception for the GAA at Áras an Uachtaráin\n\nIrish President Mary McAleese today paid tribute to the volunteer community at the heart of the GAA.", "\n\nMcAleese was speaking at a garden party hosted at Áras an Uachtaráin today to mark the 125th anniversary of the Gaelic Athletic Association.", "\n\n\"From Derry to Dingle, from Dublin to Dubai, from San Francisco to Hong Kong day after day, week after week, an army of volunteers cares for this organization and keeps it full of effort and imagination,\" she said.", "\n\n\"In parishes, townlands, villages, suburbs and cities there is nothing to match it and nothing that comes close to matching the GAA. ", "That it remains an unapologetic amateur organisation rooted deeply in the local, national and international life of the Irish family at home and abroad, is its enduring strength.\"", "\n\n\"This organization has given to millions memories to last not just one lifetime but many. ", "It has created opportunities, seeded ambition, honed skill, galvanized the individual, harnessed the team.", "\n\n\"It has brought days of massive pride and occasional broken hearts to the parish, the club, the school, the county, the province and the country. ", "Such a debt as we owe to the GAA could never be repaid but today we gather to say a heartfelt thank you.\"", "\n\nEntertainment was provided by The Artane Band as well as winners and competitors of SCÓR 2009. ", "The veteran GAA commentator Mícheál Ó Muircheartaigh was MC at the event.", "\n\nPresident Mary McAleese with the Artane Boys Band at a reception for the GAA at Áras an Uachtaráin" ]

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[ "Forest Service seeks comments on Burnt Mountain egress\n\nRelated Media\n\nSNOWMASS VILLAGE - The White River National Forest is seeking feedback on a proposal from the Aspen Skiing Co. to complete a skier egress trail in the Burnt Mountain portion of Snowmass ski area.", "\n\nThe proposed trail was first analyzed in the Snowmass Master Plan Amendment - Ski Area Improvements Environmental Assessment and approved in February 2006. ", "However, subsequent to an appeal filed on the 2006 decision, a segment of the egress trail was remanded from the 2006 Environmental Assessment approval and additional analysis was needed because it was located in an area that was at that time an inventoried roadless area. ", "The inventoried roadless area extended into the ski area's special use permit boundary. ", "In 2012, the Colorado Roadless Rule removed all inventoried roadless areas from within ski area boundaries in Colorado. ", "The Forest Service will re-analyze the environmental effects of the segment of trail remanded in 2006 to determine if any new conditions require additional analysis as directed by the National Environmental Policy Act.", "\n\nThe proposed trail would provide egress from the newly gladed ski terrain on the eastern portions of Burnt Mountain to the Long Shot ski trail. ", "This would allow users to continue down to the Two Creeks base area and lift. ", "The trail segment will be approximately 3,100 feet long with an average width of 35 feet. ", "It will require removing select trees within a 2.5-acre area. ", "Additionally, up to 500 linear feet of spot grading within the area proposed for tree removal might be required. ", "To minimize impacts, tree removal and trail preparation would be conducted using design criteria and best management practices." ]

{ "pile_set_name": "Pile-CC" }

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[ "1. ", "Introduction {#sec1-molecules-24-02317}\n===============\n\nCancer therapy mainly involves surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy, and hormone therapy. ", "Chemotherapy generally refers to the use of cytotoxic drugs to treat cancer. ", "Plant alkaloids are one major class of chemotherapeutic drugs \\[[@B1-molecules-24-02317],[@B2-molecules-24-02317],[@B3-molecules-24-02317],[@B4-molecules-24-02317],[@B5-molecules-24-02317],[@B6-molecules-24-02317],[@B7-molecules-24-02317],[@B8-molecules-24-02317],[@B9-molecules-24-02317]\\]. ", "Chemotherapeutic drugs that affect cell division by preventing the normal functioning of micro-tubules include the vinca alkaloids.", "\n\nNumerous diterpenoid alkaloids have been isolated from various *Aconitum*, *Delphinium*, and *Garrya* (Family Ranunculaceae) species and are classified according to their chemical structures as C~18~-, C~19~- or C~20~-diterpenoid alkaloids ([Figure 1](#molecules-24-02317-f001){ref-type=\"fig\"}) \\[[@B10-molecules-24-02317],[@B11-molecules-24-02317]\\]. ", "The C~19~-diterpenoid alkaloids may be divided into six types: aconitine, lycoctonine, pyro (C~8~=C~15~ or C~15~=O), lactone (δ-valerolactone rather than cyclopentyl C-ring), 7,17-*seco*, and rearranged ones \\[[@B10-molecules-24-02317],[@B11-molecules-24-02317]\\]. ", "Most of the isolated C~19~-diterpenoid alkaloids are aconitine- and lycoctonine-types and include aconitine, mesaconitine, hypaconitine and jesaconitine, all of which are extremely toxic. ", "The C~20~-diterpenoid alkaloids may be divided into ten types: atisine, denudatine, hetidine, hetisine, vakognavine, napelline, kusnezoline, racemulosine, arcutine, and tricalysiamide \\[[@B10-molecules-24-02317],[@B11-molecules-24-02317]\\]. ", "Most of the isolated C~20~-diterpenoid alkaloids are atisine-, hetisine-, and napelline-types and include atisine, kobusine, pseudokobusine and lucidusculine, which are far less toxic \\[[@B12-molecules-24-02317]\\].", "\n\nThe pharmacological properties of the C~19~-diterpenoid alkaloids have been studied extensively and reviewed \\[[@B12-molecules-24-02317]\\]. ", "Aconitine is a toxin that exhibits activity both centrally and peripherally, acting predominantly on the cardiovascular and respiratory systems by preventing the normal closing of sodium channels \\[[@B12-molecules-24-02317]\\]. ", "This extreme toxicity resulted in the use of *Aconitum* extracts as poisons in hunting and warfare \\[[@B13-molecules-24-02317]\\], although extracts were also used as traditional medicines by oral and topical routes. ", "For example, the roots of *Aconitum* plants have been used as \"bushi\", an herbal drug in some prescriptions of traditional Japanese medicine for the treatment of hypometabolism, dysuria, cardiac weakness, chills, neuralgia, gout, and certain rheumatic diseases \\[[@B14-molecules-24-02317]\\]. ", "However, proper processing is essential to reduce the content of toxic alkaloids and avoid inadvertent poisoning \\[[@B15-molecules-24-02317],[@B16-molecules-24-02317],[@B17-molecules-24-02317]\\]. ", "Such obstacles encourage a good understanding of the relationships between structure and cytotoxic activity of aconitine and related compounds before they can be considered for modification and development as chemotherapeutic agents.", "\n\nOur previous study demonstrated the effects of various naturally occurring and semi-synthetic C~19~- and C~20~-diterpenoid alkaloids on the growth of the A172 human malignant glioma cell line \\[[@B18-molecules-24-02317]\\]. ", "Antitumor properties and radiation-sensitizing effects of various types of novel derivatives prepared from C~19~- and C~20~-diterpenoid alkaloids were also investigated \\[[@B19-molecules-24-02317]\\]. ", "Two novel hetisine-type C~20~-diterpenoid derivatives showed significant suppressive effects against the Raji non-Hodgkin's lymphoma cell line \\[[@B20-molecules-24-02317]\\]. ", "In addition, the effects of various semi-synthetic novel hetisine-type C~20~-diterpenoid alkaloids on the growth of the A549 human lung cancer cell line were examined and subsequent structure-activity relationships for the antiproliferative effects against A549 cells were considered \\[[@B21-molecules-24-02317]\\]. ", "Since 2012, several diterpenoid alkaloid components and their derivatives exhibited antiproliferative activity against human tumor cell lines, including A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (estrogen and progesterone receptor-negative & HER2-negative triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN \\[P-glycoprotein (P-gp) overexpressing vincristine-resistant KB subline\\]. ", "Among such alkaloids, C~19~-diterpenoid (e.g., lipojesaconitine, delpheline, and delcosine derivative) and C~20~-diterpenoid (e.g., kobusine and pseudokobusine derivatives) alkaloids have shown significant antiproliferative activity, as well as provided promising new leads for further development as antitumor agents.", "\n\n2. ", "Antiproliferative Activity of C~19~-Diterpenoid Alkaloid Derivatives {#sec2-molecules-24-02317}\n=======================================================================\n\n2.1. ", "Aconitine-Type C~19~-Diterpenoid Alkaloids {#sec2dot1-molecules-24-02317}\n-----------------------------------------------\n\nThe tested aconitine-type C~19~-diterpenoid alkaloids included 21 natural alkaloids, aconitine (**1**), deoxyaconitine (**2**), jesaconitine (**3**), deoxyjesaconitine (**4**), aljesaconitine A (**5**), secojesaconitine (**6**), mesaconitine (**8**), hypaconitine (**9**), hokbusine A (**10**), 14-anisoyllasianine (**12**), *N*-deethylaljesaconitine A (**13**), aconine (**14**), lipomesaconitine (**15**), lipoaconitine (**16**), lipojesaconitine (**17**), neolinine (**18**), neoline (**19**), 14-benzoylneoline (**20**), isotalatizidine (**21**), karacoline (**22**), and 3-hydroxykaracoline (**23**), isolated from the rhizoma of *Aconitum japonicum* THUNB. ", "subsp. *", "subcuneatum* (NAKAI) KADOTA \\[[@B22-molecules-24-02317],[@B23-molecules-24-02317],[@B24-molecules-24-02317],[@B25-molecules-24-02317],[@B26-molecules-24-02317],[@B27-molecules-24-02317],[@B28-molecules-24-02317]\\] ([Figure 2](#molecules-24-02317-f002){ref-type=\"fig\"}). ", "Two synthetic aconitine-type C~19~-diterpenoid alkaloids, 3,15-diacetyljesaconitine (**7**) \\[[@B26-molecules-24-02317]\\] and 3-acetylmesaconitine (**11**) \\[[@B29-molecules-24-02317]\\] prepared from secojesaconitine (**6**) and mesaconitine (**8**), respectively ([Figure 2](#molecules-24-02317-f002){ref-type=\"fig\"}), were also tested.", "\n\nEighteen of the 23 tested aconitine-type C~19~-diterpenoid alkaloids, both natural alkaloids (**1**\\~**6**, **8**\\~**10**, **12**\\~**14**, **18**\\~**23**) and synthetic analogs (**7** and **11**), were inactive (IC~50~ \\> 20 or 40 μM) \\[[@B27-molecules-24-02317],[@B28-molecules-24-02317],[@B30-molecules-24-02317]\\] ([Table 1](#molecules-24-02317-t001){ref-type=\"table\"}). ", "Three natural diterpenoid alkaloids (**15**\\~**17**) exhibited cytotoxic activity against five human tumor cell lines (A549, MDA-MB-231, MCF-7, KB, and MDR KB subline KB-VIN) ([Table 1](#molecules-24-02317-t001){ref-type=\"table\"}). ", "Lipojesaconitine (**17**) showed significant cytotoxicity against four tested cell lines with IC~50~ values of 6.0 to 7.3 μM, but weak cytotoxicity against KB-VIN (IC~50~ = 18.6 μM) \\[[@B28-molecules-24-02317]\\]. ", "Lipomesaconitine (**15**) showed moderate cytotoxicity against the KB cell line (IC~50~ = 9.9 μM), but weak cytotoxicity against the other four human tumor cell lines (IC~50~ =17.2 \\~ 21.5 μM) \\[[@B27-molecules-24-02317]\\]. ", "Lipoaconitine (**16**) was weakly cytotoxic (IC~50~ = 13.7 \\~ 20.3 μM) against all five human tumor cell lines \\[[@B28-molecules-24-02317]\\]. ", "Based on the results, the fatty acid ester at C-8 and the anisoyl group at C-14 found in **17** may be important to the cytotoxic activity of aconitine-type C~19~-diterpenoid alkaloids.", "\n\n2.2. ", "Lycoctonine-Type (7,8-diol) C~19~-Diterpenoid Alkaloids {#sec2dot2-molecules-24-02317}\n------------------------------------------------------------\n\nThe tested lycoctonine-type (7,8-diol) C~19~-diterpenoid alkaloid group included 12 natural alkaloids, namely nevadensine (**24**), *N*-deethylnevadensine (**25**), and virescenine (**27**), purified from rhizoma of *Aconitum japonicum* subsp. *", "subcuneatum* \\[[@B27-molecules-24-02317]\\], and 18-methoxygadesine (**26**), delphinifoline (**28**), delcosine (**34**), 14-acetyldelcosine (**34--43**), and 14-acetylbrowniine (**35**), purified from root of *Aconitum yesoense* var. *", "macroyesoense* (NAKAI) TAMURA \\[[@B31-molecules-24-02317],[@B32-molecules-24-02317],[@B33-molecules-24-02317],[@B34-molecules-24-02317]\\], and andersonidine (**30**), pacifiline (**31**), pacifinine (**32**), and pacifidine (**33**), purified from seeds of *Delphinium elatum* cv. ", "Pacific Giant \\[[@B35-molecules-24-02317]\\] ([Figure 3](#molecules-24-02317-f003){ref-type=\"fig\"}). ", "The remaining tested C~19~-diterpenoid alkaloids from this subtype were synthetic alkaloids, *N*-deethyldelsoline (**29**) \\[[@B18-molecules-24-02317]\\], 1-acetyldelcosine (**34-1**) \\[[@B36-molecules-24-02317]\\], 1,14-diacetyldelcosine (**34-2**) \\[[@B37-molecules-24-02317]\\], 1-(4-trifluoromethylbenzoyl)delcosine (**34-24**) \\[[@B30-molecules-24-02317]\\], delsoline (**34-42**) \\[[@B37-molecules-24-02317]\\], 1,14-di-(4-nitrobenzoyl)-delcosine (**34-45**) \\[[@B30-molecules-24-02317]\\], 14-acetyl-1-(4-nitrobenzoyl)delcosine (**34-46**) \\[[@B30-molecules-24-02317]\\], and 1-acyl or 1,14-diacyldelcosine derivatives (**34-3**\\~**34-23**, **34-25**\\~**34-41**, **34-44**, and **34-47**) \\[[@B38-molecules-24-02317]\\], prepared from delcosine (**34**) or delsoline (**34-42**) ([Figure 3](#molecules-24-02317-f003){ref-type=\"fig\"}). ", "These 42 C~19~-diterpenoid alkaloids were evaluated for antiproliferative activity against four to five human tumor cell lines (A549, DU145, MDA-MB-231, MCF-7, KB, and KB-VIN) \\[[@B30-molecules-24-02317],[@B38-molecules-24-02317]\\] ([Table 2](#molecules-24-02317-t002){ref-type=\"table\"}). ", "Several tested lycoctonine-type (7,8-diol) C~19~-diterpenoid alkaloids, both natural alkaloids (**24**\\~**28**, **30**\\~**33**) and a synthetic alkaloid (**29**), were inactive (IC~50~ \\> 20 or 40 μM). ", "All tested delcosine derivatives that contain an acetyl or methoxy group, both natural alkaloids (**34**, **34-43**, **35**) and synthetic analogs (**34-1**, **34-2**, **34-42**), were inactive (IC~50~ \\> 20 μM). ", "However, acylation, except with an acetyl group, of the C-1 and/or C-14 hydroxy group of **34** led to various degrees of antiproliferative activity. ", "Among the C-1 esterified alkaloids, the synthetic derivatives **34-6**, **34-8**, **34-10**, and **34-18** exhibited significant potency against all cell lines (average IC~50~ 9.3, 5.3, 5.0, and 6.9 µM, respectively). ", "Also, alkaloids **34-3**, **34-16**, **34-17**, **34-21**, **34-25**, **34-27**, **34-31**, **34-32**, **34-38**, and **34-40** showed moderate potency toward all cell lines (average IC~50~ 12.7−20.7 µM). ", "While alkaloid **34-32** displayed good antiproliferative activity (IC~50~ 8.7 µM) against KB cells, it was much less potent against A549, MDA-MB-231, and KB-VIN cells. ", "Alkaloids **34-5**, **34-13**, **34-15**, **34-29**, **34-35**, **34-37**, and **34-41** exhibited only weak potency against all cell lines (average IC~50~ 22.0−26.5 µM). ", "Finally, alkaloids **34-24**, **34-30**, and **34-34** were inactive against all five human tumor cell lines, while **34-12**, **34-33**, and **34-39** showed limited potency.", "\n\nAmong the derivatives esterified at both C-1 and -14, alkaloids **34-19** and **34-20** exhibited significant potency against all five tested cell lines (average IC~50~ 4.9 and 5.0 µM, respectively). ", "Alkaloid **34-9** (average IC~50~ 11.9 µM) showed significant antiproliferative activity against MDA-MB- 231 and KB cells (IC~50~ 4.7 and 5.8 µM, respectively) comparable with **34-19** and **34-20**, but was less potent against MCF-7 and A549 (IC~50~ 12.2 and 24.8 µM, respectively) and inactive against KB-VIN. ", "Alkaloid **34-23** exhibited only weak potency toward all cell lines (average IC~50~ 23.7 µM). ", "Alkaloids **34-4**, **34-7**, **34-11**, **34-14**, **34-26**, **34-36**, **34-45**, **34-46**, and **34-47** were inactive against all five human tumor cell lines, while **34-22** and **34-28** showed limited potency.", "\n\nParticularly, C-1 monoacylated delcosine derivatives (**34-3**, **34-6**, **34-8**, **34-10**, **34-13**, **34-21**, **34-25**, **34-27**, and **34-35**) were significantly more potent compared with corresponding C-1,14 diacylated delcosine derivatives (**34-4**, **34-7**, **34-9**, **34-11**, **34-14**, **34-22**, **34-23**, **34-26**, **34-28** and **34-36**). ", "Thus, a C-1 acyloxy group and C-14 hydroxy group are crucial for enhanced antiproliferative activity of **1**-derivatives. ", "Regarding alkaloids **34-18** (pentafluorobenzoate at C-1, hydroxy at C-14), **34-19** (pentafluorobenzoate at C-1 and C-14), and **34-20** (pentafluorobenzoate at C-1, acetate at C-14), all three alkaloids were essentially equipotent against three of the five tumor cell lines, while **34-18** was somewhat less potent than the diacylated alkaloids against MCF-7 and KB-VIN cells.", "\n\nStriking observations from the data in [Table 2](#molecules-24-02317-t002){ref-type=\"table\"} were the consistent identities of the most potent alkaloids. ", "Alkaloids **34-8**, **34-10**, **34-19**, and **34-20** exhibited the highest potency against all five tested tumor cell lines with IC~50~ values ranging from 4.3 to 6.0 µM. The same range of potency was found with alkaloid **34-18** against A549 cells, with alkaloids **34-9** and **34-18** against MDA-MB-231 cells, and with **34-6**, **34-9**, and **34-18** against KB cells. ", "The potencies of **34-6** and **34-17** (IC~50~ 5.6−11.8 µM) generally ranked somewhat below those of the most potent alkaloids, except against the MCF-7 cell line, where they were even less active.", "\n\nThe identity of the substituent(s) on the acyl group affected the antiproliferative potency. ", "Notably, among the 1,14-diacyl and 1-acyl-14-acetyl derivatives, only alkaloids **34-19** and **34-20** with one or two pentafluorinated benzoyl esters, respectively, showed significant potency against all five tested cell lines. ", "Alkaloid **34-9** with two 3-nitro-4-chlorobenzoyl groups showed good potency against certain cell lines. ", "Similarly, the 1-monoacylated alkaloids with the highest potency against the five tumor cell lines contained 3-nitro-4-chloro- (**34-8**) and pentafluoro- (**34-18**) as well as 4-dichloro-methyl- (**34-10**) benzoyl esters. ", "The chlorinated alkaloids **34-8** and **34-10** as well as **34-6**, which has 3,5-dichloro substitution on the benzoate ester, were more potent than **34-5** with only a single chloro group or **34-13** with chloro and fluoro groups. ", "Similarly, alkaloid **34-18** showed increased antiproliferative activity against the five tumor cell lines compared with other fluorinated alkaloids **34-13**\\~**34-17**, **34-21**\\~**34-27**. ", "Moreover, with some exceptions against certain cell lines, alkaloids with bromo (**34-3** and **34-4**), dimethylamino (**34-12**), dimethoxy (**34-29**), trimethoxy (**34-30**), diethoxy (**34-31**), benzyloxy (**34-32**), cyano (**34-33**), methylenedioxy (**34-34** and **34-35**), nitro (**34-45** and **34-46**), and ethoxy (**34-47**) substituted benzoate esters or phenylacetyl (**34-37**), cinnamoyl (**34-38** and **34-39**), 1-naphthoyl (**34-40**), and anthraquinone-2-carbonyl (**34-41**) esters were less potent or inactive.", "\n\nInterestingly, the active alkaloids were generally effective against P-gp overexpressing MDR subline KB-VIN, while alkaloids such as vincristine and paclitaxel are ineffective due to excretion from the MDR cells by P-gp. ", "These results suggest that these diterpenoids are not substrates for P-gp.", "\n\n2.3. ", "Lycoctonine-Type (7,8-methylenedioxy) C~19~-Diterpenoid Alkaloids {#sec2dot3-molecules-24-02317}\n----------------------------------------------------------------------\n\nThe tested lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids included 19 natural alkaloids, delcorine (**36**), delpheline (**37**), pacinine (**38**), yunnadelphinine (**39**), melpheline (**40**), bonvalotidine C (**41**), *N*-deethyl-*N*-formylpaciline (**42**), *N*-deethyl-*N*-formylpacinine (**43**), isodel-pheline (**44**), pacidine (**45**), eladine (**46**), *N*-formyl-4,19-secopacinine (**47**), *N*-formyl-4,19-secoyunna-delphinine (**48**), iminoisodelpheline (**49**), iminodelpheline (**50**), laxicyminine (**51**), *N*-deethyl-19-oxo-isodelpheline (**52**), *N*-deethyl-19-oxodelpheline (**53**), and 19-oxoisodelpheline (**54**), purified from seeds of *Delphinium elatum* cv. ", "Pacific Giant \\[[@B35-molecules-24-02317],[@B39-molecules-24-02317],[@B40-molecules-24-02317],[@B41-molecules-24-02317],[@B42-molecules-24-02317]\\] ([Figure 4](#molecules-24-02317-f004){ref-type=\"fig\"}). ", "The remaining 22 tested C~19~-diterpenoids were synthetic derivatives (**37-1**\\~**37-22**) \\[[@B43-molecules-24-02317]\\] prepared from **37** ([Figure 4](#molecules-24-02317-f004){ref-type=\"fig\"}).", "\n\nAll tested lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids were evaluated for antiproliferative activity against human tumor cell lines \\[[@B30-molecules-24-02317],[@B40-molecules-24-02317],[@B41-molecules-24-02317],[@B42-molecules-24-02317],[@B43-molecules-24-02317]\\] ([Table 3](#molecules-24-02317-t003){ref-type=\"table\"}). ", "The lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids, both the natural alkaloids (**36**\\~**54**) and synthetic analogs that did not contain a C-6 ester group (**37-20** and **37-22**), were inactive (IC~50~ \\> 20 or 40 μM). ", "Among the C-6 esterified alkaloids, **37-1**, **37-17**, and **37-18** exhibited the highest average potency toward four tested cell lines (A549, DU145, KB and KB-VIN; average IC~50~ 9.83, 9.57, and 9.41 μM, respectively). ", "Alkaloids **37-3**, **37-5**\\~**37-7**, **37-9**, **37-10**, **37-12**, **37-13**, **37-16**, and **37-19** showed moderate potency against all tested cell lines (average IC~50~ 13.9−20.8 µM). ", "However, alkaloid **37-13** showed significantly increased cytotoxic activity (IC~50~ 10.2 μM) against A549 cells compared with **37-1**, **37-17**, and **37-18**, but was generally less potent against DU145 and KB cells. ", "While alkaloids **37-12**, **37-13**, **37-16**, and **37-19** displayed good antiproliferative activity (IC~50~ 6.8, 9.1, 6.5, and 4.7 µM, respectively) against KB-VIN cells, they were much less potent against A549, DU145, and KB cells. ", "Alkaloids **37-4** and **37-21** were inactive against all tested cancer cell lines, while **37-2**, **37-8**, **37-11**, and **37-14** exhibited only weak potency toward all cell lines (average IC~50~ 23.0−29.2 µM).", "\n\nThe most noticeable observations from the data in [Table 3](#molecules-24-02317-t003){ref-type=\"table\"} were the degree and relative ratio of KB/KB-VIN potency. ", "Among the four cancer cell lines tested, the highest potency was found against the KB-VIN cell line by alkaloids **37-17**\\~**37-19** (IC~50~ 4.22, 4.40, and 4.71 μM, respectively), followed by alkaloids **37-16**, **37-12**, **37-1**, **37-13**, and **37-9** (IC~50~ 6.50, 6.80, 8.27, 9.10, and 11.9 μM, respectively). ", "Generally, all active alkaloids showed the highest potency against the KB-VIN cell line compared with the other three tested cancer cell lines. ", "Moreover, alkaloids **37-12**, **37-16**, **37-13**, and **37-19** showed over two-fold selectivity between the two cell lines (ratio of IC~50~ KB/IC~50~ KB-VIN: 2.15, 2.28, 2.31, and 2.57, respectively). ", "Alkaloids **37-2**, **37-5**, and **37-17** displayed weak selectivity between the KB and KB-VIN cell lines (ratio of IC~50~ KB/IC~50~ KB-VIN: 1.55, 1.36, and 1.62, respectively). ", "Finally, alkaloids **37-1**, **37-3**, **37-6**\\~**37-9**, **37-11**, **37-14**, **37-15**, and **37-18** displayed similar potency against the KB and KB-VIN cell lines (ratio of IC~50~ KB/IC~50~ KB-VIN: 1.07, 1.17, 1.06, 1.21, 1.04, 1.25, 1.07, 1.07, 1.17, and 1.23, respectively).", "\n\nThe identity of the substituent on the C-6 acyl group affected the cytotoxic potency. ", "For instance, the alkaloids with the highest potency against the KB-VIN cell line contained chloro (**37-1**), fluoro (**37-12**, **37-18**, and **37-19**), trifluoromethyl (**37-9**, **37-13**, and **37-18**), ethoxy (**37-16**), or benzyloxy (**37-17**) substituents on the acyl group. ", "Against the KB-VIN cell line, alkaloids **37-18** and **37-19** with both fluoro and trifluoromethyl/methyl groups were more potent than **37-9** with only a single trifluoromethyl group and even more potent than **37-2** with a single fluoro group. ", "Similarly, alkaloid **37-13** showed increased cytotoxic activity against most cell lines compared with the related fluorinated alkaloids **37-14** and **37-15**. ", "Moreover, alkaloids with nitro, methoxy, phenyl, trifluoromethoxy, trifluoromethythio, and methyl carboxylate groups on a C-6 benzoate ester were generally less potent.", "\n\n3. ", "Antiproliferative Activity of C~20~-Diterpenoid Alkaloid Derivatives {#sec3-molecules-24-02317}\n=======================================================================\n\n3.1. ", "Actaline and Napelline-Type C~20~-Diterpenoid Alkaloids {#sec3dot1-molecules-24-02317}\n------------------------------------------------------------\n\nOne natural actaline-type C~20~-diterpenoid alkaloid \\[[@B44-molecules-24-02317]\\], aconicarchamine A (**55**), isolated from rhizoma of *Aconitum japonicum* subsp. *", "subcuneatum* \\[[@B30-molecules-24-02317]\\], ([Figure 5](#molecules-24-02317-f005){ref-type=\"fig\"}) and seven natural napelline-type C~20~-diterpenoid alkaloids, lucidusculine (**57**), flavadine (**58**), 12-acetyllucidusculine (**59**), 1-acetyl-luciculine (**60**), dehydrolucidusculine (**61**), dehydroluciculine (**62**), and 12-acetyldehydroluciduscu-line (**63**), purified from roots of *Aconitum yesoense* var. *", "macroyesoense* \\[[@B31-molecules-24-02317],[@B32-molecules-24-02317],[@B33-molecules-24-02317]\\], ([Figure 5](#molecules-24-02317-f005){ref-type=\"fig\"}) were tested. ", "Seven synthetic napelline-type C~20~-diterpenoid alkaloid derivatives (**56-1**\\~**56-7**) \\[[@B18-molecules-24-02317],[@B32-molecules-24-02317],[@B45-molecules-24-02317]\\] were prepared from luciculine (**56**) ([Figure 5](#molecules-24-02317-f005){ref-type=\"fig\"}) and tested also. ", "All tested actaline- and napelline-type C~20~-diterpenoid alkaloids were evaluated for antiproliferative activity against four to five human tumor cell lines \\[[@B28-molecules-24-02317],[@B30-molecules-24-02317]\\] ([Table 4](#molecules-24-02317-t004){ref-type=\"table\"}). ", "Tested actaline- and napelline-type C~20~-diterpenoid alkaloids, both the natural alkaloids (**55** and **57**\\~**63**) and synthetic analogs (**56-1**\\~**56-4**, **56-6**, and **56-7**), were inactive (IC~50~ \\> 20 or 40 μM). ", "Among the synthetic alkaloids, alkaloid **56-5** exhibited only weak potency toward the tested cell lines (A549, DU145, KB and KB-VIN; average IC~50~ 27.8 μM). ", "Because the related alkaloids **57**, **60, 56-2**\\~**56-4**, **56-6**, and **56-7** were inactive against all tested cancer cell lines, a C-1 hydroxy group, C-12 acyloxy group, and C-15 acetoxy group found in **56-5** could be needed for antiproliferative activity of luciculine derivatives.", "\n\n3.2. ", "Hetisine-Type (Analogs of Kobusine) C~20~-Diterpenoid Alkaloids {#sec3dot2-molecules-24-02317}\n--------------------------------------------------------------------\n\nTested hetisine-type (analogs of kobusine) C~20~-diterpenoid alkaloids included four natural alkaloids, ryosenamine (**64**), 9-hydroxynominine (**65**), and torokonine (**66**), isolated from rhizoma of *Aconitum japonicum* subsp. *", "subcuneatum* \\[[@B27-molecules-24-02317],[@B28-molecules-24-02317]\\] ([Figure 6](#molecules-24-02317-f006){ref-type=\"fig\"}) and kobusine (**67**), purified from roots of *Aconitum yesoense* var. *", "macroyesoense* \\[[@B31-molecules-24-02317]\\] ([Figure 6](#molecules-24-02317-f006){ref-type=\"fig\"}). ", "Nineteen synthetic derivatives (**67-1**\\~**67-19**) \\[[@B18-molecules-24-02317],[@B21-molecules-24-02317],[@B30-molecules-24-02317],[@B46-molecules-24-02317],[@B47-molecules-24-02317]\\] ([Figure 6](#molecules-24-02317-f006){ref-type=\"fig\"}) prepared from **67** were tested also.", "\n\nAll tested hetisine-type (kobusine analogs) C~20~-diterpenoid alkaloids were evaluated for antiproliferative activity against four human tumor cell lines \\[[@B27-molecules-24-02317],[@B28-molecules-24-02317],[@B30-molecules-24-02317]\\] ([Table 5](#molecules-24-02317-t005){ref-type=\"table\"}). ", "Fifteen of the 23 alkaloids, both natural (**64**\\~**67**) and synthetic (**67-1**\\~**67-4**, **67-6**, **67-9**, **67-11**, **67-12**, **67-15**\\~**67-17**), were inactive (IC~50~ \\> 20 or 40 μM). ", "Kobusine derivatives **67-5**, **67-7**, **67-10**, **67-18**, and **67-19** exhibited the highest average potency over the four tested cell lines (A549, DU145, KB and KB-VIN; average IC~50~ 7.8, 6.1, 6.2, 6.8, and 4.7 μM, respectively), and alkaloids **67-8**, **67-13**, and **67-14** showed moderate potency (average IC~50~ 16.6, 14.3, and 11.6 µM, respectively). ", "However, while alkaloid **67-14** showed good cytotoxic activity (IC~50~ 9.6 μM) against DU145 cells, it was much less potent against A549, KB, and KB-VIN cells.", "\n\nAmong these analogs of **67**, esterification of C-15 in addition to C-11 increased potency significantly (compare **67-8** to **67-10**) or even converted an inactive to an active alkaloid (compare **67-3** to **67-5**, **67-6** to **67-7**, **67-16** to **67-18**). ", "Consequently, all of the most potent analogs (**67-5**, **67-7**, **67-10**, **67-18**, and **67-19**) of **67** were esterified at both C-11 and C-15.", "\n\nStriking observations from the data in [Table 5](#molecules-24-02317-t005){ref-type=\"table\"} were the degree and comparative ratio of KB/KB-VIN potency. ", "Five alkaloids (**67-5**, **67-7**, **67-10**, **67-18**, and **67-19**) were quite potent (IC~50~ \\< 10 µM) against KB-VIN. ", "Indeed, alkaloid **67-19** exhibited a significantly low IC~50~ value of 3.1 µM. The ratios of KB to KB-VIN (IC~50~ KB/IC~50~ KB-VIN) were greater than 0.73 for all active alkaloids, with many alkaloids displaying comparable potency against the two cell lines, in contrast with paclitaxel (ratio of 0.0067). ", "Alkaloid **67-19** showed over 1.3-fold selectivity with the greatest cytotoxic activity against KB-VIN (IC~50~ KB/IC~50~ KB-VIN: 1.32).", "\n\n3.3. ", "Hetisine-Type (Analogs of Pseudokobusine) C~20~-Diterpenoid Alkaloids {#sec3dot3-molecules-24-02317}\n--------------------------------------------------------------------------\n\nThe two tested natural hetisine-type (analogs of pseudokobusine) C~20~-diterpenoid alkaloids pseudokobusine (**68**) and 15-veratroylpseudokobusine (**68-11**) were purified from the roots of *Aconitum yesoense* var. *", "macroyesoense* \\[[@B31-molecules-24-02317],[@B32-molecules-24-02317]\\] ([Figure 7](#molecules-24-02317-f007){ref-type=\"fig\"}). ", "The 36 tested synthetic derivatives (**68-1**\\~**68-10**, **68-12**\\~**68-37**) \\[[@B18-molecules-24-02317],[@B21-molecules-24-02317],[@B30-molecules-24-02317],[@B32-molecules-24-02317],[@B46-molecules-24-02317],[@B47-molecules-24-02317],[@B48-molecules-24-02317],[@B49-molecules-24-02317]\\] ([Figure 7](#molecules-24-02317-f007){ref-type=\"fig\"}) were prepared from **68**.", "\n\nAll tested hetisine-type (**68** analogs) C~20~-diterpenoid alkaloids were evaluated for antiproliferative activity against four human tumor cell lines \\[[@B30-molecules-24-02317]\\] ([Table 6](#molecules-24-02317-t006){ref-type=\"table\"}). ", "Many alkaloids, both natural alkaloids (**68** and **68-11**) and synthetic analogs (**68-1**\\~**68-3**, **68-6**, **68-8**, **68-9**, **68-14**, **68-16**\\~**68-18**, **68-21**, **68-23**, **68-25**\\~**68-31**, **68-33**\\~**68-37**), were inactive (IC~50~ \\> 20 µM). ", "The pseudokobusine derivatives **68-5**, **68-15**, **68-19**, **68-20**, **68-24**, and **68-32** exhibited the highest average potency over the tested cell lines (A549, DU145, KB and KB-VIN; average IC~50~ 7.0, 5.2, 5.3, 7.4, 7.1, and 6.1 µM, respectively). ", "Alkaloids **68-7**, **68-10**, **68-12**, **68-13**, and **68-22** showed moderate potency over all tested cell lines (average IC~50~ 13.5-16.8 µM). ", "However, although alkaloid **68-10** showed good cytotoxic activity (IC~50~ 8.0 µM) against A549 cells, it was much less potent against DU145, KB, and KB-VIN cells.", "\n\nAmong the analogs of **68**, four C-11 mono-substituted alkaloids (**68-15**, **68-20**, **68-24**, and **68-32**) and two C-11,15 di-esterified alkaloids (**68-5** and **68-19**) exhibited average IC~50~ values of less than 10 μM. Certain C-11 (**68-7**, **68-10**, and **68-22**), C-6,11 (**68-4** and **68-12**) and C-6,15 (**68-13**) esterified alkaloids were generally less potent, while all C-6 (**68-3**, **68-6**, **68-14**, and **68-23**) and C-15 (**68-1**, **68-11**, **68-16**, **68-25**, **68-28**, and **68-30**) mono-substituted alkaloids, as well as the tri-substituted analog (**68-18**), were inactive. ", "Thus, all more active (IC~50~ \\< 10 µM) C~20~-diterpenoid alkaloids in this classification had an ester or ether group on the C-11 hydroxy and were 11-monoester/11,15-diester analogs of **68** (OH at C-6).", "\n\nThe data in [Table 6](#molecules-24-02317-t006){ref-type=\"table\"} led to noticeable observations about the degree and comparative ratio of KB/KB-VIN potency. ", "Six alkaloids (**68-5**, **68-15**, **68-19**, **68-20**, **68-24**, and **68-32**) were quite potent (IC~50~ \\< 10 µM) against KB-VIN. ", "Indeed, alkaloid **68-32** exhibited a low IC~50~ value of 5.2 µM. The ratios of KB to KB-VIN (IC~50~ KB/IC~50~ KB-VIN) were greater than 0.70 for all active alkaloids, with many alkaloids displaying comparable potency against the two cell lines, in contrast with paclitaxel (ratio of 0.0067). ", "Alkaloids **68-12**, **68-13**, and **68-20** showed over 1.3-fold selectivity with their greatest cytotoxic activity against KB-VIN (IC~50~ KB/IC~50~ KB-VIN: 1.34, 1.48, and 1.44, respectively).", "\n\nIn mechanism of action studies on selected diterpenoid alkaloids, the hetisine-type C~20~-diterpenoid alkaloid derivatives **68-7** and **68-22** showed important suppressive effects against Raji cells. ", "Further study indicated that **68-22** inhibited extracellular signal-regulated kinase phosphorylation but induced enhanced phosphoinositide 3 kinase phosphorylation, leading to accumulation of Raji cells in the G1 or sub G1 phase \\[[@B20-molecules-24-02317]\\]. ", "More investigation is certainly warranted.", "\n\n4. ", "Discussion {#sec4-molecules-24-02317}\n=============\n\nWe have synthesized acylated derivatives of various C~19~- and C~20~-diterpenoid alkaloids. ", "Totally, 199 natural alkaloids and their derivatives were evaluated against four to five human tumor cell lines. ", "Among all alkaloids, 128 alkaloids were non-toxic (IC~50~ \\> 20 or 40 µM) and 51 alkaloids showed moderate antiproliferative effects (average IC~50~ = 10--40 µM). ", "General summaries are described briefly below, and the most active compounds are shown in [Figure 8](#molecules-24-02317-f008){ref-type=\"fig\"}.", "\n\nAmong the aconitine-type C~19~-diterpenoid alkaloids, the fatty acid ester at C-8 and the anisoyl group at C-14 found in **17** may be important to the cytotoxic activity. ", "Compounds without the fatty acid ester at C-8 were inactive, and compounds with an unsubstituted benzoyl group at C-14 were less potent.", "\n\nAmong the C~19~-diterpenoid alkaloids, the most active alkaloids were lycoctonine-type C~19~-diterpenoid alkaloids with two different substitution patterns, C-1 (delcosine derivatives) and C-6 (delpheline derivatives). ", "Delcosine derivatives **34-6**, **34-8**, **34-10**, and **34-18**, which are acylated at the C-1 hydroxy, as well as delpheline derivatives **37-1**, **37-17**, and **37-18**, which are acylated at the C-6 hydroxy, exhibited the greatest potency over all tested cell lines, including MDR KB-VIN.", "\n\nAmong the lycoctonine-type (7,8-diol) C~19~-diterpenoid alkaloids, a C-1 acyloxy group and C-14 hydroxy group were important for improved antiproliferative activity. ", "The C-1,14 diacylated delcosine derivatives were generally less potent than corresponding C-1 monoacylated delcosine derivatives. ", "The 1-monoacylated alkaloids with the highest potency (IC~50~ 4−6 µM) against five tested cell lines contained 3-nitro-4-chloro- (**34-8**) and pentafluoro- (**34-18**) as well as 4-dichloromethyl- (**34-10**) benzoyl esters. ", "Two or one pentafluorinated benzoyl esters were also found in the two most consistently potent alkaloids (**34-19** and **34-20**) among the 1,14-diacyl and 1-acyl-14-acetyl derivatives.", "\n\nAmong the lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids, none of the tested compound reached the potency levels of the most active 7,8-diol compounds. ", "However, three 6-acylated delpheline derivatives **37-17**\\~**37-19** did show significant potency against the KB-VIN cell line (IC~50~ 4.22, 4.40, and 4.71 μM, respectively). ", "Interestingly, the two latter compounds contained fluorinated benzoyl esters. ", "In addition, among 19 tested delpheline derivatives, four compounds (**37-12**, **37-16**, **37-13**, and **37-19**) showed over two-fold selectivity between the MDR and parental cell lines (ratio of IC~50~ KB/IC~50~ KB-VIN: 2.15, 2.28, 2.31, and 2.57, respectively).", "\n\nNone of the 15 tested actaline- and napelline-type C~20~-diterpenoid alkaloids showed significant antiproliferative potency. ", "Only 12-benzoyllucidsuculine (**56-5**) with C-1 hydroxy, C-12 acyloxy, and C-15 acetoxy groups showed even weak potency.", "\n\nAmong C~20~-diterpenoid alkaloids, the most active alkaloids were hetisine-type C~20~-diterpenoid alkaloids with two different substitution patterns, C-11,15 (kobusine) and C-6,11,15 (pseudo-kobusine). ", "Hetisine-type C~20~-diterpenoid alkaloids **67-5**, **67-7**, **67-10**, **67-18**, **67-19**, **68-5**, **68-15**, **68-19**, **68-20**, **68-25**, and **68-32**, which are acylated or tritylated at the C-11 hydroxyl, exhibited the greatest potency over all tested cell lines, including MDR KB-VIN. ", "All five most active kobusine derivatives (**67-5**, **67-7**, **67-10**, **67-18**, and **67-19**) are acylated at both C-11 and C-15. ", "All tested derivatives with a hydroxy group at either C-11 or C-15 were inactive or much less active. ", "All six most active pseudo-kobusine derivatives (**68-5**, **68-15**, **68-19**, **68-20**, **68-25**, and **68-32**) contain a free hydroxy group at C-6. ", "The substituent at C-11 is either a benzoyl/cinnamoyl ester (**68-5**, **68-15**, **68-19**, **68-20**, and **68-25**) or a trityl ether (**68-32**). ", "Finally, the moiety at C-15 is a hydroxy group (**68-15**, **68-20**, **68-25**, and **68-32**) or benzoyl ester (**68-5**, **68-19**).", "\n\nFurthermore, previously our study, Antitumor properties and radiation-sensitizing effects of various types of novel derivatives prepared from C~19~- and C~20~-diterpenoid alkaloids were also investigated \\[[@B19-molecules-24-02317]\\]. ", "Two novel hetisine-type C~20~-diterpenoid derivatives (**68-7** and **68-20**) showed significant suppressive effects against the Raji non-Hodgkin's lymphoma cell line \\[[@B20-molecules-24-02317]\\].", "\n\n5. ", "Conclusions {#sec5-molecules-24-02317}\n==============\n\nWe have synthesized acylated derivatives of various C~19~- and C~20~-diterpenoid alkaloids. ", "All alkaloids and their derivatives were screened against four to five human tumor cell lines. ", "Alkaloids **37-2**, **37-9**, **37-17**, **37-18**, **56-5**, **67-7**, **67-14**, **67-19**, **68-4**, **68-12**, **68-20**, **68-22**, **68-24**, and **68-32** showed comparable potency against KB and KB-VIN cancer cell lines, and some alkaloids showed tumor- selective activity. ", "Alkaloids **37-12**, **37-13**, **37-16**, and **37-19** exhibited greater inhibitory activity against drug-resistant KB-VIN cells (2.15\\~2.57-fold) than the parental KB cells. ", "These results demonstrate that modified lycoctonine-type C~19~-diterpenoid alkaloids and hetisine-type C~20~-diterpenoid alkaloids are not substrates of P-gp and could be effective against P-gp overexpressing MDR tumors. ", "These promising new lead alkaloids merit continued studies to evaluate their potential as antitumor agents, particularly with enhanced resistant tumor selectivity. ", "In addition, our results from modification-based antitumor activity studies can be used for further development of anticancer drugs overcoming an MDR phenotype.", "\n\nThe author gratefully acknowledges Lee, K.H., Goto, M., Morris-Natschke, S.L., Ohkoshi, E., Zhao, Yu., ", "Li, K.P., Bastow, K.F., Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill; and Mizukami, M., Kaneda, K., Suzuki, Y., Shimizu, T., Kusanagi, N., Takeda, K., Haraguchi, M., Abe, Y., Kuwahara, N., Suzuki, S., Terui, A., Masaka, T., Munakata, N., Uchida, M., Nunokawa, M., Chiba, R., Kanazawa, R., Matsuoka, K., Suzuki, M., Ikuta, M., Asakawa, E., Tosho, Y., Nakata, A., Hasegawa, Y., Katoh, M., Kokubun, A., Uchimura, A., Mikami, S., Takeuchi, A., Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, for their helpful advice and support throughout this work.", "\n\nThis study was supported in part by NIH grant CA177584 from the National Cancer Institute awarded to K.H.L. as well as the Eshelman Institute for Innovation, Chapel Hill, North Carolina, awarded to M.G.\n\nThe authors declare no conflict of interest.", "\n\n{#molecules-24-02317-f001}\n\n{#molecules-24-02317-f002}\n\n###### \n\nChemical structures of lycoctonine-type (7,8-diol) C~19~-diterpenoid alkaloids **24**--**35**.", "\n\n![](", "molecules-24-02317-g003a)\n\n![](", "molecules-24-02317-g003b)\n\n###### \n\nChemical structures of lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids **36**-**54**.", "\n\n![](", "molecules-24-02317-g004a)\n\n![](", "molecules-24-02317-g004b)\n\n{#molecules-24-02317-f005}\n\n{#molecules-24-02317-f006}\n\n###### \n\nChemical structures of hetisine-type (analogs of pseudokobusine) C~20~-diterpenoid alkaloids **68**\\~**68-37**.", "\n\n![](", "molecules-24-02317-g007a)\n\n![](", "molecules-24-02317-g007b)\n\n{#molecules-24-02317-f008}\n\nmolecules-24-02317-t001_Table 1\n\n###### \n\nCytotoxic activity data for aconitine-type C~19~-diterpenoid alkaloids and derivatives **1**--**23**.", "\n\n Cell Line/IC~50~ (μM) ^1^ \n -------------------------------------- --------------------------- ----------- ------------ ------------ ------------ ---------------\n Aconitine (**1**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Deoxyaconitine (**2**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Jesaconitine (**3**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Deoxyjesaconitine (**4**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Aljesaconitine A (**5**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Secojesaconitine (**6**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **7** \\>20 \\>20 \\- \\- \\>20 \\>20\n Mesaconitine (**8**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Hypaconitine (**9**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Hokbusine A (**10**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **11** \\>20 \\>20 \\- \\- \\>20 \\>20\n 14-Anisoyllasianine (**12**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n *N*-Deethylaljesaconitine A (**13**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Aconine (**14**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Lipomesaconitine (**15**) 17.2 ± 2.3 \\- 20.0 ± 0.2 19.0 ± 1.0 10.0 ± 3.3 21.5 ± 0.9\n Lipoaconitine (**16**) 17.4 ± 1.1 \\- 15.5 ± 0.5 16.0 ± 0.3 13.7 ± 1.3 20.3 ± 1.1\n Lipojesaconitine (**17**) 7.3 ± 0.3 \\- 6.0 ± 0.2 6.7 ± 0.2 6.0 ± 0.2 18.6 ± 0.9\n Neolinine (**18**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Neoline (**19**) \\>20 \\>20 \\- \\- \\>20 \\>20\n 14-benzoylneoline (**20**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Isotalatizidine (**21**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Karacoline (**22**) \\>20 \\>20 \\- \\- \\>20 \\>20\n 3-Hydroxykaracoline (**23**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 8.4 ± 0.8 10.2 ± 0.9 5.8 ± 0.2 2405.4 ± 44.8\n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n\nmolecules-24-02317-t002_Table 2\n\n###### \n\nCytotoxic activity data for lycoctonine-type (7,8-diol) C~19~-diterpenoid alkaloids and synthetic analogs of delcosine **24**\\~**35**.", "\n\n Cell Line/IC~50~ (μM) ^1^ \n --------------------------------- --------------------------- ----------- -------------- ------------ -------------- ---------------\n Nevadensine (**24**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n *N*-Deethylnevadensine (**25**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n 18-Methoxygadesine (**26**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Virescenine (**27**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Delphinifoline (**28**) \\>20 \\>20 \\- \\- \\>20 \\>20\n *N*-Deethyldelsoline (**29**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Andersonidine (**30**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Pacifiline (**31**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Pacifinine (**32**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Pacifidine (**33**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Delcosine (**34**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-1** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-2** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-3** 20.6 ± 0.3 \\- 19.4± 1.0 17.9 ± 0.3 14.6 ± 0.6 17.1 ± 0.8\n **34-4** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-5** 18.7 ± 0.1 \\- 29.1 ± 1.6 25.8 ± 1.4 19.6 ± 0.3 21.1 ± 1.5\n **34-6** 7.7 ± 0.9 \\- 8.6 ± 6.0 15.8 ± 4.2 5.6 ± 1.2 8.6 ± 1.9\n **34-7** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-8** 4.5 ± 0.5 \\- 5.0 ± 0.1 5.9 ± 0.3 5.4 ± 0.3 5.6 ± 0.4\n **34-9** 24.8 ± 0.1 \\- 4.7 ± 0.1 12.2 ± 0.3 5.8 ± 0.4 \\>40\n **34-10** 4.8 ± 0.3 \\- 4.8 ± 0.7 5.7 ± 0.4 4.3 ± 0.5 5.3 ± 0.4\n **34-11** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-12** 26.5 ± 0.3 \\- \\>40 40.6 ± 2.5 27.8 ± 1.7 28.1 ± 3.0\n **34-13** 20.8 ± 1.7 \\- 32.4 ± 1.8 25.9 ± 2.4 23.0 ± 2.4 21.5 ± 1.3\n **34-14** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-15** 21.7 ± 1.6 \\- 30.2 ± 2.7 26.9 ± 1.4 20.7 ± 1.2 21.5 ± 3.6\n **34-16** 14.4 ± 2.1 \\- 20.1 ± 0.7 16.4 ± 2.1 13.6 ± 1.1 15.7 ± 0.8\n **34-17** 11.4 ± 1.4 \\- 10.4 ± 1.7 22.5 ± 1.5 10\\. 8 ± 1.9 11.8 ± 3.2\n **34-18** 4.7 ± 0.1 \\- 5.3 ± 0.2 9.2 ± 0.4 5.8 ± 0.6 9.5 ± 0.5\n **34-19** 4.9 ± 0.1 \\- 4.9 ± 0.1 5.3 ± 0.3 4.7 ± 0.1 4.9 ± 0.1\n **34-20** 4.8 ± 0.1 \\- 4.6 ± 0.3 6.0 ± 0.1 4.8 ± 0.4 4.9 ± 0.4\n **34-21** 20.8 ± 2.1 \\- 21.5 ± 0.6 21.4± 0.3 18.6 ± 1.7 15.0 ± 0.1\n **34-22** \\>40 \\- \\>40 \\>40 \\>40 39.1 ± 2.0\n **34-23** 23.8 ± 2.0 \\- 25.2 ± 1.0 23.3 ± 1.1 23.7 ± 1.1 22\\. 6 ± 0.3\n **34-24** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-25** 20.6 ± 1.2 \\- 21.3 ± 1.3 22.4 ± 1.2 20\\. 8 ± 2.1 18.0 ± 1.0\n **34-26** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-27** 18.6 ± 2.6 \\- 19.7 ± 2.0 20.6 ± 1.2 22.2± 1.8 19.8 ± 1.9\n **34-28** 33.0 ± 2.1 \\- 32.4 ± 1.7 31.1 ± 0.8 23.2 ± 1.1 40.0 ± 1.0\n **34-29** 23.8 ± 2.6 \\- 33.4 ± 1.7 29.8 ± 1.2 22.8 ± 1.7 22.6 ± 2.4\n **34-30** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-31** 17\\. 3 ± 2.2 \\- 23\\. 1 ± 0.5 20.0 ± 0.7 16.2 ± 1.8 17.4 ± 1.9\n **34-32** 16.5 ± 1.3 \\- 22.5 ± 0.8 \\- 8.71 ± 0.7 15.8 ± 0.8\n **34-33** 40.9 ± 5.3 \\- \\>40 \\>40 36.3 ± 1.0 29.3 ± 0.6\n **34-34** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-35** 21.2 ± 0.1 \\- 24.8 ± 1.6 24.6 ± 1.0 18.7 ± 1.2 21.7± 0.6\n **34-36** \\>40 \\- \\>40 \\>40 \\>40 \\>40\n **34-37** 23.8 ± 0.5 \\- 32.9 ± 1.0 22.6 ± 1.5 21.2 ± 0.1 19.2 ± 0.1\n **34-38** 11.2 ± 0.7 \\>20 \\- \\- 21.1 ± 3.9 19.5 ± 8.2\n **34-39** 29.7 ± 0.7 \\- 43.2 ± 1.8 32.0 ± 0.6 36.0 ± 0.4 45.1 ± 3.4\n **34-40** 18.5 ± 0.5 \\- 17.9 ± 0.5 15.5± 0.6 13.7± 0.1 14.2 ± 0.5\n **34-41** 22.9± 0.5 \\- 20.7 ± 2.1 20.5 ± 1.0 21.6 ± 0.1 24.4 ± 0.5\n **34-42** \\>20 \\>20 \\- \\- \\>20 \\>20\n 14-Acetyldelcosine (**34-43**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-44** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-45** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-46** \\>20 \\>20 \\- \\- \\>20 \\>20\n **34-47** \\>20 \\>20 \\- \\>20 \\>20 \\>20\n 14-Acetylbrowniine (**35**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 8.4 ± 0.8 10.2 ± 0.9 5.8 ± 0.2 2405.4 ± 44.8\n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n\nmolecules-24-02317-t003_Table 3\n\n###### \n\nCytotoxic activity data for lycoctonine-type (7,8-methylenedioxy) C~19~-diterpenoid alkaloids and synthetic analogs of delpheline **36**\\~**54**.", "\n\n Cell Line/IC~50~ (μM) ^1^ KB/KB-VIN Ratio \n ---------------------------------------------- --------------------------- ----------------- ----------- ------------- --------------- ------\n Delcorine (**36**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Delpheline (**37**) \\>20 \\>20 \\- \\>20 \\>20 \\-\n Pacinine (**38**) \\>20 \\>20 \\- \\>20 \\>20 \\-\n Yunnadelphinine (**39**) \\>20 \\>20 \\- \\>20 \\>20 \\-\n Melpheline (**40**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Bonvalotidine C (**41**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Deethyl-*N*-formylpaciline (**42**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Deethyl-*N*-formylpacinine (**43**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Isodelpheline (**44**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Pacidine (**45**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Eladine (**46**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Formyl-4,19-secopacinine (**47**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Formyl-4,19-secoyunnadelphinine (**48**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Iminoisodelpheline (**49**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Iminodelpheline (**50**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n Laxicyminine (**51**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Deethyl-19-oxoisodelpheline (**52**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n *N*-Deethyl-19-oxo-delpheline (**53**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n 19-Oxoisodelpheline (**54**) \\>40 \\- \\>40 \\>40 \\>40 \\-\n **37-1** 14.8 ± 3.8 7.4 ± 1.2 \\- 8.9 ± 2.0 8.3 ± 1.6 1.07\n **37-2** 38.1 ± 11.8 15.6 ± 5.4 \\- 23.3 ± 3.9 15.0 ± 6.5 1.55\n **37-3** 22.7 ± 0.3 17.2 ± 3.3 \\- 20.7 ± 0.9 17.7 ± 3.5 1.17\n **37-4** \\>20 \\>20 \\- \\>20 \\>20 \\-\n **37-5** 24.1 ± 2.7 17.1 ± 11.4 \\- 23.6 ± 0.4 17.4 ± 7.4 1.36\n **37-6** 18.7 ± 6.6 20.3 ± 7.1 \\- 20.1 ± 7.6 18.9 ± 5.0 1.06\n **37-7** 21.1 ± 9.2 16.6 ± 12.7 \\- 21.7 ± 11.6 17.9 ± 4.2 1.21\n **37-8** 28.7 ± 13.6 28.7 ± 7.2 \\- 24.3 ± 5.7 23.3 ± 3.7 1.04\n **37-9** 21.2 ± 4.7 12.6 ± 3.0 \\- 14.9 ± 4.9 11.9 ± 3.3 1.25\n **37-10** 20.9 ± 4.3 22.7 ± 6.0 \\- 19.1 ± 4.8 20.3 ± 2.7 0.94\n **37-11** 30.8 ± 13.3 28.9 ± 4.7 \\- 29.5 ± 3.5 27.5 ± 3.1 1.07\n **37-12** 19.9 ± 10.1 16.9 ± 6.7 \\- 14.6 ± 7.1 6.80 ± 5.0 2.15\n **37-13** 10.2 ± 2.6 15.1 ± 6.0 \\- 21.0 ± 9.4 9.10 ± 1.5 2.31\n **37-14** 22.4 ± 7.1 22.8 ± 8.5 \\- 25.9 ± 9.3 24.2 ± 4.4 1.07\n **37-15** 29.7 ± 11.6 29.0 ± 5.4 \\- 21.8 ± 1.4 18.7 ± 5.2 1.17\n **37-16** 20.0 ± 0.9 15.6 ± 2.6 \\- 14.8 ± 3.3 6.5 ± 2.2 2.28\n **37-17** 14.1 ± 2.9 13.2 ± 5.7 \\- 6.8 ± 1.7 4.2 ± 1.1 1.62\n **37-18** 16.5 ± 2.2 11.3 ± 7.9 \\- 5.4 ± 1.8 4.4 ± 0.8 1.23\n **37-19** 25.6 ± 1.2 19.8 ± 4.6 \\- 12.1 ± 7.8 4.7 ± 1.4 2.57\n **37-20** \\>20 \\>20 \\- \\>20 \\>20 \\-\n **37-21** \\>20 \\>20 \\- \\>20 \\>20 \\-\n **37-22** \\>20 \\>20 \\- \\>20 \\>20 \\-\n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 8.4 ± 0.8 5.8 ± 0.2 2405.4 ± 44.8 \\-\n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n\nmolecules-24-02317-t004_Table 4\n\n###### \n\nCytotoxic activity data for actaline and napelline-type C~20~-diterpenoid alkaloids **55**\\~**63** and synthetic analogs **56-1**\\~**56-7** of luciculine.", "\n\n Cell Line/IC~50~ (μM) ^1^ \n ---------------------------------------- --------------------------- ------------- ----------- ------------ ------------- ---------------\n Aconicarchamine A (**55**) \\>40 \\- \\>40 \\>40 \\>40 \\>40\n Lucidusculine (**57**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Flavadine (**58**) \\>20 \\>20 \\- \\- \\>20 \\>20\n 12-Acetyllucidusculine (**59**) \\>20 \\>20 \\- \\- \\>20 \\>20\n 1-Acetylluciculine (**60**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Dehydrolucidusculine (**61**) \\>20 \\>20 \\- \\- \\>20 \\>20\n Dehydroluciculine (**62**) \\>20 \\>20 \\- \\- \\>20 \\>20\n 12-Acetyldehydrolucidusculine (**63**) \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-1** \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-2** \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-3** \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-4** \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-5** 23.3 ± 6.1 28.1 ± 11.1 \\- \\- 31.8 ± 10.5 27.8 ± 1.9\n **56-6** \\>20 \\>20 \\- \\- \\>20 \\>20\n **56-7** \\>20 \\>20 \\- \\- \\>20 \\>20\n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 8.4 ± 0.8 10.2 ± 0.9 5.8 ± 0.2 2405.4 ± 44.8\n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n\nmolecules-24-02317-t005_Table 5\n\n###### \n\nCytotoxic activity data for hetisine-type C~20~-diterpenoid alkaloids **64**\\~**67** and synthetic derivatives **67-1**\\~**67-19** of kobusine.", "\n\n Cell Line/IC~50~ (μM) ^1^ KB/KB-VIN Ratio \n ---------------------------- --------------------------- ----------------- ----------- ------------ ------------ --------------- --------\n Ryosenamine (**64**) \\>40 \\- \\>40 \\>40 \\>40 \\>40 \n 9-Hydroxynominine (**65**) \\>40 \\- \\>40 \\>40 \\>40 \\>40 \n Torokonine (**66**) \\>40 \\- \\>40 \\>40 \\>40 \\>40 \n Kobusine (**67**) \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-1** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-2** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-3** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-4** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-5** 8.4 ± 1.4 9.3 ± 3.0 \\- \\- 6.0 ± 0.8 7.5 ± 3.7 0.80\n **67-6** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-7** 6.7 ± 2.4 7.1 ± 2.0 \\- \\- 5.3 ± 0.3 5.2 ± 1.2 1.02\n **67-8** 19.5 ± 3.3 15.3 ± 5.6 \\- \\- 13.9 ± 2.8 17.9 ± 1.8 0.78\n **67-9** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-10** 6.9 ± 1.7 7.0 ± 2.2 \\- \\- 5.3 ± 0.6 5.5 ± 0.7 0.96\n **67-11** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-12** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-13** 17.2 ± 0.9 13.2 ± 2.8 \\- \\- 12.7 ± 1.1 14.1 ± 1.0 0.90\n **67-14** 14.1 ± 0.7 9.6 ± 2.4 \\- \\- 11.7 ± 0.6 10.9 ± 0.7 1.07\n **67-15** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-16** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-17** \\>20 \\>20 \\- \\- \\>20 \\>20 \n **67-18** 8.1 ± 4.7 6.8 ± 2.0 \\- \\- 5.2 ± 0.6 7.1 ± 2.6 0.73\n **67-19** 5.5 ± 1.9 6.2 ± 3.1 \\- \\- 4.1 ± 0.7 3.1 ± 1.6 1.32\n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 8.4 ± 0.8 10.2 ± 0.9 5.8 ± 0.2 2405.4 ± 44.8 0.0067\n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n\nmolecules-24-02317-t006_Table 6\n\n###### \n\nCytotoxic activity data for hetisine-type C~20~-diterpenoid alkaloids pseudokobusine (**68**) and its synthetic analogs **68-1**\\~**68-37**.", "\n\n Cell Line/IC~50~ (μM) ^1^ KB/KB-VIN Ratio \n ---------------------------------------- --------------------------- ----------------- ------------ --------------- ------\n Pseudokobusine (**68**) \\>20 \\>20 \\>20 \\>20 \n **68-1** \\>20 \\>20 \\>20 \\>20 \n **68-2** \\>20 \\>20 \\>20 \\>20 \n **68-3** \\>20 \\>20 \\>20 \\>20 \n **68-4** 19.3 ± 4.5 15.3 ± 4.3 12.8 ± 1.7 10.2 ± 0.9 1.25\n **68-5** 8.8 ± 4.5 7.6 ± 2.5 5.2 ± 1.3 6.3 ± 0.6 0.83\n **68-6** \\>20 \\>20 \\>20 \\>20 \n **68-7** 15.4 ± 3.7 13.2 ± 2.0 11.1 ± 5.5 15.7 ± 1.5 0.70\n **68-8** \\>20 \\>20 \\>20 \\>20 \n **68-9** \\>20 \\>20 \\>20 \\>20 \n **68-10** 8.0 ± 5.1 15.3 ± 2.9 14.9 ± 3.6 20.1 ± 13.5 0.74\n 15-Veratroylpseudokobusine (**68-11**) \\>20 \\>20 \\>20 \\>20 \n **68-12** 16.0 ± 5.5 16.9 ± 7.8 19.7 ± 3.1 14.7 ± 7.0 1.34\n **68-13** 15.2 ± 6.4 16.6 ± 7.9 18.1 ± 4.3 12.2 ± 5.6 1.48\n **68-14** \\>20 \\>20 \\>20 \\>20 \n **68-15** 5.8 ± 0.7 7.2 ± 1.9 6.4 ± 0.8 6.4 ± 1.8 1.00\n **68-16** \\>20 \\>20 \\>20 \\>20 \n **68-17** \\>20 \\>20 \\>20 \\>20 \n **68-18** \\>20 \\>20 \\>20 \\>20 \n **68-19** 5.0 ± 1.1 5.2 ± 1.8 5.6 ± 1.2 5.6 ± 2.9 1.00\n **68-20** 6.8 ± 0.7 7.7 ± 3.8 8.9 ± 3.7 6.2 ± 1.3 1.44\n **68-21** \\>20 \\>20 \\>20 \\>20 \n **68-22** 17.9 ± 7.2 14.5 ± 7.2 15.7 ± 4.1 13.9 ± 3.3 1.13\n **68-23** \\>20 \\>20 \\>20 \\>20 \n **68-24** 8.4 ± 1.7 6.5 ± 0.5 7.0 ± 1.3 6.4 ± 0.9 1.09\n **68-25** \\>20 \\>20 \\>20 \\>20 \n **68-26** \\>20 \\>20 \\>20 \\>20 \n **68-27** \\>20 \\>20 \\>20 \\>20 \n **68-28** \\>20 \\>20 \\>20 \\>20 \n **68-29** \\>20 \\>20 \\>20 \\>20 \n **68-30** \\>20 \\>20 \\>20 \\>20 \n **68-31** \\>20 \\>20 \\>20 \\>20 \n **68-32** 6.4 ± 1.2 6.0 ± 3.3 6.6 ± 3.1 5.2 ± 1.0 1.27\n **68-33** \\>20 \\>20 \\>20 \\>20 \n **68-34** \\>20 \\>20 \\>20 \\>20 \n **68-35** \\>20 \\>20 \\>20 \\>20 \n **68-36** \\>20 \\>20 \\>20 \\>20 \n **68-37** \\>20 \\>20 \\>20 \\>20 \n **PXL**^2^ (nM) 4.8 ± 0.6 5.9 ± 1.9 5.8 ± 0.2 2405.4 ± 44.8 \n\n^1^ Values are means ± standard deviation; ^2^ Paclitaxel (PXL; nM) was used as an experimental control.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Q:\n\nNginx permissions with wordpress\n\nI am trying to set up wordpress on digitalocean with nginx. ", " I am running into permissions issues though. ", " When I upload a file or try to install a plugin I get the cannot create in directory warning. ", " So I came across the post Here that says I need to give nginx access to the folder. ", " So I executed the following: \nsudo chown -R www-data:www-data /path/to/folder\nsudo chmod -R 755 /path/to/folder\n\nThis works except now I cannot add and delete files with filezilla. ", " Obviously because the permissions to the folder are no longer with the me the user they are now with www-data.", "\nSo my question is what is the correct way to configure nginx to work with wordpress and still allow me to upload and delete files with ftp.", "\n\nA:\n\nWhen using digital ocean droplets you will probably be using sftp access to your server.", "\nTry the following commands in your terminal when logged in.", "\n\nAdd your currently logged in user to the www-data group:\nsudo usermod -aG www-data $USER\nThen change your vhost directory and all files and subdirectories to be owned by www-data group:\nsudo chown -R www-data:www-data /var/www\nSet the proper permissions so you can upload files via sftp, manage files via command-line, and upload plugins and media directly in WordPress:\nsudo chmod -R 774 /var/www\n\nHope this helps\nSaskia\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "PHILADELPHIA (CBS) –A teenager was caught on surveillance camera kicking a dog outside of a Center City pizza joint. ", "Those who work and live in the area say it’s part of an alarming trend of teens causing chaos.", "\n\nBusiness owners say students from nearby charter schools are creating chaos in Center City.", "\n\nIn the past few months, some places have even put age restrictions on who can enter after some disturbing incidents were caught on camera.", "\n\nThis all took place on Nov. 2 around 6:30 p.m. in front of Giovani’s Bar and Grill on the 1500 block of Chestnut Street. ", "Cashier Sarah Snyder was working.", "\n\n“So a customer came in to get food and these kids were in here. ", "They seemed nice, they seemed polite,” Snyder said.", "\n\nBut that all changed when the young kids followed the customer out the front door.", "\n\n“Nine, 10, 12, 13 — they threw water on him,” Snyder said.", "\n\nThe customer appears to throw his drink back at the group and then this.", "\n\n“They kicked his dog and then they ran off and stole his food,” Snyder said.", "\n\nIt’s not the first time the restaurant and other businesses between 15th and 16th Streets have had issues with kids and teens.", "\n\nJust this week, police say a young man kicked a side mirror off a car. ", "When the driver got out, the teen and at least three others, beat him.", "\n\n“Right now, it’s out of control,” Michael Dixon said.", "\n\nDixon, who patronizes many of the businesses, says he wants to see stepped up patrols in the area.", "\n\n“I think they just need a little more security around here,” Dixon said.", "\n\nMore security, and perhaps more respect.", "\n\n“Other kids the same age, they come in and they’ll take our tips. ", "They’ll steal tips from the jar,” Snyder said. ", "They came in one day and stole someone’s pizza before we could get them out of the door. ", "It’s all different kids doing the same things.”", "\n\nPolice have not made any arrests in the dog-kicking incident." ]

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[ " [DO NOT PUBLISH]\n\n IN THE UNITED STATES COURT OF APPEALS\n FILED\n FOR THE ELEVENTH CIRCUIT COURT OF APPEALS\n U.S.\n ________________________ ELEVENTH CIRCUIT\n OCT 15, 2010\n No. ", "10-12437 JOHN LEY\n Non-Argument Calendar CLERK\n ________________________\n\n D.C. Docket No. ", "1:05-cv-01930-GET\n\nPHILLIP R. NEELY,\n\n Plaintiff - Appellant,\n\n versus\n\n\nCITY OF RIVERDALE,\nIRIS JESSIE,\nIndividually and in her official capacity as city manager,\nTHETUS A. KNOX,\nindividually and in her official capacity as city police chief,\nT. MICHAEL MARTIN,\nindividually and in his official capacity as city hearing officer,\nWANDA WALLACE,\nindividually and in her official capacity as city councilwoman,\n\n Defendants - Appellees.", "\n\f ________________________\n\n Appeal from the United States District Court\n for the Northern District of Georgia\n ________________________\n\n (October 15, 2010)\n\nBefore MARCUS, PRYOR and ANDERSON, Circuit Judges.", "\n\nPER CURIAM:\n\n Phillip Neely appeals the denial of his motion to vacate an order that\n\nimposed sanctions against his attorney, Michael King. ", "Fed. ", "R. Civ. ", "P. 60(b). ", "We\n\naffirm.", "\n\n The district court did not abuse its discretion by denying Neely’s motion.", "\n\nNeely argues that he and King were denied due process, but King was given notice\n\nof the charge of misconduct and defended that misconduct in his objection to a\n\nrecommendation to grant the motion to impose sanctions. ", "See Attwood v.\n\nSingletary, 105 F.3d 610, 613 (11th Cir. ", "1997). ", "Neely also argues that the\n\nsanctions are excessive, but he failed to object to the amount requested by the City\n\nor the finding that the amount was reasonable. ", "Neely’s objection “comes too late.”", "\n\nStuart I. Levin & Assocs., ", "P.A. v. Rogers, 156 F.3d 1135, 1142 (11th Cir. ", "1998).", "\n\n We AFFIRM the denial of Neely’s motion to vacate.", "\n\n\n\n\n 2\n\f" ]

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[ "Q:\n\nTypescript declare an optional method on super prototype\n\nI have the following code:\nclass Test {\n value: any;\n\n getSomething() {\n // doSomething doesn't exist on type Test\n if (typeof this.doSomething === 'function') {\n return this.doSomething(this.value);\n }\n }\n}\n\nclass A extends Test {\n doSomething(value) {\n console.log(value);\n }\n}\n\nconst a = new A();\n\na.getSomething();\n\nI want the doSomething method to be optional. ", "If sub classes want to implement it, they could, but they don't have to. ", "How can I declare it in the super class as undefined and prevent the ts error?", "\n\nA:\n\nYou can declare the method as optional on the Test class\nclass Test {\n value: any;\n doSomething?(p: any): any;\n getSomething() {\n // doSomething doesn't exist on type Test\n if (typeof this.doSomething === 'function') {\n return this.doSomething(this.value);\n }\n }\n}\n\nclass A extends Test {\n doSomething(value) {\n console.log(value);\n }\n}\n\nconst a = new A();\na.getSomething();\n\nPersonal Note: you learn something new each day, had no idea it was possible, but I thought to myself what would be the syntax if this existed, and lo and behold it worked .", "\n\n" ]

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[ "Q:\n\nUsing aar Library with Qt\n\nis it possible to use a Android Studio Library (aar file) in a Qt app?", "\nThe problem is, that I want to implement a mobile App with Qt, but there is only a library for Android Studio. ", "Is it possible to include the library in the Qt project or have I to write a wrapper class for it?", "\nIf I have to implement a wrapper, do I have to use the JNI and are there any examples for using it with C++ and a Java lib? ", "\n\nA:\n\nI found the answer, that worked for me.", "\nFirst you have to unzip the aar file, so you can get your jar library file.", "\nThen you can follow the instructions in this link to include the library to your apk:\nhttp://doc.qt.io/qt-5/android3rdpartylibs.html\nWhen you have finished this, you have to implement your own Java wrapper class to interact with the library. ", "Therfore you have to use the QAndroidJniObject class from Qt. ", "Here are more information about it.", "\nhttp://doc.qt.io/qt-5/qandroidjniobject.html\nYou could also have a look at this example, where they use their own java class. ", "http://doc.qt.io/qt-5/qtandroidextras-notification-example.html\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "yeah, 3-bet is better option pf\nI think you have to play stacks postflop or fold on the flop consider his bet size. ", "AK seems quite strong, so I´d raise to 0.85$ and call shove. ", "If you only think his range overbetting pot is AA+ then fold is also ok" ]

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[ "/*\nCOPYRIGHT STATUS:\n Dec 1st 2001, Fermi National Accelerator Laboratory (FNAL) documents and\n software are sponsored by the U.S. Department of Energy under Contract No.", "\n DE-AC02-76CH03000. ", "Therefore, the U.S. Government retains a world-wide\n non-exclusive, royalty-free license to publish or reproduce these documents\n and software for U.S. Government purposes. ", " All documents and software\n available from this server are protected under the U.S. and Foreign\n Copyright Laws, and FNAL reserves all rights.", "\n\n\n Distribution of the software available from this server is free of\n charge subject to the user following the terms of the Fermitools\n Software Legal Information.", "\n\n Redistribution and/or modification of the software shall be accompanied\n by the Fermitools Software Legal Information (including the copyright\n notice).", "\n\n The user is asked to feed back problems, benefits, and/or suggestions\n about the software to the Fermilab Software Providers.", "\n\n\n Neither the name of Fermilab, the URA, nor the names of the contributors\n may be used to endorse or promote products derived from this software\n without specific prior written permission.", "\n\n\n\n DISCLAIMER OF LIABILITY (BSD):\n\n THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS\n \"AS IS\" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT\n LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS\n FOR A PARTICULAR PURPOSE ARE DISCLAIMED. ", "IN NO EVENT SHALL FERMILAB,\n OR THE URA, OR THE U.S. DEPARTMENT of ENERGY, OR CONTRIBUTORS BE LIABLE\n FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR\n CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT\n OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR\n BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF\n LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT (INCLUDING\n NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS\n SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.", "\n\n\n Liabilities of the Government:\n\n This software is provided by URA, independent from its Prime Contract\n with the U.S. Department of Energy. ", "URA is acting independently from\n the Government and in its own private capacity and is not acting on\n behalf of the U.S. Government, nor as its contractor nor its agent.", "\n Correspondingly, it is understood and agreed that the U.S. Government\n has no connection to this software and in no manner whatsoever shall\n be liable for nor assume any responsibility or obligation for any claim,\n cost, or damages arising out of or resulting from the use of the software\n available from this server.", "\n\n\n Export Control:\n\n All documents and software available from this server are subject to U.S.\n export control laws. ", " Anyone downloading information from this server is\n obligated to secure any necessary Government licenses before exporting\n documents or software obtained from this server.", "\n*/\n\npackage org.dcache.ftp.door;\n\nimport org.apache.commons.math3.stat.descriptive.", "SummaryStatistics;\n\nimport java.io.", "PrintWriter;\nimport java.time.", "Duration;\nimport java.time.", "Instant;\nimport java.util.", "Optional;\n\nimport static java.time.temporal.", "ChronoUnit.", "SECONDS;\nimport static org.dcache.util.", "Strings.*;", "\n\n/**\n * <p>Title: GFtpPerfMarker.java</p>\n *\n * <p>Description: GridFTP Performance Marker Implementation</p>\n *\n * <p>Copyright: Copyright (c) 2005</p>\n *\n * <p>Company: FNAL</p>\n *\n * @author AIK\n * @version 1.0\n *\n *\n * $Id: GFtpPerfMarker.java,v 1.2 2005-10-26 17:56:41 aik Exp $\n */\n\n/**\n *\n * NO SYNCHRONIZATION done (yet) !!!", "\n */\npublic class GFtpPerfMarker {\n private static final String _cvsId = \"$Id: GFtpPerfMarker.java,v 1.2 2005-10-26 17:56:41 aik Exp $\";\n\n private long _timeStamp;\n private long _stripeIndex;\n private long _stripeBytesTransferred;\n private long _totalStripeCount;\n private boolean _hasBeenUpdated;\n private Optional<Instant> _stalledSince = Optional.empty();\n private final SummaryStatistics _bandwidth = new SummaryStatistics();\n private Instant lastUpdated = Instant.now();\n\n /** Constructor */\n public GFtpPerfMarker( long stripeIndex, long totalStripeCount ) {\n _timeStamp = System.currentTimeMillis();\n _stripeIndex = stripeIndex;\n _totalStripeCount = totalStripeCount;\n _stripeBytesTransferred = 0;\n }\n\n // Getters\n //\n /** */\n public long getTimeStamp() { return _timeStamp; }\n /** */\n public long getStripeIndex() { return _stripeIndex; }\n /** */\n public long getstripeBytesTransferred() { return _stripeBytesTransferred; }\n /** */\n public long getStripeCount() { return _totalStripeCount; }\n\n public Optional<Instant> stalledSince() {\n return _stalledSince;\n }\n\n public Optional<Instant> lastUpdated() {\n return _hasBeenUpdated\n ? ", "Optional.of(Instant.ofEpochMilli(_timeStamp))\n : Optional.empty();\n }\n\n // Setters\n //\n /** set Time Stamp*/\n public void setTimeStamp(long timeStamp) {\n _timeStamp = timeStamp;\n _hasBeenUpdated = true;\n }\n /** update Time Stamp - set current time */\n public void updateTimeStamp() {\n setTimeStamp(System.currentTimeMillis());\n }\n\n /** */\n public void setStripeBytesTransferred(long byteCount) {\n _bandwidth.addValue(calculateBandwidth(byteCount));\n\n if (_stripeBytesTransferred == byteCount) {\n if (!_", "stalledSince.isPresent()) {\n _stalledSince = Optional.of(Instant.now());\n }\n } else {\n _stalledSince = Optional.empty();\n }\n _stripeBytesTransferred = byteCount;\n }\n\n public SummaryStatistics getBandwidthStatistics()\n {\n return _bandwidth.copy();\n }\n\n private double calculateBandwidth(long byteCount) {\n long delta = byteCount - _stripeBytesTransferred;\n Instant now = Instant.now();\n Duration elapsed = Duration.between(lastUpdated, now);\n lastUpdated = now;\n double elapsedSeconds = (double)elapsed.getNano() / SECONDS.getDuration().toNanos() + elapsed.getSeconds();\n return delta / elapsedSeconds;\n }\n\n // More Setters\n //\n\n /** */\n public void setBytesWithTime(long byteCount, long time) {\n setStripeBytesTransferred(byteCount);\n setTimeStamp(time);\n }\n\n /** Set counter stripeBytesTransferred by byteCountAdd and update timestamp\n */\n public void setBytesWithTime(long byteCount) {\n setStripeBytesTransferred(byteCount);\n updateTimeStamp();\n }\n /** increment counter stripeBytesTransferred by byteCountAdd and update timestamp */\n public void addBytesWithTime(long byteCountAdd ) {\n setStripeBytesTransferred(_stripeBytesTransferred + byteCountAdd);\n updateTimeStamp();\n }\n\n // Conversion to string\n //\n\n /** @return String formatted according gridftp protocol extension to be sent to the ftp control line\n */\n public String getReply(){\n long sec = _timeStamp/1000;\n long hms = (_timeStamp%1000)/100; // hundreds of millisec; one digit only\n String s =\n \"112-Perf Marker\\r\\n\"\n +\" Timestamp: \" +sec +\".\" ", "+hms+ \"\\r\\n\"\n +\" Stripe Index: \"+_stripeIndex+\"\\r\\n\"\n +\" Stripe Bytes Transferred: \"+_stripeBytesTransferred+\"\\r\\n\"\n +\" Total Stripe Count: \"+_totalStripeCount+\"\\r\\n\"\n +\"112 End.\";", "\n /** @todo: bug in grid ftp client implementation, it check for '.' ", "at the end,\n * '.' ", "is not in standard/\n */\n\n // Globus Grid Ftp has dot '.' ", "in \"112 End.\\r\\n\",\n // this is not in standard GWD-R: GridFTP: Protocol Extensions to FTP... 4/2003\n return s;\n }\n\n /** @return String - one line printout */\n public String toString(){\n long sec = _timeStamp/1000;\n long hms = (_timeStamp%1000); // hundreds of millisec; one digit only\n String s = \"GFtpPerfMarker: Timestamp=\" +sec +\".\" ", "+hms\n +\"; StripeIndex=\" +_stripeIndex\n +\"; StripeBytesTransferred=\" +_stripeBytesTransferred\n +\"; TotalStripeCount=\" +_totalStripeCount\n +\";\";\n return s;\n }\n\n public void getInfo(PrintWriter pw)\n {\n pw.println(\"Transferred: \" + describeSize(getstripeBytesTransferred()));\n pw.println(\"Last updated: \" + describe(lastUpdated()));\n SummaryStatistics bandwidth = getBandwidthStatistics();\n if (bandwidth.getN() > 0) {\n pw.println(\"Bandwidth: \" + describeBandwidth(bandwidth));\n }\n Optional<Instant> stall = stalledSince();\n if (stall.isPresent()) {\n pw.println(\"Stalled since: \" + describe(stall));\n }\n }\n}\n\n//\n// $Log: not supported by cvs2svn $\n// Revision 1.1.2.2 2005/10/14 21:48:00 aik\n// <No Comment Entered>\n//\n// Revision 1.1.2.1 2005/10/05 22:54:09 aik\n// GridFtp Perfomance Marker class\n//\n//\n" ]

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[ "\"I'm friends with [Obama's former aide] Reggie Love and I was at the White House,\" Munn explained. \"", "I looked up and realized I was in the Oval Office.", "\n\n\"Of course, I'm texting because that's what I'm always doing. ", "I am texting somebody and I look up and I see Obama and I look back down - it's not registering that it's him. ", "I totally gave him the brush-off, like, 'Oh hey, what's up, Obama?'\"", "\n\nMunn continued: \"I had to do a double-take, like, 'Oh my God, I am so sorry'. ", "It was so embarrassing. ", "I was like, 'I don't want you to think that I was the girl that was like uhhh'.\"" ]

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[ "\n\n\n\nProduced by readbueno, Suzanne Shell and the Online\nDistributed Proofreading Team at http://www.pgdp.net (This\nfile was produced from images generously made available\nby The Internet Archive/American Libraries.)", "\n\n\n\n\n\n\n------------------------------------------------------------------------\n\n\n\n\n Fifty Years of Freedom\n\n WITH MATTERS OF VITAL IMPORTANCE TO BOTH THE\n WHITE AND <DW52> PEOPLE OF\n THE UNITED STATES\n\n\n —BY—\n\n REV. ", "FRANCIS J. GRIMKE, D. D.\n\n\n Delivered before the Presbyterian Council in the Madison Street\n Presbyterian Church, Baltimore, Maryland, October 17, 1913.", "\n And before the Fifteenth Street Presbyterian Church,\n Washington, D. C., October 26, 1913.", "\n\n \"Oh, speed the moment on\n When Wrong shall cease, and Liberty and Love\n And Truth and Right throughout the\n earth be known\n As in their home above.\"", "\n\n -------\n\n \"Voice of a ransomed race, sing on\n Till Freedom's every right is won,\n And slavery's every wrong undone!\"", "\n\n -------\n\n \"Sail on! ", "The morning cometh,\n The port ye yet shall win;\n All all the bells of God shall ring\n The good ship bravely in!\"", "\n\n ----------\n\n PRINTED BY REQUEST\n\n------------------------------------------------------------------------\n\n\n\n\n FIFTY YEARS OF FREEDOM.", "\n\n LEVITICUS 25:11.", "\n\n A JUBILEE SHALL THAT FIFTIETH YEAR BE UNTO\n YOU.", "\n\n\nOn the twenty-second of September, 1862, President Lincoln issued his\nPreliminary Proclamation, which was in the nature of a notice to the\nstates in rebellion, that unless they returned to their allegiance\nwithin a specified time the slaves within their borders would be\ndeclared free. ", "The time expired without accomplishing the desired\nresult. ", "Accordingly on January 1, 1863, the President issued his\nSupplemental Proclamation manumitting the slaves within the rebellious\nstates. ", "This did not, of course, set them free. ", "They were still slaves\nand continued to be as long as the war lasted. ", "Freedom did not come, as\na matter of fact, until the surrender of Lee at Appomattox Courthouse\nApril 9, 1865. ", "The effectiveness of the Proclamation depended upon\ncrushing the rebellion. ", "It was the victorious army of the North, under\nthe leadership of General Grant, that gave efficacy to the Proclamation.", "\nFor all practical purposes, however, we may assume that fifty years have\nelapsed since freedom came to us as a race. ", "Fifty years is a long time\nin the history of an individual, but not very long in that of a race. ", "It\nis sufficiently long, however, to make it worth while for us to stop and\nthink a little about what these fifty years have meant to us, and to see\nif there are any lessons in them that may be helpful to us as we enter\nupon the second half of a century of freedom.", "\n\nAt the end of these fifty years we find:\n\nI. That we have made considerable progress. ", "We are not now where we were\nfifty years ago. ", "We are not as poor; we are not as ignorant; we are not\nas morally debased. ", "The plane upon which we stand now is higher. ", "This\nprogress, in some respects, has been unparalleled. ", "It is not necessary\nfor me to speak in detail of what has been accomplished along\neducational lines. ", "The record is before the whole country. ", "No one can\nread the last report of the Commissioner of Education of the National\nGovernment without realizing that very marvelous changes for the better\nhave taken place in the condition of the <DW52> people. ", "The facts as\npresented there, touching the number of public schools and public school\nteachers ministering to the intellectual wants of this race, as well as\nthe large number of higher educational institutions having the same end\nin view, show conclusively that conditions now are very different and\nvery much superior to what they were fifty years ago. ", "The large number\nof teachers, lawyers, doctors, ministers, now to be found among us, as\ncompared with fifty years ago, show the same thing.", "\n\nNor need I speak of the changed condition that these fifty years have\nwrought in our economic condition. ", "We are still poor; we still have to\nstruggle to make ends meet, to keep the wolf from the door; but there\ncan be no doubt that we are very much better off now than we were fifty\nyears ago. ", "We live in better houses; we dress better; we eat better\nfood; we own more property; we have more on deposit in banks and other\nsaving institutions; we have more invested in business; we travel more;\nwe give more to religion, to charity, to education. ", "Even our worst\nenemies, however, they might wish it were otherwise, will hardly be\nfound affirming that we are no farther on materially than we were fifty\nyears ago, that no substantial progress has been made by the race. ", "In\nevery direction the evidences are too plainly apparent to be denied. ", "The\nfollowing statement, taken from the declarations of the National\nBusiness League at its recent session in Philadelphia, tells in a word\nthe simple story of what has been accomplished during these fifty years:\n\"Starting half a century ago, without experience, without education, and\nwithout property, we to-day own and pay taxes on 20,000,000 acres of\nland, an area as large as the State of South Carolina; we own and\ncontrol 100 insurance companies, 300 drug stores, 64 banks, 450\nnewspapers, and more than 20,000 other businesses of various kinds, and\nthe total wealth of American <DW64>s in land, homes, schools, churches,\nand other forms of property, amounts to more than $700,000,000.", "\n\n\"In submitting this brief record of material progress, we do not\noverlook the advance made in other directions. ", "Fifty years ago more than\n90 per cent of the race was wholly illiterate. ", "To-day more than 70 per\ncent can both read and write.\"", "\n\nII. ", "At the end of these fifty years we find the race still aspiring,\nstill wishing to go forward. ", "The progress that has been made is not\nsomething that has been forced upon the race against its will, as\nmembers of it are forced to ride in \"Jim Crow\" cars in the South; it is\nwhat the race has wished to do. ", "It is not now, and never has been\nwilling to remain in the condition in which slavery left it. ", "From the\nvery beginning there has been the desire for better things, for enlarged\nopportunities. ", "And it still has dreams and visions of larger and better\nthings which it hopes some day to realize and towards which it is still\npressing. ", "Any one who is calculating upon a retrograde movement on the\npart of the race will be sadly disappointed, if we may judge from what\nthese last fifty years have revealed of capacity and aspiration on its\npart. ", "The outlook, in some respects, may be dark, but it is not because\nof any lack of interest in matters material and educational, or because\nof any evidence of decay, of the growth of demoralizing tendencies in\nthe race as a whole. ", "There is, of course, in all races an idle, vicious,\nlawless, dare-devil, reprobate element. ", "And such an element we find\namong us, especially in the urban population; but the existence of such\nan element in the <DW64> race is no more evidence of a retrograde\ntendency on the part of the race as a whole, than the presence of such\nan element among the whites is an evidence of a retrograde movement on\nthe part of the white race as a whole. ", "The <DW64> race makes no claim to\nsuperiority over other races. ", "It is simply human like other races. ", "The\nsame evidences of depravity exhibited by other races it also exhibits,\nneither more nor less. ", "As bad as is a certain element among us, it is no\nworse than the same element in other races. ", "The trend of the race is not\ndownward, but upward; is not backward, but forward. ", "Moral progress, of\ncourse, is always slower than any other kind of progress. ", "It is very\nmuch easier to train the head than to train the heart; it is very much\neasier to develop brain power than moral power. ", "The most difficult thing\nin the world is to keep men straight morally, is to build up, to develop\na strong, upright, virtuous character in men of all races. ", "And this must\nbe borne in mind in estimating the moral progress of the race as\ncompared with its intellectual and material advancement. ", "If progress\nhere has been slower, it is simply because that kind of progress is\nslower among all races. ", "That the race is responding, in a measure, to\nthe many agencies that are at work for its moral and spiritual uplift\ncan hardly be doubted; nor can there be any doubt that there is an\nelement, and a steadily increasing element among us, that is laying more\nand more emphasis upon character, upon upright living.", "\n\nIII. ", "At the end of these fifty years, we find, and very naturally, as\nthe result of the progress that has been made in knowledge, in material\nresources, in social advancement—a growing self-respect on the part of\nthe race, which makes it very much more sensitive as to the deprivation\nof its rights, very much more restive under injustice, oppression, and\nall invidious distinctions. ", "It would be strange if it were not so. ", "You\ncannot surround a man with conditions which tend to develop his manhood,\nhis self-respect, and expect him to quietly acquiesce in any line of\nconduct which aims to humiliate him, to force him down beneath the level\nof what he feels to be his due. ", "The oppressive measures which the\nslave-holders took to keep the slaves in an attitude of subserviency by\nshutting all light, by keeping them in darkness, by depriving them of\nall opportunities of improvement, was the only safe, the only wise\ncourse to pursue. ", "And even under such circumstances, under such rigid\nenforcement of repressive measures, the spirit of resistance was not\nentirely extinguished. ", "How much less is it to be expected now that we\nshould quietly submit to unjust treatment, to invidious distinctions!", "\nThe race is becoming more and more alive to its rights, and, as it\nadvances, this sense of what belongs to it, of what it is entitled to\nwill increase rather than diminish. ", "There is no way by which this\ngrowing insistent demand for its rights on its part can be arrested\nexcept by recognizing these rights, or, by forcing the race back into\nthe condition of intellectual and moral darkness in which it was before\nthe great era of freedom, or, by killing it off, either slowly by\nshutting it out of all productive industries, or by the wholesale\nmassacre of it.", "\n\nThe last two lines of action, on the part of the dominant race, are\namong the possibilities, but scarcely among the probabilities of the\nfuture. ", "The <DW64> in this country can never, never again be forced back\ninto the condition in which he was before the War. ", "Nor is there any\nlikelihood of a wholesale slaughter of the race. ", "There is very little\nhesitancy or compunction about killing an individual or a small group of\nindividuals, but when it comes to making war on the race as a whole,\nwith a view to exterminating it, even our worst enemies will hesitate,\nwill hardly venture upon so violent a measure; if not from a sense of\nright, at least, from fear of arousing the moral sentiment of the\ncivilized world. ", "The race is not likely to be less insistent in the\nfuture in demanding its rights than it is now at the end of the first\nhalf century of growth, of development.", "\n\nIV. ", "At the end of these fifty years of freedom, in spite of the\nremarkable progress that we have made along all lines, we find race\nprejudice increasing instead of diminishing. ", "The remarkable record of\nprogress that we have made has had no appreciable influence, so far as\nappears on the surface, in lessening the feeling of hostility to us.", "\nRace prejudice is stronger, is more bitter, more aggressive to-day than\never before. ", "The enemies of the race are more united and more determined\nthan ever to throw themselves across the pathway of our progress and to\ncompel us by sheer brute force, whatever our attainments may be, into a\nposition of permanent inferiority. ", "Not content with what has already\nbeen done to humiliate us, it is now demanding segregation, is now\ninsisting upon restricting the rights of <DW52> people to live in\ncertain prescribed sections of communities only. ", "And it has become so\nemboldened, so insolently aggressive that it is demanding segregation\namong the employees of the General Government itself. ", "And its demand is\nbeing acceded to. ", "Segregation, as a matter of fact, has already begun in\nsome of the Departments of the Government. ", "A bill recently introduced\ninto Congress makes it a criminal offense to mix the races—to have white\nand clerks working together in the same room. ", "For nearly a half\ncentury white and clerks have worked side by side, and nothing\nwas thought of it; but now through this insane desire to humiliate a\nrace, to impress it more and more with its inferiority, it is now\nproposed to make it a crime, not under laws enacted by <DW64>-hating\nSouthern legislatures, but by the National Government itself, which is\nsupposed to represent all the people, and to represent equality of\nrights for all the people. ", "That prejudice is increasing; that more and\nmore the effort is being made, and in ever-widening areas, to hedge us\nabout with limitations, with restrictions which are not imposed upon\nother elements of the population, is manifest to any one whose eyes are\nopen to what is going on in the country, not in one section only, but in\nall sections.", "\n\nV. At the end of these fifty years, we find nearly all the rights\nguaranteed to us under the constitution, especially under the Fourteenth\nand Fifteenth Amendments, practically nullified in a large section of\nthe country. ", "In the South we have been disfranchised. ", "We have no rights,\ncivil or political, which the white man is bound to respect. ", "The only\ngood <DW64> in the estimation of the dominant sentiment of the South\nto-day after fifty years of freedom, is the <DW64> who knows his place,\nand who is willing to keep his place of subjection, of subordination to\nthe white man.", "\n\nVI. ", "At the end of fifty years, in spite of the facts just narrated, with\na full knowledge of the gross injustice from which the <DW52> man is\nsuffering, the rest of the white people of the country, as a whole, are\nfound standing silently by looking on while this cruel and relentless\nwarfare against the race is going on, with only occasionally a word of\nprotest, or of mild remonstrance. ", "The great mass of the white people in\nother sections of the Union, seemingly, cares nothing about what\ntreatment is accorded to us. ", "They don't seem to think that it is a\nmatter about which they need to concern themselves. ", "If there is any\nfeeling at all it is rather one of sympathy with the oppressor.", "\n\nHow white men of the North and West whose fathers fought and died to\nsave the Union, and through whom freedom and the great amendments to the\nconstitution came, can stand silently by and see the same rebel spirit\nthat sought to destroy the Union set upon the <DW52> man and rob him of\nhis rights—the very rights that came to him as the result of the blood\nshed by their fathers, I have never been able to understand. ", "The sons of\nthe rebels are still true to the principles for which their fathers\nfought and died. ", "It is only in the North and West, among the descendants\nof the men who fought and died for the Union, that we find the\nprinciples for which their fathers stood, forgotten or cowardly\nsurrendered. ", "For these men to allow the <DW52> man to be robbed of his\nrights by the descendants of those who fought to destroy the Union and\nto perpetuate slavery is to dishonor the memory of their fathers; is\nvirtually to say, that they were wrong, and that the rebels were right.", "\nSuch an attitude is an affront to every loyal white man who fell during\nthe war or who fought for the Union and the cause of freedom. ", "It is\namazing that the descendants of these brave men should be so little\nconcerned about matters for which their fathers were willing to lay down\ntheir lives. ", "Shame on such descendants!", "\n\nVII. ", "At the end of these fifty years, in spite of the indifference of\nthe many we still have left, however, a remnant of men and women with\nthe spirit of the old abolitionists—a remnant of men and women who stand\nsquarely, uncompromisingly for the principles of liberty, of equality,\nof fraternity for all; and who, in one way and another, have shown their\nsympathy with us in the efforts we are making to develop ourselves and\nto maintain our rights. ", "The number is small; but small as it is we are\nthankful for their sympathy and support—thankful to know that we are not\nleft in our weakness to fight our battles alone. ", "It encourages us to\nknow that in the city of Boston, there is an A. E. Pillsbury and a\nMoorfield Story; in the city of New York, an Oswald Garrison Villard; in\nthe city of Cincinnati, a J. B. Foraker; in the city of Philadelphia, a\nJohn Elmer Milholland; in the city of Washington, a Wendell Phillips\nStafford; in the city of Chicago, a Jane Addams; in the United States\nSenate, a Moses E. Clapp. ", "There are others equally worthy of mention who\nare known to be our friends, our sympathizers, our well-wishers.", "\n\nVIII. ", "At the end of these fifty years of freedom, we find ourselves shut\nout of a great many avenues of employment. ", "There are not many things\nthat we can get to do. ", "This is due mainly to race antipathy, to a\ngrowing indisposition on the part of the whites, to work with us. ", "The\noutlook in this respect is not growing brighter, but rather darker and\ndarker. ", "The disposition seems to be to limit our activities to the most\nmenial occupations, or to shut us out entirely. ", "This is especially true\nin the North; and the same sentiment is also growing in the South, and\nwould grow very much more rapidly than it has, but for lack of white\nlabor supply.", "\n\nIX. ", "At the end of these fifty years of freedom, we find that one of the\nchief sources of demoralization to the race is strong drink. ", "A careful\nexamination of the facts as they exist, and as they have existed during\nthese fifty years will show that to it, more than to any other single\ninfluence, the bad record of crime which the race has made and is still\nmaking, is due. ", "It has been an unmitigated curse to the race, eating up\nits hard earnings, sapping its physical strength, engendering idle and\nvicious habits, and breaking down character at all points. ", "Thousands of\nour young men are finding their way into saloons and into gambling and\nother places of demoralization closely affiliated with them. ", "Strong\ndrink is responsible for most of the things that have given us a black\neye, that have furnished the enemies of the race with the materials\nwhich they have used in the assaults which they have made upon us from\ntime to time. ", "The intemperate <DW64> who is found lurking about these\ndrinking places is the one who is taken as representative of the race;\nand in this way the race's good name has been injured and is still being\ninjured. ", "The race has not escaped during these fifty years the blighting\neffects of strong drink, especially, in the cities, is this fact most\nnoticeable.", "\n\nX. At the end of these fifty years another fact should be noted in\npassing, we have grown in numbers, we have more than doubled in\nnumerical strength. ", "In spite of many adverse circumstances—in spite of\ndisease and poverty, bad sanitary conditions and an enormous death rate,\nthe race has not only during these fifty years been able to maintain its\nown, but has steadily increased in numbers. ", "There is no evidence, at the\nend of the first half century of freedom, that the race is dying out;\nthat it is deficient in physical stamina.", "\n\nSuch are some of the facts that stand out in this record of fifty years.", "\n\nIn the light of these facts, as we enter upon the second half of the\ncentury of freedom, there are a few things that we ought to impress\nourselves with; and a few things that ought to be said to our white\nfellow citizens.", "\n\nI. A word to ourselves. ", "There are certain things that we need to\nthoroughly impress ourselves with.", "\n\n(1). ", "With the importance of being industrious. ", "A lazy, thriftless,\nindolent race is bound to go to the wall. ", "The necessity of work on the\npart of everybody must be fully appreciated ourselves and must be\ncarefully instilled into the young people who are to take our places\nwhen we are gone. \"", "The man who will not work,\" the apostle says,\n\"neither shall he eat.