MRI of the lung (3/3)-current applications and future perspectives

BACKGROUND: MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. METHODS: Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. RESULTS: In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. CONCLUSION: New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations

MRI of the lung (2/3). Why … when … how?

Background Among the modalities for lung imaging, proton magnetic resonance imaging (MRI) has been the latest to be introduced into clinical practice. Its value to replace X-ray and computed tomography (CT) when radiation exposure or iodinated contrast material is contra-indicated is well acknowledged: i.e. for paediatric patients and pregnant women or for scientific use. One of the reasons why MRI of the lung is still rarely used, except in a few centres, is the lack of consistent protocols customised to clinical needs. Methods This article makes non-vendor-specific protocol suggestions for general use with state-of-the-art MRI scanners, based on the available literature and a consensus discussion within a panel of experts experienced in lung MRI. Results Various sequences have been successfully tested within scientific or clinical environments. MRI of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination. It serves in difficult clinical problems encountered in daily routine, such as assessment of the mediastinum and chest wall, and even might challenge molecular imaging techniques in the near future. Conclusion This article helps new users to implement appropriate protocols on their own MRI platforms. Main Messages • MRI of the lung can be readily performed on state-of-the-art 1.5-T MRI scanners. • Protocol suggestions based on the available literature facilitate its use for routine • MRI offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. • MRI is an option for paediatrics and science when CT is contra-indicate

Folding-competent and folding-defective forms of Ricin A chain have different fates following retrotranslocation from the endoplasmic reticulum

We report that a toxic polypeptide retaining the potential to refold upon dislocation from the endoplasmic reticulum (ER) to the cytosol (ricin A chain; RTA) and a misfolded version that cannot (termed RTAΔ), follow ER-associated degradation (ERAD) pathways in Saccharomyces cerevisiae that substantially diverge in the cytosol. Both polypeptides are dislocated in a step mediated by the transmembrane Hrd1p ubiquitin ligase complex and subsequently degraded. Canonical polyubiquitylation is not a prerequisite for this interaction because a catalytically inactive Hrd1p E3 ubiquitin ligase retains the ability to retrotranslocate RTA, and variants lacking one or both endogenous lysyl residues also require the Hrd1p complex. In the case of native RTA, we established that dislocation also depends on other components of the classical ERAD-L pathway as well as an ongoing ER–Golgi transport. However, the dislocation pathways deviate strikingly upon entry into the cytosol. Here, the CDC48 complex is required only for RTAΔ, although the involvement of individual ATPases (Rpt proteins) in the 19S regulatory particle (RP) of the proteasome, and the 20S catalytic chamber itself, is very different for the two RTA variants. We conclude that cytosolic ERAD components, particularly the proteasome RP, can discriminate between structural features of the same substrate

Magnetic resonance imaging in children: common problems and possible solutions for lung and airways imaging

Pediatric chest MRI is challenging. High-resolution scans of the lungs and airways are compromised by long imaging times, low lung proton density and motion. Low signal is a problem of normal lung. Lung abnormalities commonly cause increased signal intenstities. Among the most important factors for a successful MRI is patient cooperation, so the long acquisition times make patient preparation crucial. Children usually have problems with long breath-holds and with the concept of quiet breathing. Young children are even more challenging because of higher cardiac and respiratory rates giving motion blurring. For these reasons, CT has often been preferred over MRI for chest pediatric imaging. Despite its drawbacks, MRI also has advantages over CT, which justifies its further development and clinical use. The most important advantage is the absence of ionizing radiation, which allows frequent scanning for short- and long-term follow-up studie

Local SAR constrained Hotspot Reduction by Temporal Averaging

Introduction With increasing field strength the local specific absorption rate (SAR) becomes a limiting factor for many MR imaging applications. Minimal SAR RF pulses can be selected from the large solution space due to the extra degrees of freedom in the RF pulse desig

Cadm1-Expressing Synapses on Purkinje Cell Dendrites Are Involved in Mouse Ultrasonic Vocalization Activity

Foxp2(R552H) knock-in (KI) mouse pups with a mutation related to human speech–language disorders exhibit poor development of cerebellar Purkinje cells and impaired ultrasonic vocalization (USV), a communication tool for mother-offspring interactions. Thus, human speech and mouse USV appear to have a Foxp2-mediated common molecular basis in the cerebellum. Mutations in the gene encoding the synaptic adhesion molecule CADM1 (RA175/Necl2/SynCAM1/Cadm1) have been identified in people with autism spectrum disorder (ASD) who have impaired speech and language. In the present study, we show that both Cadm1-deficient knockout (KO) pups and Foxp2(R552H) KI pups exhibit impaired USV and smaller cerebellums. Cadm1 was preferentially localized to the apical–distal portion of the dendritic arbor of Purkinje cells in the molecular layer of wild-type pups, and VGluT1 level decreased in the cerebellum of Cadm1 KO mice. In addition, we detected reduced immunoreactivity of Cadm1 and VGluT1 on the poorly developed dendritic arbor of Purkinje cells in the Foxp2(R552H) KI pups. However, Cadm1 mRNA expression was not altered in the Foxp2(R552H) KI pups. These results suggest that although the Foxp2 transcription factor does not target Cadm1, Cadm1 at the synapses of Purkinje cells and parallel fibers is necessary for USV function. The loss of Cadm1-expressing synapses on the dendrites of Purkinje cells may be associated with the USV impairment that Cadm1 KO and Foxp2(R552H) KI mice exhibit

Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders

Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology.1 We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD;2 the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism;3 and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles,4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution

MRI of the lung (1/3):methods

Proton magnetic resonance imaging (MRI) has recently emerged as a clinical tool to image the lungs. This paper outlines the current technical aspects of MRI pulse sequences, radiofrequency (RF) coils and MRI system requirements needed for imaging the pulmonary parenchyma and vasculature. Lung MRI techniques are presented as a “technical toolkit”, from which MR protocols will be composed in the subsequent papers for comprehensive imaging of lung disease and function (parts 2 and 3). This paper is pitched at MR scientists, technicians and radiologists who are interested in understanding and establishing lung MRI methods. Images from a 1.5 T scanner are used for illustration of the sequences and methods that are highlighted. Main Messages • Outline of the hardware and pulse sequence requirements for proton lung MRI • Overview of pulse sequences for lung parenchyma, vascular and functional imaging with protons • Demonstration of the pulse-sequence building blocks for clinical lung MRI protocol

The Intracellular Threonine of Amyloid Precursor Protein That Is Essential for Docking of Pin1 Is Dispensable for Developmental Function

Background: Processing of Ab-precursor protein (APP) plays an important role in Alzheimer’s Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr 668 is replaced by an Ala (T 668 A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T 668 A allele into the APLP2 knockout background showed that mutation of Thr 668 does not cause a defective phenotype. Notably, the T 668 A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr 668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved i