Correction to: Perfusion MRI in CNS disease: current concepts.

The above article was published with one author name being incorrect. The published paper states "H. von Tengg", whereas it should be "H. von Tengg-Kobligk". The author name has been corrected above.

Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms.

The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L1 (linker between the two halves of the exporter); L0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics.

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

High-grade glioma management and response assessment-recent advances and current challenges.

The management of high-grade gliomas (hggs) is complex and ever-evolving. The standard of care for the treatment of hggs consists of surgery, chemotherapy, and radiotherapy. However, treatment options are influenced by multiple factors such as patient age and performance status, extent of tumour resection, biomarker profile, and tumour histology and grade. Follow-up cranial magnetic resonance imaging (mri) to differentiate treatment response from treatment effect can be challenging and affects clinical decision-making. An assortment of advanced radiologic techniques-including perfusion imaging with dynamic susceptibility contrast mri, dynamic contrast-enhanced mri, diffusion-weighted imaging, proton spectroscopy, mri subtraction imaging, and amino acid radiotracer imaging-can now incorporate novel physiologic data, providing new methods to help characterize tumour progression, pseudoprogression, and pseudoresponse. In the present review, we provide an overview of current treatment options for hgg and summarize recent advances and challenges in imaging technology.

EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part II. Diagnostic Ultrasound-Guided Interventional Procedures (Short Version).

This is the second part of the series on interventional ultrasound guidelines of the Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). It deals with the diagnostic interventional procedure. General points are discussed which are pertinent to all patients, followed by organ-specific imaging that will allow the correct pathway and planning for the interventional procedure. This will allow for the appropriate imaging workup for each individual interventional procedure (Long version/ short version; the long version is published online).

EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part II. Diagnostic Ultrasound-Guided Interventional Procedures (Long Version).

This is the second part of the series on interventional ultrasound guidelines of the Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). It deals with the diagnostic interventional procedure. General points are discussed which are pertinent to all patients, followed by organ-specific imaging that will allow the correct pathway and planning for the interventional procedure. This will allow for the appropriate imaging workup for each individual interventional procedure (Long version).

Comparison of gadofosveset (Vasovist(®)) with gadobenate dimeglumine (Multihance(®))-enhanced MR angiography for high-grade carotid artery stenosis.

OBJECTIVE: To prove superiority of blood pool contrast agent gadofosveset over conventional contrast agent gadobenate dimeglumine for assessment of stenotic internal carotid artery (ICA). METHODS: Eleven patients with high-grade ICA stenosis (≥75%), confirmed by duplex sonography, underwent MR angiography (MRA) with gadofosveset and gadobenate dimeglumine. RESULTS: Agreement in stenosis grade was reached in 7 of 10 stenotic ICAs. In two ICAs, gadobenate dimeglumine led to underestimation of stenosis grade. There was a significant difference in signal intensity (pre-/post-stenotic segments), showing higher values for gadofosveset (P<0.01; P<0.05). Impression of contrast intensity with gadofosveset was better in 8 ICAs and only in 1 ICA with gadobenate dimeglumine (P<0.05). CONCLUSION: Gadofosveset-enhanced MR angiography may be superior for assessment of high-grade ICA stenosis compared with gadobenate dimeglumine MR angiography.

Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

Bordetella holmesii bacteremia in a renal transplant recipient: emergence of a new pathogen.

Bordetella holmesii is a gram-negative rod that was initially identified in 1995. It causes bacteremia, pneumonia, and endocarditis mostly in patients with anatomical or functional asplenia. We report here, to the best of our knowledge, the first case of B. holmesii bacteremia in a renal transplant recipient following rituximab therapy for recurrence of membranoproliferative glomerulonephritis.

[Visualization of radiation effects on the central nervous system]. / Visualisierung von Strahlenfolgen am Zentralnervensystem.

Therapy-related side effects, which are detectable with magnetic resonance imaging (MRI) at high sensitivity, are one of the most frequent causes of morbidity in cancer patients. They can be observed in the treatment of central nervous system (CNS) diseases as well as in systemic therapy, including whole brain irradiation and chemotherapy and are more often seen due to the better overall survival. This review describes the most frequent acute and chronic therapy-related changes in the CNS and the imaging findings. Acute changes are often reversible while chronic changes can be observed up to several years after treatment.The differentiation of treatment-related from tumor-related changes might be very difficult, although modern imaging modalities such as MR spectroscopy or MR perfusion measurements supply helpful differential diagnostic information.

Uterine allotransplantation in ewes using an aortocava patch.

BACKGROUND: We investigated a novel allotransplantation model using an aortocava patch in ewes. METHODS AND RESULTS: We carried out 10 uterine orthotopic allotransplantations in ewes with end-to-side anastomosis of the aortocava donor patch on the left external iliac vessel recipient. The immunosuppressive protocol was a combination of cyclosporine (10 mg/kg/day) and mycophenolic acid (3 g/day). An estimation of the immunosuppressive therapy exposure was performed by measuring the area under the curve (AUC) of immunosuppressive plasma concentrations. The graft was assessed by vaginoscopy, magnetic resonance imaging (MRI) and second look laparotomy at 6, 8 and 10 weeks, respectively. The median (range) times for cold and warm ischemia were 95 min (75-130) and 91 min (55-165), respectively. All the vascular anastomoses were patent at the end of the surgery. The median AUC of cyclosporine and mycophenolic acid were 1.24 mg h/l (0.34-3.85) and 18.40 mg h/l (3.76-42.35), respectively. Of the 10 ewes receiving a transplant, 6 could be assessed. Cervical biopsies showed signs of necrosis in all six ewes. The MRI results correlated with the macroscopic observations of the 'second look' laparotomy. The aortocava vascular pedicles were thrombosed, adding to the peripheral neovascularization. Graft histology showed endometrial tissue in two out of six ewes. CONCLUSIONS: Mobility of the transplant within the pelvis, the length of the vascular pedicle and rejection can explain the high rate of transplant necrosis. The particular digestive anatomy and physiology of ruminants makes it difficult to administer an optimal immunosuppressive treatment. MRI appears to be a good non-invasive examination for graft estimation.

[Normal aging and imaging correlations]. / Normales Altern und seine Bildgebungskorrelate.

Age-related structural, functional and biochemical changes of the brain can be visualized by neuroimaging methods. Physiological aging of the brain has to be clearly distinguished from pathological alterations of the brain for reliable and early diagnoses of neurodegenerative diseases. Concerning the speed of the cerebral aging process, significant inter-individual differences can be observed. In general, aging is associated with a decline of cognitive functions. Simultaneously, a decay of the average brain volume, especially in the frontal lobe accompanies the process of aging. Correspondingly, a strong susceptibility for age-related degeneration has been observed in the fronto-striato-thalamic network. Due to increasing age the white matter is affected by a progressive loss of fiber integrity mirrored in a significant decay of the fractionated anisotropy (FA) measured by diffusion tensor imaging (DTI). Age-related degeneration of the white matter further leads to a growing number of T2 hyperintense white-matter lesions. Aging also influences the cerebral perfusion pattern leading to a perceptible decay of the global cerebral blood flow (CBF) and blood volume (CBV). During life, iron accumulates in the brain, predominantly in the globus pallidus and in the substantia nigra. By 1H-MR spectroscopy, a decrease of N-acetyl-aspartate (NAA) as a correlate for reduced neuronal metabolism is found in the brain of elderly individuals.

[Symptoms and imaging diagnostics of neurodegenerative dementia]. / Klinik und bildgebende Diagnostik neurodegenerativer Demenzen.

A variety of neurodegenerative diseases can underlie dementia syndromes. In addition to Alzheimer's disease (AD) and its prodromal stages, these include in particular frontotemporal degeneration, Lewy body dementia and Parkinson's dementia, progressive supranuclear paresis, corticobasal degeneration and chorea Huntington. Although not classified as a neurodegenerative brain disease, for all clinical diagnoses there must be a differential diagnostic separation from vascular forms of dementia. Furthermore an exclusion of affective disorders, such as minor depression is necessary from a clinical psychiatric perspective. Moreover the preclinical stages of AD often present with uncharacteristic symptoms. Especially affective symptoms can occur in addition to initial cognitive deficits such as memory decline. In summary, clinical and neuropsychological procedures together with functional imaging techniques allow a detailed diagnostic assessment of neurodegenerative dementia syndromes which can be additionally supported by neurochemical biomarkers and innovative imaging procedures, such as diffusion imaging or magnetic resonance spectroscopy.

[Mild cognitive impairment: diagnostic value of different MR techniques]. / "Mild cognitive impairment": Diagnostische Wertigkeit verschiedener MR-Techniken.

In view of an increasingly aging population the prevalence of dementia is also expected to increase rapidly. As well as clinical, neuropsychological and laboratory procedures magnetic resonance imaging (MRI) plays an important role in the early diagnosis of dementia which is important in the precursor stage of mild cognitive impairment (MCI). On the one hand this stage is associated with an increased risk of dementia and on the other hand an early treatment in this stage could attenuate development of the disease. In addition to morphological changes different functional MRI techniques can help in the early diagnosis of dementia and the precursor stages. Moreover, it is important to detect those MCI patients who are at particularly risk for developing dementia. In the differentiation of converters to non-converters initial studies suggest that particularly voxel-based morphometry, MR spectroscopy and diffusion tensor imaging can provide important additional information.

[Significance of MR angiography for imaging diagnostics of carotid artery diseases]. / Stellenwert der MR-Angiographie zur bildgebenden Diagnostik von Erkrankungen der Karotiden.

During the last decade, magnetic resonance angiography (MRA) evolved to an essential method for radiological diagnostics of extracranial arteries' diseases. Contrast enhanced MRA enables meanwhile the acquisition of angiographic series in high diagnostic quality comparable to that originating from conventional DSA. Due to MRA, conventional DSA anymore plays a crucial role in the diagnostic assessment of carotid artery disease or highly vascularised tumors of the head and neck region. Besides reliable quantification of carotid stenoses, highly resolved MRI sequences provide a promising approach for characterization of plaque morphologies and thereby contribute to turn the risk for a stroke calculable. Furthermore, MRA has nearly replaced DSA in radiographics of carotid artery dissections whereas MRA has especially emerged as an appropriate method to visualize the intramural hematoma which is evidentiary for the diagnosis. However, not all methods of MRA are equivalent in respect to their diagnostic value. While CE MRA is able to completely substitute DSA in many clinical questions, applicability of flow-dependent Time-of-flight (TOF) or phase-contrast (PC) MRA is limited due to their distinct susceptibility to motion or flow-related artefacts.

[MR spectroscopy in dementia]. / MR-Spektroskopie bei Demenz.

With an increasingly aging population we are faced with the problem of an increasing number of dementia patients. In addition to clinical, neuropsychological and laboratory procedures, MRI plays an important role in the early diagnosis of dementia. In addition to various morphological changes functional changes can also help in the diagnosis and differential diagnosis of dementia. Overall the diagnosis of dementia can be improved by using parameters from MR spectroscopy. This article focuses on MR spectroscopic changes in the physiological aging process as well as on changes in mild cognitive impairment a precursor of Alzheimer's dementia, in Alzheimer's dementia, frontotemporal dementia, vascular dementia and Lewy body dementia.

Predicting Motor Outcome in Acute Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Predicting motor outcome following intracerebral hemorrhage is challenging. We tested whether the combination of clinical scores and DTI-based assessment of corticospinal tract damage within the first 12 hours of symptom onset after intracerebral hemorrhage predicts motor outcome at 3 months. MATERIALS AND METHODS: We prospectively studied patients with motor deficits secondary to primary intracerebral hemorrhage within the first 12 hours of symptom onset. Patients underwent multimodal MR imaging including DTI. We assessed intracerebral hemorrhage and perihematomal edema location and volume, and corticospinal tract involvement. The corticospinal tract was considered affected when the tractogram passed through the intracerebral hemorrhage or/and the perihematomal edema. We also calculated affected corticospinal tract-to-unaffected corticospinal tract ratios for fractional anisotropy, mean diffusivity, and axial and radial diffusivities. Motor impairment was graded by the motor subindex scores of the modified NIHSS. Motor outcome at 3 months was classified as good (modified NIHSS 0-3) or poor (modified NIHSS 4-8). RESULTS: Of 62 patients, 43 were included. At admission, the median NIHSS score was 13 (interquartile range = 8-17), and the median modified NIHSS score was 5 (interquartile range = 2-8). At 3 months, 13 (30.23%) had poor motor outcome. Significant independent predictors of motor outcome were NIHSS and modified NIHSS at admission, posterior limb of the internal capsule involvement by intracerebral hemorrhage at admission, intracerebral hemorrhage volume at admission, 72-hour NIHSS, and 72-hour modified NIHSS. The sensitivity, specificity, and positive and negative predictive values for poor motor outcome at 3 months by a combined modified NIHSS of >6 and posterior limb of the internal capsule involvement in the first 12 hours from symptom onset were 84%, 79%, 65%, and 92%, respectively (area under the curve = 0.89; 95% CI, 0.78-1). CONCLUSIONS: Combined assessment of motor function and posterior limb of the internal capsule damage during acute intracerebral hemorrhage accurately predicts motor outcome.

[Radiological diagnostics of muscle diseases]. / Radiologische Diagnostik von Muskelerkrankungen.

Muscular diseases are a heterogeneous group of diseases with difficult differential diagnosis. This article reviews morphological and functional radiological techniques for assessment of muscular diseases. Morphological techniques can describe edema-like changes, lipomatous and atrophic changes of muscular tissue. However, these imaging signs are often not disease-specific. As a result, clinicians assign radiology a secondary role in the management of muscular diseases. Meanwhile, functional radiological techniques allow the assessment of muscle fiber architecture, skeletal muscle perfusion, myocellular sodium-homoeostasis, lipid- and energy-phosphate metabolism, etc. By detecting and spatially localizing pathophysiological phenomena, these new techniques can increase the role of radiology in muscular diseases.

[Haemolytic uremic syndrome and acute mesenteric ischemia caused by interferon-alpha-2b in the treatment of Kaposi's sarcoma in an AIDS patient]. / Syndrome hémolytique et urémique et ischémie mésentérique aiguë lors d'un traitement par interféron alpha-2b pour une maladie de Kaposi associée au VIH.

BACKGROUND: Interferon alpha is approved for the treatment of Kaposi's sarcoma in HIV infected patients. Hemolytic and uremic syndrome (HUS) is a rare side-effect of interferon alpha and has been reported primarily in chronic myelogenous leukemia. CASE REPORT: A 44-year-old HIV-infected woman from Cameroon was admitted for treatment of cutaneous Kaposi's sarcoma. Two days later, she presented severe HUS. Abdominal pains subsequently revealed non-occlusive mesenteric ischemia. The patient rapidly improved after interferon withdrawal. DISCUSSION: To our knowledge this is the first case of HUS induced by interferon alpha given for Kaposi's sarcoma. Further, no cases of acute mesenteric ischemia have been reported with interferon alpha. It is possible that the condition may have been induced or aggravated by HUS or a low infusion rate. Interferon can exert vascular toxicity on both the mesenteric vessels and the renal vessels in a setting of microangiopathy.