\" ", "And this should be a fundamental principle with\nus. ", "The lazy man should be despised, should be driven out, should be\nshown no consideration. \"", "The idle man's brain is the devil's workshop,\"\nis an old saying, but it is a true one; and unless we continue to train\nthe race to the idea of steady, fixed employment as the proper, normal\ncondition for every one to sustain to the social organism of which he is\na part, the devil will be sure to get his work in, and use the\nunemployed hand and brain for evil purposes.", "\n\n(2). ", "We need to impress ourselves with the importance of being\nefficient. ", "We must know how to do things; we must know how to do things\nwell. ", "It isn't enough that a thing is done; it must be well done.", "\nQuality in work is the thing that tells; and more and more as\ncompetition increases we must impress ourselves with that fact. ", "The old\nadage, \"Whatever is worth doing at all, is worth doing well,\" we cannot\ntoo strongly impress ourselves with. ", "Inefficiency puts an individual of\na race always at a disadvantage. ", "It is skill; it is the ability to do\nwell what is to be done that will always be preferred. ", "It is the\nskillful mechanic; the skillful artisan, the skillful stenographer and\ntypewriter that is always preferred, and that always wins out in the\nstruggle of life, other things being equal. ", "It is the fittest that\nsurvives in the industrial struggle and in every other avenue of life.", "\nIn planning for the future we must lay more and more stress therefore\nupon the work of properly qualifying ourselves for service in all the\navenues of life. ", "Carelessness, indifference here, the disposition to be\ncontent with shoddy work, will be fatal to our success. ", "We are living in\nan age when the demand for efficiency, and efficiency of the highest\norder, is becoming more and more insistent. ", "Unless this fact is\nrecognized by us, and is allowed to shape our course, the struggle in\nwhich we are engaged is a hopeless one; we are bound to go to the wall.", "\n\n(3). ", "We must impress ourselves with the importance of being reliable,\ntrustworthy. ", "However skillful we may become, however efficient, unless\nwe can be depended upon to do what we undertake to do, our efficiency\nwill count for but little. ", "If people can't depend on us; if our word\ncounts for nothing; if we are deficient in a sense of obligation; if\nresponsibilities weigh lightly upon us, we will be sure to lose the\nconfidence of others, and will be sure also to lose their patronage.", "\nEven the inefficient man who can be depended upon will be preferred to\nthe efficient man upon whom no dependence can be put. ", "The two things\nmust go together, reliability and efficiency, if efficiency is to be of\nany real advantage. ", "This is a point which we need particularly to lay to\nheart, and to keep before us in the training of the young. ", "Unfortunately\nthere is considerable ground for just complaint against a large\npercentage of the race just here. ", "It is a serious defect, and one that\nought to be remedied, that ought to claim our immediate and earnest\nattention.", "\n\n(4). ", "It is well for us to impress ourselves with the importance, with\nthe transcendent importance of character. ", "Character is the foundation\nupon which everything else must rest if it is to endure, if it is to be\nof any permanent value in the elevation of the race. ", "There must be a\nsound moral basis. ", "In the heart of the race there must be implanted the\ngreat principles of morality. ", "The race must not only be taught, but must\naccept, must be governed by sentiments of justice, of veracity, of\npurity, of honesty. ", "It must make up its mind to square its life by the\nTen Commandments and the Sermon on the Mount. ", "There is nothing that can\ncompensate for, or take the place of a sturdy, upright character. ", "It\nisn't something which it would simply be well for us to possess, which\nit would be to our advantage to possess; it is absolutely indispensable.", "\nThere is no future for us, no honorable future for us, without it. ", "This\nis the way we must feel; this is the way we must make our children feel.", "\nCharacter, high character, is not something which we may or may not set\nbefore us as we face the future, as we enter upon the second half of the\ncentury of freedom; but something which we must set definitely before us\nas of transcendent importance. ", "There is no option left us if we have any\nregard to our highest and best interest, and the best interest of those\nwho are to follow us. ", "If the moral atmosphere in which the race lives\nand moves and has its being is not kept pure and healthful and\ninvigorating it can never hope to become a strong, virile,\nself-respecting race, or a race that will be likely to command much\nrespect from others. ", "The race has, be it said to its credit, all along\nattached some importance to character, but the emphasis which it puts\nupon it must steadily increase. ", "We must come, more and more, to realize\nthe fact that while knowledge is power, and while there is power in the\npossession of material things, that the greatest power lies in\ncharacter, in a strong, sturdy, upright, virtuous manhood and womanhood.", "\n\n(5). ", "In this connection it is well for us also to remember that the\nagencies that are most helpful in the development of character are the\nfamily, the church, the school. ", "I heard the President of the Board of\nEducation of one of our most important cities say, not long ago, after\nlistening to an address highly eulogistic of the public schools, that in\nhis judgment the greatest asset of the nation is the family. ", "And in this\nI think he was right. ", "He meant, of course, the family properly\nconstituted, with the right kind of man and woman at the head of it. ", "The\nimportance of the home, as an educational force, is seen in the fact\nthat the children begin life in the home, and that they are under the\nalmost exclusive influence of the home when the young life is most\nplastic, is most easily moulded. ", "Where this home influence is pure,\nelevating, ennobling, there is no other agency that is comparable with\nit. ", "The church and school also, however, are very important agencies.", "\nAnd I have called attention, in this connection, to these three\ninstitutions in order that, as we face the future, we may recognize\ntheir importance, and may come to feel more and more the necessity of\nimproving them, and of utilizing them in the development of the race. ", "We\nneed better homes and must have them—homes that will not be indifferent\nto intellectual culture and material comforts, but that will value more\nhighly than either the things that make for purity of heart and life. ", "We\nneed better churches and must have them—churches that will be more\nconcerned about properly instructing the people in the knowledge of the\nWord of God, with a view to spiritualizing their lives, to lifting them\nto the high plane of Christian living and thinking, rather than with\nendless entertainments and schemes for money getting. ", "We need better\nschools—schools in which the teachers will recognize that their vocation\nis not simply to train the head, or chiefly to train the head, but the\nheart also—schools in which the teachers will recognize the\nopportunities which their calling affords of giving shape and direction\nto the budding and expanding lives entrusted to their care, and who are\ngladly availing themselves of these opportunities. ", "There are some\nteachers, of course, who are doing this, who are making their influence\nfelt in character building; but there are others who are indifferent to\nthese opportunities—who are not making their influence felt and who feel\nthat it is no part of their business to do so. ", "Not long ago I was\nspeaking to a school official in one of our cities about the great\nopportunities that teachers have for this kind of work; and his reply\nwas, \"Yes, but many of our teachers teach only for the money they get,\nand they want the money simply to decorate their bodies.\" ", "How far this\nis true of our teachers as a class I do not know; but that it is true of\nsome of them I have not the slightest doubt. ", "What we need, therefore, as\nwe face the future, is to endeavor to get the active and hearty\ncoöperation of all the teachers in all of our schools in this higher\nmission of character building in their pupils. ", "The teachers, if they can\nonly be made to see it, hold a place second in importance only to the\nhome in the service which they can render in the stupendous task which\nconfronts us as a race. ", "We must all of us, as we begin this new half\ncentury of freedom, be more thoughtful about our homes, more concerned\nto make them proper habitats for the rearing of children; more concerned\nabout our schools and the character of the men and women who are in\ncharge of them; and more concerned about our churches to see that they\nare properly manned, properly conducted, properly supported by our\npresence and by our financial aid. ", "None of these institutions can be\nallowed to deteriorate, to fall behind, without affecting unfavorably\nthe progress of the race.", "\n\n(6). ", "It is important that we impress ourselves with the evil of strong\ndrink, and that we set definitely before us the work of educating the\nrace with reference to the poisonous nature of alcohol and its baleful\neffects. ", "Sobriety, abstinence from all alcoholic liquors as a beverage,\nwe must be at special pains to impress upon all—old and young alike. ", "We\nmust organize temperance societies; we must encourage those that are\nalready in existence; we must gather the children into temperance bands,\nin our Sabbath schools and in our day schools as far as may be possible.", "\nIn the new half century upon which we have now entered, we must firmly\nresolve, and must bend every effort towards lessening the evil of strong\ndrink among us. ", "At the end of the present half century, let us hope that\nthere will be less intemperance among us; that a larger number of homes\namong us will be definitely committed to total abstinence, than we find\nto-day. ", "Whatever we can do to lessen this evil; whatever we can do to\nproduce a sober, temperate people we must do, and we must all do our\npart to secure this result. ", "Every member of the race is interested in,\nor, at least, ought to be, in saving it from the curse of intemperance,\nnot only because it will help the race economically and morally, but\nalso because it will set it in a better light before its enemies, it\nwill take away one serious ground of complaint against it.", "\n\n(7). ", "We must not allow ourselves to become discouraged because of the\nobstacles which our enemies are constantly throwing across our pathway.", "\nThese obstacles, if we are made of the right stuff, will help to\nstrengthen us, to make us more resolute, more determined. ", "It is in\nbreasting opposition, in overcoming difficulties that we develop\nstrength.", "\n\n(8). ", "Nor should we allow ourselves to become embittered by the mean and\npersistent opposition of our enemies; by the studied efforts that they\nare ever making to insult and humiliate us. ", "Unless we are watchful,\nunless we are tolerably sane, it is so easy to allow such things to\nrankle in our breasts, to engender feelings of bitterness and hatred.", "\nNatural as it is, however, we must resist it. ", "It is bad business for an\nindividual or a race to allow itself to become embittered against\nanother individual or race. ", "Such a spirit will destroy our own\nhappiness, our own peace of mind, and will not help to win over our\nenemies. ", "Out of a spirit of mutual hatred no good can possibly come to\neither race. ", "The result is bound to be evil; and the evil will grow as\nthe hatred grows.", "\n\nIf we are to fight successfully, fight in the most effective way, we\nmust be calm, we must not be spurred on by bitterness, by hatred, but by\nthe consciousness that what we are contending for is right, and,\ntherefore, is best for all, even for those against whom we are\ncontending, who are foolishly trying to obstruct our way. ", "Let us possess\nour souls in patience; let us be calm, self-possessed. ", "These enemies who\nare fighting us deserve our pity. ", "The course which they are pursuing, in\nthe long run, will prove more injurious to them than to us. ", "The more\nthey fight us, the more they resist us, the more they seek to insult and\nhumiliate us, the more are they injuring themselves, the more are they\nsinking to lower levels, the less are they becoming worthy of the\nrespect of decent, right-thinking people. ", "We may suffer in our feelings;\nwe may be deprived of our rights for a time; but they are suffering in a\nway that is eating away the only thing of real value—the only thing that\nis worth having—character. ", "We may suffer, but the penalty which we pay\nis not near so dear, so costly as the penalty which they are paying.", "\n\nThere is something really pathetic in the spectacle here presented, of\nvast numbers of people claiming to be intelligent, claiming to be\ncivilized, some claiming even to be Christians, allowing themselves to\nbe dominated, to be controlled absolutely by such an utterly ignoble\nsentiment as race prejudice. ", "You can't help asking yourself the\nquestion, Can these people really be sane? ", "Jesus, we are told, wept over\nJerusalem. ", "As he saw her condition—saw her in her blindness, stupidity,\nobstinacy—as he saw the end towards which she was madly rushing, it\ntouched his great heart with pity, and wrung tears from his eyes. ", "And\nthis is the way, it seems to me, that any right thinking man, any man\nwho has a heart of pity must feel as he looks out on the multitudes in\nthis land who are yielding themselves up to the sway of this bitter,\ndegrading, <DW64>-hating spirit; as he sees how they are being driven\nmore and more into doing so many utterly contemptible things; and, when\nhe remembers also that the reaping is to be as the sowing. ", "It is easy\nenough to hate such people, if you don't stop to think; but when you\nremember that they are human beings; that they are under the dominion of\nmoral laws that are just as inexorable in their operations as are\nphysical laws; and remember also, under these laws, what the result is\nsure to be, there is no room for hatred, for bitterness, but only for\npity, for the deepest commiseration. ", "The thing that we ought to do, and,\nthat I wish very much that we would do, and do more than we have been in\nthe habit of doing, is to pray for these misguided, unfortunate, greatly\nto be pitied individuals who are fighting us. ", "The Spirit of God can open\nblind eyes, can unstop deaf ears, can soften the hardest hearts. ", "The\nSpirit of God can regenerate, can give an entirely new bias or direction\nto character and life. ", "And this is what is needed. ", "These people need to\nbe changed, to be set right. ", "The possibility of such a change, both for\ntheir sakes and for ours, should lead us to work and pray earnestly for\nit.", "\n\n(9). ", "It is also well for us, as we face the future, not to be deceived,\nnot to be misguided by the assumption upon which some of our race\nleaders have been proceeding. ", "It has been assumed by some that the\nreason why we are treated as we are is because we are poor, because we\nare ignorant, because we are degraded, in a word, because of our\ncondition; and, that if we will only improve ourselves—will only work\nhard and better our condition—will get more knowledge, more money, more\ncharacter, it will be all right in the end. ", "Those who act upon this\nassumption think that the wise thing for us to do, therefore, is to lose\nsight entirely of the manner in which we are treated, to take no account\nof it, to make no ado about it, to bear it patiently and give ourselves\nup entirely to the work of improving ourselves. ", "This is what they\ncounsel; this is the way, they say, this race problem is to be solved.", "\n\nLooked at in the abstract this seems to be very plausible. ", "The\nassumption that if we improve ourselves; if we show ourselves worthy of\nbeing treated properly, that we would be, is what would naturally be\nexpected. ", "Unfortunately, however, the facts are all against it. ", "Things\nhave not panned out as might have been expected, under this theory of\nrace adjustment. ", "The race problem, as we understand it, may mean one of\ntwo things. ", "It may mean the problem of the race's development, which\nwould include all the agencies to be employed in securing this result;\nor it may mean the problem of getting the white man to behave\nhimself—getting him to treat the <DW52> man properly, as a man, as a\nbrother, as a citizen, having common and equal rights with himself. ", "That\nthe race's development may go on without at all affecting favorably the\nwhite man's attitude towards it, is clearly evident from what is going\non about us, and from the experience of the last forty or fifty years.", "\nDuring these years the <DW52> people have steadily improved along all\nlines; and yet the same feeling of antipathy, of hostility to them\nexists. ", "There is no indication of a desire to treat them any better. ", "The\nprogress that they have made has counted for nothing in their favor; has\nnot lessened, in the least, the opposition to them.", "\n\nA short while ago a Congressman from Louisiana, J. B. Aswell, introduced\na bill in the House of Representatives to segregate employees of\nthe Government. ", "Among other things in presenting his bill, he said:\n\n\"Every informed and right-thinking white man, while sympathizing with\nand anxious to help the <DW64> in his place, recognizes the necessity of\npreserving the integrity and supremacy of the white race. ", "The purpose of\nthis bill is to check a bad tendency in this country, before it is too\nlate, and cause thinking people everywhere to find themselves in\nrelation to the race problem and thus deal fairly and give justice to\nboth races. ", "The bill seeks to help the <DW64> by making him proficient in\nhis own sphere and by correcting a false idea of his proper\ncircumscribed position in the republic, and, at the same time, relieve\nthe white man in the public service from the intolerable humiliation of\nbeing compelled, in order to earn his daily bread, to work side by side\nwith an objectionable people, the continuation of which practice must\nresult in irreparable injury to both races, and ultimately destroy the\nefficiency of the public service. ", "Such practices will drive the\nself-respecting proficient white man and woman from the civil service of\nthe Government.\"", "\n\nThe bill provides, \"That the heads of all executive departments shall\nissue all such orders as shall be necessary to secure in all branches of\nthe civil service of the United States to the utmost extent consistent\nwith public interests, the segregation of civil employees of the white\nrace from those of African blood or descent, in the performance of their\nservices.\"", "\n\nIt also provides that, \"In all executive departments within the District\nof Columbia, clerks or employees shall not be required to occupy the\nsame office or work rooms with clerks or employees of African blood or\ndescent; nor shall any white clerk or employee be placed under the\norders, direction, or supervision of any person of African blood or\ndescent.\"", "\n\nIt also provides that, \"In the railway mail service of the Post-office\nDepartment white clerks shall not, except in cases of emergency, be\nordered to duty in the same mail car with postal clerks of African blood\nor descent.\"", "\n\nYou will notice that the course which he recommends here, and which he\nseeks to enforce by law, is not because the <DW64> is ignorant, not\nbecause he is inefficient, not because he is ungentlemanly in his\ndeportment; but simply because he is a <DW64>, or has <DW64> blood in his\nveins. ", "The fact that he is in the service at all proves that he isn't\nignorant, that he isn't inefficient, for he is there as the result of\ncivil service examination. ", "It makes no difference how much he knows, how\nefficient he is, how gentlemanly he is, the thing that makes him\nobjectionable is that he is a <DW64>, or is of <DW64> descent. ", "It doesn't\nmake any difference how highly cultivated he is, it becomes, in the\nlanguage of the Representative from Louisiana, \"an intolerable\nhumiliation for a white man to be compelled, in order to earn his daily\nbread, to work side by side with an objectionable people.\" ", "It isn't the\ncondition of the people; it isn't their backwardness that discounts\nthem, but the fact that they are of African blood or descent.", "\n\nSenator Vardaman, in his insane ravings over the nomination by President\nWilson of Adam E. Patterson, a <DW52> man from Oklahoma, as Register of\nthe Treasury, speaks in the same strain. ", "He says:\n\n\"The appointment of Patterson is a most unfortunate thing. ", "Two races\ncannot mix; it is contrary to the laws of nature. ", "I am not acquainted\nwith Patterson. ", "It is not he, personally, I am fighting; it is the\nprinciple involved. ", "I do not think any government office should be held\nby a <DW64>. ", "I think the defeat of this appointment of a <DW64> is of more\nimportance than the passage of the tariff bill and the enactment of\ncurrency legislation. ", "It rises like a mountain peak above all other\nquestions of the day. ", "It seems that the appointment was made in view of\nPatterson's campaign activities in the interest of Democracy. ", "I do not\nthink much of the policy that pays party obligations at the expense of\nthe purity of the greatest race on the globe. ", "I shall fight every <DW64>\nappointment that is made.\"", "\n\nIt is not necessary, he admits, to know anything personally of the\ncandidate—anything about his character or qualifications; it is enough\nto know that he is a <DW64> or of <DW64> descent, to disqualify him for\nany office under the Government. ", "And this, he affirms, is the sentiment\nof all Southern senators. ", "Even a man like President Wilson, with all his\nbrains and culture and high Christian character, or rather, I would say,\navowal of high Christian principles, after nominating Patterson for the\nposition permitted him to withdraw from the contest in the face of\nVardaman's declaration, \"No government office should be held by a\n<DW64>.\" ", "And instead of sending in the name of another <DW52> man, in\norder to rebuke that sentiment, he sent in the name of an Indian, which\nwas a virtual acceptance, on the part of the President, of the position\ntaken by Vardaman and other <DW64>-hating senators. ", "And the fact that a\nwhite man was named almost immediately afterwards for the post at Hayti\nshows how completely the President has surrendered to the dictation of\nSouthern <DW64> haters. ", "If the progress we have made during these fifty\nyears has had so little effect upon a man like Woodrow Wilson, how much\nis it likely to have upon the average white man? ", "Any one who has kept in\ntouch with the movements of the last half century that have had to do\nwith this vexed question, cannot fail to see that the two phases of the\nrace issue have very little to do with each other. ", "The development\nwithin the race has had no appreciable influence in creating within the\nwhite man a disposition to behave any better towards the <DW52> man, to\naccord to him his rights, to treat him as a man, as a citizen, as a\nbrother. ", "So far as we may judge from the experiences of the last fifty\nyears and from what is transpiring about us to-day, there is no hope of\nthings ever being any better as the result of race improvement. ", "It is\nright, of course, for us to make the most of our opportunities, and to\npress forward as rapidly as possible along all lines of endeavor,\nmaterial, intellectual, moral, spiritual; but let us not be deceived,\nlet us not imagine, though we ourselves will be greatly benefited by\nsuch a course, that the attitude of the white man towards us will change\nfor the better in consequence. ", "There may be a change in him, let us hope\nthat there may be, but if it comes at all, it will come in some other\nway. ", "It will not be because we are improving ourselves, because we are\ngetting to be more intelligent, are getting more property, getting on a\nhigher social plane, getting to be more virtuous, more self-respecting.", "\nThat kind of thing has little or no influence in favorably inclining the\naverage white man towards the <DW64>. ", "It makes no difference what he has,\nwhat he has achieved, what he has made of himself, he is still only a\n<DW64>, is still undesirable, is still to be hedged about by limitations\nand restrictions.", "\n\nSenator Vardaman in his \"high-blown pride\" speaks of the white race as\n\"the greatest race on the globe.\" ", "If the Senator is a specimen of its\ngreatness, the so-called inferior races need not concern themselves very\nmuch about catching up with it in the march of progress. ", "As a matter of\nfact, there are scores of <DW52> men who, in intelligence, in brain\npower, in scholarship, in all the elements that go to make up true\nmanhood, are superior to Mr. Vardaman. ", "The only respect in which the\nSenator shows any superiority, in the sense of surpassing others, so far\nas I can see, is in the exhibition of a coarse, vulgar, and brutal\nspirit. ", "The white race may be the greatest race on the globe, but the\nassertion of that fact would come with a little better grace from one\nwho reflects its greatness rather than from one who is a reproach to it,\nwho discredits it. ", "The white people themselves would hardly select Mr.\nVardaman as a specimen by which it would care to be judged in this or in\nfuture generations. ", "The <DW64> may be inferior, greatly inferior to the\nwhite race, but there would have to be some better specimen of the white\nrace than Mr. Vardaman to prove it. ", "My purpose, however, is not to\ncriticise the honorable Senator from Mississippi. ", "I have mentioned his\nname in this connection merely as illustrative of the aggressive,\never-growing spirit of race hatred, of race antagonism, which still\nconfronts us after fifty years of freedom.", "\n\n(10). ", "In this connection we ought to impress ourselves also, as we leave\nthe first half century of freedom and enter upon the second half, with\nthe fact that God is and that he is a present help in time of need. ", "We\nneed to emphasize, more strongly than we are in the habit of doing, the\nimportance of religion as a factor in this race struggle in which we are\nengaged. ", "In Exodus 14, we are told that after Pharaoh had given the\nchildren of Israel permission to leave Egypt, and after they had left,\nhe repented, changed his mind, and started in pursuit of them with all\nhis hosts, his chariots and horsemen, to bring them back. ", "We are also\ntold that when the children of Israel saw them approaching they were\nterrified. ", "And then occurs this passage: \"And the angel of the Lord,\nwhich went before the camp of Israel, removed and went behind them; and\nthe pillar of cloud went from before their face, and stood behind them:\nand it came between the camp of the Egyptians, and the camp of Israel,\nand it was a cloud of darkness to them, but it gave light by night to\nthese: so that the one came not near the other all the night.\" ", "God stood\nbetween Israel and the enemy. ", "And that is just where we want to have him\nstand, between us and our enemies. ", "What we need to do is to rest in the\nLord, is to put our trust in him. ", "He is more than a match for our\nenemies. ", "The song which Moses and the children of Israel sang after they\nhad seen the advancing hosts of the enemy approaching was,\n\n \"The Lord hath triumphed gloriously.", "\n The horse and his rider hath he thrown into the sea.", "\n The Lord is my strength and song,\n And he is become my salvation.\"", "\n\nAnd if we trust him, if we make him our hope, we will be able in the end\nto sing the same song; we, too, will triumph gloriously.", "\n\nIn the voyage of the apostle Paul to Rome the ship was caught in a\nterrible storm. ", "For fourteen days and nights it raged. ", "The wind blew\nfuriously; heavy, dark clouds shut out the light of the sun by day and\nof the stars by night. ", "There seemed no hope of escape. ", "Of the nearly\nthree hundred souls on board, all except one man were filled with the\nmost appalling apprehension. ", "That man was the apostle Paul. ", "During all\nthose awful days and nights he alone was calm, self-possessed; he alone\nshowed no fear, no apprehension. ", "And why? ", "It was because the angel of\nthe Lord had stood by him and had said to him, \"Fear not, Paul; thou\nmust be brought before Caesar: and lo, God hath given thee all them that\nsail with thee.\" ", "And it was because he believed what the angel had said\nto him. ", "The fierceness of the storm, the raging of the elements, the\nappalling darkness that enveloped them, had no disquieting effect upon\nhim. ", "It was the triumph of faith—faith that saw safety, and rested in\nsweet content in the face of the raging storm. ", "And faith in God is what\nwe need if we are not to become discouraged in face of the gathering\nhosts of darkness, in face of the constant accessions to the ranks of\nthe enemy. ", "David once exclaimed,\n\n \"Jehovah, how are mine enemies increased!", "\n Many are they that rise up against me.\"", "\n\nBut he comforted himself with the thought,\n\n \"But thou, O Jehovah, art a shield about me;\n My glory and the lifter up of my head.\"", "\n\nAnd we may find comfort in the same thought. ", "Let this new half century\nbe one of abounding trust in God; let us more and more accustom\nourselves to dwell in the secret place of the Most High, under the\nshadow of the Almighty.", "\n\nII. ", "In leaving this first half century of freedom and in entering upon\nthe second half, a word also ought to be said to the white people of the\ncountry. ", "There are four things that I want to say to them:\n\n(1). ", "I want to remind them of the fact that we came here originally\nthrough no volition of our own. ", "We were brought here against our will,\nand brought here for purely selfish purposes, to serve their interest.", "\nWe are not responsible for being here—the responsibility is with the\nwhite race. ", "That fact ought to be remembered by them. ", "If our presence in\nthis country is undesirable, as is frequently alleged, it is not for the\nwhite man to set that up as an excuse or justification for ill-treating\nus. ", "If it had not been for their selfishness we would not be here. ", "If\nour presence here is an evil, they are not the ones to complain, they at\nleast, ought to be willing quietly to accept it as it is an evil of\ntheir own making. ", "This is one of the things that has always seemed to me\nto render the treatment of the <DW64> by the white man particularly\ncontemptible. ", "After forcing him away from his home against his will; and\nafter getting out of him all that he could without compensation, when\nthat is no longer possible, then to turn upon him and tell him to get\nout, that he is no longer wanted, is conduct of which even savages ought\nto be ashamed. ", "Whenever you are tempted to ill-treat the <DW52> man, to\ndeny him a man's chance in the race of life, remember that you brought\nhim here, and that the least that you can do, the least that you owe\nhim, is to treat him decently, humanely.", "\n\n(2). ", "I want to say, that for two hundred and fifty years you had our\nunrequited toil; we tilled your soil, we gathered your crops, we cut\ndown your forests, we built your houses, made your clothes, worked for\nyou in manifold ways. ", "We worked for you in the days of slavery, and you\nseemed satisfied with our labor; why do you withhold your work from us\nnow? ", "Why do you now shut us out of employment? ", "We are just as able, and\njust as willing to work now as then. ", "Work is what we need; work is what\nwe must have if we are to support ourselves in decency, if we are to\nlive honestly and honorably. ", "You are bound by every consideration of\njustice, of fair play, to make a place for us, to give us the same\nchance that is given to others to support themselves and their families.", "\nFor two hundred and fifty years we worked for you, as your slaves; are\nyou unwilling to help us now that we are free and are working for\nourselves? ", "You, who brought us here; you, who are responsible for our\npresence here, ought to want to encourage us to be industrious, to be\nself-respecting.", "\n\n(3). ", "I want to remind you of the fact that we are now free; that we are\nAmerican citizens; that under the laws we are entitled to the same\nrights and privileges as yourselves. ", "Slavery no longer exists in this\ncountry—all are now free men. ", "What is freedom to mean to us? ", "Why were we\nmade free? ", "Why were the fetters stricken from our limbs? ", "Why were we\nmade citizens? ", "Why have schools been provided for our intellectual\ndevelopment? ", "Why emancipation at all, if we are not to have the same\nchance as other freemen? ", "What is the value of freedom if it doesn't\ncarry with it the guarantee of protection in the enjoyment of all rights\nthat are common to all citizens? ", "Is freedom to mean one thing to the\nwhite man, and another thing to the <DW52> man? ", "Freedom and citizenship\ncannot mean one thing to a white man and another to a black man in a\nrepublic without creating needless and endless trouble; and without in\nthe end destroying the spirit that is essential to the perpetuity of\nrepublican or democratic institutions. ", "Is it wise? ", "Is it consistent? ", "Is\nit the part of true patriotism to continue longer to make invidious\ndistinctions between citizens who must forever live side by side, and\nupon the mutual co-operation and sympathy of whom, the welfare and\nhappiness of the whole will depend? ", "Is it wise to encourage, to help fan\nthe flame of race prejudice from which no good can possibly come, but\nonly evil, and evil more and more as it is encouraged? ", "Isn't it a great\ndeal better to use a little common sense, now that we are here, now that\nwe are here to stay, now that we are free, now that we are citizens, to\nrecognize us as such, and to accord to us the same treatment as is\naccorded to others? ", "One thing you may be assured of, we will never be\nsatisfied with anything less. ", "Unless these rights be conceded; unless we\nbe treated as we have a right to expect you to treat us, this friction,\nwhich is doing so much to demoralize the whole country, will continue.", "\nIs it not better for the thoughtful, sane, sober, right-thinking men and\nwomen among you to call a halt to those, who, keeping the humiliation of\nthe <DW64> before them as their chief aim, are willing to sacrifice\neverything else to it? ", "The humiliation of the <DW64>; the hedging of him\nabout with degrading restrictions; the forcing him down into a position\nof subordination, of inferiority, even if you should succeed in doing\nit, after all, is it worth the price that must be paid; that you are\npaying? ", "The policy of giving the <DW64> a man's chance in the Republic;\nof treating him with the same consideration as others are treated, has\nvastly more good in it for the Republic than the measure of repression,\nof enforced subordination, of invidious distinctions upon which you are\nnow insisting. ", "Such a policy will make the <DW64> forget that he is a\n<DW64>, and will lead him to think of himself simply as an American\ncitizen; will stimulate his patriotism; will render it no longer\nnecessary for him to be particularly concerned about race interests, but\nwill leave him free to be concerned about those interests which are\ncommon to all the people. ", "Such a policy will also set free for higher\nand nobler uses all the ability, the energy, the resources that are now\nbeing expended in efforts to keep the <DW64> down and which will be of\nincalculable benefit to the Nation. ", "Think of how much time, how much\nthought, how much energy are used up in this needless race friction, and\nhow much the Nation is losing by this misuse of valuable time, thought,\nenergy! ", "If you, who are fighting the <DW64>,—you who are determined to\nreduce him to a pariah class, would only turn your thought and energy\ntowards upbuilding the Republic—materially, intellectually, morally,\nspiritually,—towards fighting those evils that are really endangering\nthe Republic,—greed, corruption, impurity, lawlessness, intemperance,\nhow much more valuable your services would be. ", "There never was a time\nwhen the Republic needed your services more than if does to-day, in\nharmonizing the elements of its population, in encouraging a spirit of\nfraternity, of brotherhood. ", "It is not the function of a patriot, of a\nlover of his country to array class against class, race against race;\nthat is the role of the demagogue, the low panderer to passion and\nprejudice for selfish ends. ", "This race friction ought to cease; and it\nwill cease if you will do the right thing; if you will listen to reason\nand common sense. ", "It is not the <DW64> that is keeping up the friction,\nbut the white man.", "\n\n(4). ", "I want to say to those who are friendly to us; who believe that we\nhave rights under the constitution, and that those rights ought to be\nrecognized:\n\n(1). ", "We are profoundly thankful to you for your sympathy, for your\ngood-will, and for all that you have done to cheer and encourage us.", "\nSome of you have taught in our schools, have worked among us as\nmissionaries, have contributed of your means to aid us in our education,\nin our development; for all of which we are grateful.", "\n\n(2). ", "We wish very much that you would be a little more outspoken in your\nsympathy. ", "We have, it may be, many silent friends among you. ", "It is\nbetter, of course, in some respects to have a silent friend than to have\nno friend at all. ", "Such friends constitute a reserve force which may\nserve us well at some future time, in an emergency which may arise\nunexpectedly. ", "The friendship, however, that counts for most, that is of\nmost value, is the friendship that is known, that openly, publicly\nexpresses itself. ", "The importance of thus openly showing your sympathy,\nyour friendship is to be seen in that in this way public sentiment is\nmade and influenced. ", "The people who speak out, or, who act out their\nsentiment are the ones who count in shaping, in moulding public\nsentiment. ", "Our enemies are never silent. ", "The opposition, the hostility\nwhich they feel is never concealed, it always comes to the surface,\nalways expresses itself. ", "And this is one reason why they have influence,\nwhy they are so potential. ", "Take the segregation idea which has been\nprojecting itself upon the attention of the country. ", "When the agitation\nwas started, e. g., in the city of Washington, there were many meetings\nheld in various parts of the city among the whites; but they were all in\nthe interest of segregation, they were gotten up and managed by those\nwho wanted to force this humiliation upon the <DW52> people. ", "I cannot\nbelieve that the purpose of these meetings met the approval of all the\nwhite people of the capital; I know that it did not of some of them. ", "And\nyet no meeting was held; no public expression was given to indicate that\nsuch was the case, that there was any dissenting opinion among the\nwhites. ", "Not one white church; not one ministerial association; not one\nChristian Endeavor society, nor any other organization among the whites,\nincluding the Young Men's Christian Association, the Young Women's\nChristian Association, gave expression to any dissenting opinion. ", "So far\nas any public expression was concerned, it looked as if the entire white\npopulation approved of the movement to segregate the <DW52> people in\nstreet cars and otherwise. ", "What we are asking of you, our white friends,\nis to show your colors, is to be just as pronounced in your sympathy for\nus as our enemies are pronounced in their opposition to us. ", "If you will\ndo this; if you will let the people about you know where you stand, it\nwill greatly help matters. ", "Lowell, in his sonnet on Wendell Phillips,\nsays,\n\n \"He saw God stand upon the weaker side,—\n And humbly joined him to the weaker part.\"", "\n\nAnd it is necessary that this be done—that the weaker part be joined,\nand joined openly as he did, if it is to be strengthened. ", "There is a\ngood deal in numbers. ", "Somehow people have a great deal more respect, are\ninclined to be very much more considerate of a cause that has many\nadherents, or whose adherents are increasing in numbers. ", "Where we are\nsilent we are never counted. ", "Elijah is sometimes criticised for his\nso-called pessimistic statement when he was running from Jezebel—\"The\nchildren of Israel have forsaken thy covenant, thrown down thine altars,\nand slain thy prophets with the sword; and I, even I only am left.\" ", "In\nthis he was mistaken. ", "It seems there were seven thousand who had not\nbowed the knee to Baal. ", "But, as some one said, no one knew it, and\ntherefore they counted for nothing. ", "Now we don't want our friends among\nthe whites who want us to get our rights, who think that we ought to be\ntreated fairly, justly, to count for nothing; we don't want them to be\nso silently sympathetic that no one will know of it. ", "We want them to be\noutspoken; to be openly for us, and thus help to mould public sentiment\nin our favor. ", "It would have helped greatly if, during this segregation\nagitation there had been some meetings held among the whites giving\nexpression to a different sentiment. ", "Even a simple protest from a single\nindividual helps. ", "A letter like the one published not long ago by the\nHon. ", "A. E. Pillsbury of Boston, Massachusetts, declining to pay his\nannual dues to the treasurer of the National Bar Association, and giving\nas his reason his positive and emphatic dissent from the action of the\nAssociation in discriminating against <DW52> men, is bound to have its\neffect in educating public sentiment, in helping to break down invidious\ndistinctions. ", "Carl Schurz, in his Life of Henry Clay, in speaking of the\nAbolitionists, says, \"The immediate effect of their work has frequently\nbeen much underrated. ", "They served to keep alive in the Northern mind\nthat secret trouble of conscience about slavery which later, in a ripe\npolitical situation, was to break out as a great force.\" ", "And so here,\nthe protest of our white friends in the struggle we are making now will\nserve to keep alive in others the sense of right, which will ultimately\nbecome a great force before which the wrongs from which we are now\nsuffering will be righted. ", "Silent sympathy is better than no sympathy;\nbut the sympathy that expresses itself in word and act is greatly to be\npreferred. ", "If you think we are not treated right; if you think that\ninvidious distinctions based upon color, upon race ought not to exist,\nsay so; and say it so loud that all about you will hear it. ", "This is the\nrequest that we make of you, as we enter upon another half century of\nfreedom.", "\n\nAnd now just a word more. ", "The struggle before us is a long and hard one;\nbut with faith in God, and faith in ourselves, and indomitable\nperseverance, and the purpose to do right, in spite of the forces that\nare arrayed against us, we need have no fears as to the ultimate result.", "\nSuccess is sure to crown our efforts. ", "We are not always going to be\nbehind; we are not always going to be discriminated against; we are not\nalways going to be denied our rights. ", "For as Sojourner Truth said, \"God\nis not dead.\" ", "And some day, in his own good time, the right will\ntriumph. ", "As the poet has expressed it,\n\n \"Right is right since God is God,\n And Right the day will win.\"", "\n\nWhat is needed is a New EMANCIPATION PROCLAMATION—a proclamation that\nwill set the white man free from the degrading influence of race\nprejudice—a proclamation that will register a decree or purpose on the\npart of the white race to free itself not only from the narrowing lust\nof gold, but from the still more narrowing lust of race hatred and\nproscription. ", "O, for another and greater Lincoln to speak the word of\npower,—another and greater Lincoln to set the thought and heart of white\nAmerica going in a new and better way—the way of righteousness—the way\nof the fatherhood of God and the brotherhood of man. ", "In the inspired\nrecord we read: \"The wolf shall dwell with the lamb, and the leopard\nshall lie down with the kid; and the calf and the young lion and the\nfatling together; and a little child shall lead them. ", "And the cow and\nthe bear shall feed; their young ones shall lie down together; and the\nlion shall eat straw like the ox. ", "And the sucking child shall play on\nthe hole of the asp, and the weaned child shall put his hand on the\nadder's den. ", "They shall not hurt nor destroy in all my holy mountain;\nfor the earth shall be full of the knowledge of Jehovah as the waters\ncover the sea.\" ", "Surely if this be true; if this is a prophecy of what is\nto be, there is reason and good reason to believe that the savage\nelement in the white man's nature, which corresponds to the nature of\nthese ferocious animals, and which leads him to devise and execute his\nvarious schemes of disfranchisement, of segregation, of restricted\nopportunities, in order to annoy and degrade us, will yet undergo a\nchange. ", "If the wolf and lamb can dwell together, and the lamb be\nperfectly safe, surely the white man in this country is not so\nabsolutely beyond being amenable to reason and common sense and decency\nas to make it impossible, some time in the future, for him and his\nbrother in black to dwell together, and the brother in black feel no\nuneasiness, no fear of being molested, or of having his rights infringed\nupon by him. ", "The white man, when it comes to the <DW64>, is pretty bad, I\nknow, but I cannot believe that he is so hopelessly bad as to render it\nimpossible for the <DW52> man to dwell with him and be treated by him\nas a man and brother. ", "It may ultimately turn out to be true; but I am\nnot yet willing to believe it. ", "It cannot be that this white race, which\nprides itself upon its superiority to all other races, under this\nhighest test of superiority—the ability to accord to every man his right\nand to treat every man as a brother of whatever race or nationality, is\ngoing to be found so sadly deficient. ", "It is a great race. ", "It has done\nmany wonderful things. ", "All the greater is the reason, therefore, why it\nshould not permit itself to be controlled by such an ignoble spirit. ", "It\nhas done, too, many wonderful things to have its greatness marred by\nsettling down permanently on the low level of race prejudice. ", "No; I\ncannot believe that the white man is so hopelessly bad, so absolutely\npossessed by this demon of race hatred that there is no honorable future\nin this country for the <DW52> man. ", "The Tillmans, Vardamans, Hoke\nSmiths are not always going to be the leaders of even Southern public\nsentiment. ", "A better day is coming, with truer, saner, wiser leaders. ", "Dr.\nJosiah Strong, in his last volume, \"Our World,\" in the chapter on \"The\nNew Race Problem,\" after some remarks on the improbability and the\nundesirability of blending all races into one says,—\"If we recognize any\nplan in creation, we must accept a differentiation of the human family\nas an expression of the divine purpose, infinitely wise and benevolent.", "\nAnd it behooves us as colaborers together with God to find that purpose,\nif possible, that we may work with him and not against him.\"", "\n\n\"This conclusion affords not the slightest excuse for race antipathy.", "\nThe experience of mankind has convinced all peoples that close\nconsanguinity must be a bar to marriage; and scientific observation\nseems likely to show that the mixture of races most widely divergent is\nperhaps hardly less a violation of nature. ", "But there is in this fact no\nreason why there should not be as genuine respect and esteem and\nfellowship between the races as between brother and sister; no reason\nwhy the spirit of brotherhood which obtains in the home should not\nextend to the family of nations and races.\" ", "And Hamilton W. Mabie, in\nhis article in the Outlook for August 2nd on \"Americans and the Far\nEast,\" says: \"Race differences must be clearly and frankly recognized;\neconomical differences must be candidly faced; but race hatred must be\ndriven beyond the pale of civilization; it is a survival of barbarism\nand it must go back where it belongs.\"", "\n\nThis great white race will some day, I believe, in its sober second\nthought, recognize the truth of these words; and will augment its\ngreatness by emancipating itself from this detestable spirit of race\nhatred. ", "It cannot be that this great white race is always going to be\ncontent to prostrate itself before this mean and degrading spirit. ", "It\nowes it to itself, as well as to this black race and to all the other\nraces to free itself from so debasing an influence. ", "If it is to maintain\nits leadership in the world, under the ever-growing influence of\nChristianity, which knows neither Greek nor Jew, barbarian, Scythian\nbond, nor free, it cannot hope to do so with race prejudice inscribed on\nits banner. ", "It must change, or else it will be relegated to the rear.", "\nRIGHTEOUSNESS AND BROTHERHOOD are the great forces that are to dominate\nthe future. ", "The white man may be strong enough to fight the black man in\nthis country, but he is not strong enough to fight God Almighty and his\neternal and inexorable laws of RIGHTEOUSNESS and BROTHERHOOD. ", "These laws\nwill ultimately remake him, or break him and cast him \"as rubbish to the\nvoid.\" ", "Which shall it be? ", "Let this great white race take warning.", "\n\n \"Short is the triumph of evil.", "\n Long is the reign of right.", "\n The men who win by the aid of sin,\n The nation that rules by might,\n The party that lives by corruption,\n The trickster, the knave, the thief,\n May thrive for a time on the fruits of crime,\n But their seeming success is brief.", "\n\n Know that the truth shall triumph,\n That evil shall find its doom;\n That the cause of right, tho' subdued by might,\n Shall break from the strongest tomb,\n That wrong, tho' it seems to triumph,\n Lasts only for a day,\n While the cause of truth has eternal youth,\n And shall rule o'er the world for aye.\"", "\n\n ----------\n\n\n TRANSCRIBER'S NOTE\n\n\nSome spelling mistakes have been corrected.", "\n\nItalicized words and phrases are presented by surrounding the text with\nunderscores.", "\n\n\n\n\n\nEnd of Project Gutenberg's Fifty Years of Freedom, by Francis J. Grimke\n\n*** " ]

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[ "Comments\n\nNCAAF Picks\n\nCollege Football Picks: USC Trojans Future Betting Odds\n\nWhen college football betting odds are released later in the summer, USC will not be the favorite to win the Pac-12 South, that will belong to UCLA.", "\n\nNevertheless, if you consider how much\nand how far the Trojans program has changed since they lost to Arizona State\n62-41 on the last Saturday of September, well, if the Men of Troy are on your\nlist of frequent college football picks, you have to like the direction they are headed.", "\n\nUSC Seeking Stability\n\nFrom the time Peter Carroll\nleft for Seattle, words that easily roll out of one’s mouth are tumultuous and\nupheaval. ", "Lane Kiffin was a lightening rod for negative attention before he became\nthe Trojans head coach and nothing changed in his tenure. ", "When USC was ambushed\nin the desert by the Sun Devils, athletic director Pat Haden went with is gut\nand fired Kiffin, which he said was \"the best\ndecision for USC.\"", "\n\nEd Orgeron was\nnamed interim coach and did a fantastic job at stabilizing an impossible\nsituation, leading the Trojans on a six-game winning streak. ", "In the latter\nstages of the streak Orgeron openly campaigned for the job, but Haden had other\nideas. ", "In early December he hired former USC assistant and Washington head\ncoach Steve Sarkisian to run his team, which meant assistant Clay Helton would\nbe coaching the Las Vegas Bowl.", "\n\nFour head coaches\nin just over nine weeks, USC has to hope they found the right person.", "\n\nTrojans Have to Overcome Recruiting Shortages\n\nKiffin and Sarkisian were\nboth very aware of what they were walking into at USC. ", "The NCAA came down hard\non the football program for “lack of institutional control” and limited\nscholarships dramatically.", "\n\nCollege football handicappers\nfor years have watched USC injury reports because the number of available\nscholarship players has been no more than 70, leaving the Trojans to serious\ndepth issues.", "\n\nThis will be the last year of\nthe sanctions, but even Sarkisian acknowledges \"We'll\nprobably feel the effects of those sanctions for two more seasons, quite\nhonestly,\"\n\nHe understands\nno matter how many 5* recruits he brings in this year, he has a way to go to\ndevelop quality at all positions.", "\n\nCody Kessler\nfinished the season as “the guy’ under center for the Trojans but with a brand\nnew coaching staff and redshirt freshman sensation Max Browne, the competition\nwill be fierce.", "\n\nWhoever is\nquarterback, wide receiver Nelson Agholor will\nbe No. ", "1 target. ", "With Sarkisian, expect the use of the tight end to be more a\nfactor.", "\n\nThe college football odds might\nnot be stacked against USC, but having to replace three starters from what was\nalready a thin group will not be easy. ", "The presumption is the Men of Troy hope\nto put together a semblance of a good offensive line and let talented backs\nlike Javorius Allen, Tre Madden and Ty Isaac earn their way to playing time.", "\n\nDefense will be Fine, without Injuries\n\nUSC had a few\nlosses on the other side of the ball when safety\nDion Bailey and lineman George Uko left early for the NFL Draft. ", "But the rest\nof the defense returns largely intact, including DE Leonard Williams, LB Hayes\nPullard and S Su’a Cravens. ", "The real question here is the continuity and how\nquickly everything comes together. ", "While the talent is in place, the defense\nwill be susceptible to wearing down in the second half of the season and\ninjures would cause major issues.", "\n\nSchedule Will Still Be Rugged\n\nIn an unusual twist, USC\nfaced Fresno State in their bowl game and will play them again in their first\ncontest of the year. ", "This will be followed by a very early Pac-12 matchup at\nStanford and the very next week they will fly cross-country to Boston College.", "\nThose making college football picks will no doubt be focused on those two\ngames.", "\n\nAfter a bye week Oregon State\nand Arizona State will be L.A. the latter a big payback encounter. ", "The rest of\nthe schedule is home and away until the last two weeks when the Trojans have to\nprepare for cross-town rival UCLA at their place and back home for the season\nfinale with Notre Dame.", "\n\nRecruiting Efforts\n\nOn national\nsigning day, USC addressed their top need, with five offensive linemen and four\nwere rated as 4* studs. ", "Rivals.com rated this as the No. ", "10 class, but the\nsignings of Adoree' Jackson, Juju Smith and Damien Mama gave the Trojans the\nelite talent only LSU and Florida State could match as first-year players.", "\n\nWay Too Early Conclusion\n\nAt this juncture, Sark’s\nsquad figures to be underdogs at Stanford and at UCLA. ", "A victory in either\nlocation could set up at least a 10-win." ]

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