In vivo evaluation of the translations of the gleno-humeral joint using Magnetic resonance imaging

Gleno-humeral joint (GHJ) is the most mobile joint of the human body. This is related to theincongr uence between the large humeral head articulating with the much smaller glenoid (ratio 3:1). The GHJ laxity is the ability of the humeral head to be passively translated on the glenoid fossa and, when physiological, it guarantees the normal range of motion of the joint. Three-dimensional GHJ linear displacements have been measured, both in vivo and in vitro by means of different instrumental techniques. In vivo gleno-humeral displacements have been assessed by means of stereophotogrammetry, electromagnetic tracking sensors, and bio-imaging techniques. Both stereophotogrammetric systems and electromagnetic tracking devices, due to the deformation of the soft tissues surrounding the bones, are not capable to accurately assess small displacements, such as gleno-humeral joint translations. The bio-imaging techniques can ensure for an accurate joint kinematic (linear and angular displacement) description, but, due to the radiation exposure, most of these techniques, such as computer tomography or fluoroscopy, are invasive for patients. Among the bioimaging techniques, an alternative which could provide an acceptable level of accuracy and that is innocuous for patients is represented by magnetic resonance imaging (MRI). Unfortunately, only few studies have been conducted for three-dimensional analysis and very limited data is available in situations where preset loads are being applied. The general aim of this doctoral thesis is to develop a non-invasive methodology based on open-MRI for in-vivo evaluation of the gleno-humeral translation components in healthy subjects under the application of external loads.

First measurements of the aSPECT spectrometer

The aSPECT spectrometer has been constructed to measure, with high precision, the integral proton spectrum of the free neutron decay. From this spectrum the neutrino electron angular correlation coefficient a can be inferred. The coefficient a is involved in several Standard Model tests, like the unitarity test of the Cabibbo-Kobayashi-Maskawa quark mixing matrix. aSPECT has been designed to determine the coefficient a with an accuracy better than 3×10−4, that is, one order of magnitude better than the best current accuracy. First measurements with neutron beam with the aSPECT spectrometer were performed in the Forschungsneutronenquelle Heinz Maier-Leibnitz, in Munich. A study of the data taken in this period is presented in this thesis, demonstrating the proof of principle of the spectrometer. However, the observation of situation and time-dependent background instabilities impedes the report of a new value of the coefficient a. A thorough data analysis is carried out to identify sources of these background instabilities in order to improve the aSPECT experiment for future beam times. The investigation indicates that trapped particles are most likely the reason for the background problems. Furthermore, it has been observed that measurements containing less trapped particles provide a-values closer to the currently Particle Data Group value. Based on this findings, different measures are proposed to eliminate potential traps in the spectrometer. Indeed, with the proposed modifications realized for the following beam-times, the observed background instabilities were greatly reduced.

Airborne in situ measurements of ice particles in the tropical tropopause layer

Ice clouds have a strong effect on the Earth-atmosphere radiative energy balance, on the distribution of condensable gases in the atmosphere, as well as on the chemical composition of the air. The ice particles in these clouds can take on a variety of shapes which makes the description of the cloud microphysical properties more difficult. In the tropical upper troposphere/lower stratosphere (UTLS), a region where ice cloud abundance is relatively high, different types of ice clouds can be observed. However, in situ measurements are rare due to the high altitude of these clouds and the few available research aircraft, only three worldwide, that can fly at such altitudes.rnThis work focuses on in situ measurements of the tropical UTLS clouds performedrnwith a Cloud Imaging Probe (CIP) and a Forward Scattering Spectrometer Probern(FSSP-100), whereof the CIP is the key instrument of this thesis. The CIP is anrnairborne in situ instrument that obtains two-dimensional shadow images of cloud particles. Several cloud microphysical parameters can be derived from these measurements, e.g. number concentrations and size distributions. In order to obtain a high quality data set, a careful image analysis and several corrections need to be applied to the CIP observations. These methods are described in detail.rnMeasurements within the tropical UTLS have been performed during two campaigns:rnSCOUT-O3, 2005 in Northern Australia and SCOUT-AMMA, 2006 inWest Africa. Thernobtained data set includes first observations of subvisible cirrus clouds over a continental area and observations of the anvils of deep convective clouds. The latter can be further divided into clouds in mesoscale convective system outflows of different ages and clouds in overshooting cloud turrets that even penetrated the stratosphere. The microphysical properties of these three cloud types are discussed in detail. Furthermore, the vertical structure of the ice clouds in the UTLS is investigated. The values of the microphysical parameters were found to decrease with increasing altitude in the upper troposphere. Particle numbers and maximum sizes were also decreasing with increasing age of the outflow clouds. Further differences between the deep convective clouds and subvisible cirrus were found in the particle morphology as well as in the ratio of the observed aerosol particles to cloud particles which indicates that the different freezing processes (deposition, contact, immersion freezing) play different roles in the formation of the respective clouds. For the achievementrnof a better microphysical characterisation and description numerical fits have been adjusted onto the cloud particle size distributions of the subvisible cirrus as well as on the size distributions of the clouds at different altitudes in the UTLS.

Measurement of the proton recoil spectrum in neutron beta decay with the spectrometer aSPECT : study of systematic effects

Precision measurements of observables in neutron beta decay address important open questions of particle physics and cosmology. In this thesis, a measurement of the proton recoil spectrum with the spectrometer aSPECT is described. From this spectrum the antineutrino-electron angular correlation coefficient a can be derived. In our first beam time at the FRM II in Munich, background instabilities prevented us from presenting a new value for a. In the latest beam time at the ILL in Grenoble, the background has been reduced sufficiently. As a result of the data analysis, we identified and fixed a problem in the detector electronics which caused a significant systematic error. The aim of the latest beam time was a new value for a with an error well below the present literature value of 4%. A statistical accuracy of about 1.4% was reached, but we could only set upper limits on the correction of the problem in the detector electronics, too high to determine a meaningful result. This thesis focused on the investigation of different systematic effects. With the knowledge of the systematics gained in this thesis, we are able to improve aSPECT to perform a 1% measurement of a in a further beam time.

Measurement of the unpolarized K+ Lambda and K+ Sigma 0 electroproduction cross-section off the proton with KAOS-spectrometer

The new stage of the Mainz Microtron, MAMI, at the Institute for Nuclear Physics of the Johannes Gutenberg-University, operational since 2007, allows open strangeness experiments to be performed. Covering the lack of electroproduction data at very low Q2, p(e,K+)Lambda and p(e,K+)Sigma0, reactions have been studied at Q^2 = 0.036(GeV/c)^2 andrnQ^2 = 0.05(GeV=c)^2 in a large angular range. Cross-section at W=1.75rnGeV will be given in angular bins and compared with the predictions of Saclay-Lyon and Kaon Maid isobaric models. We conclude that the original Kaon-Maid model, which has large longitudinal couplings of the photon to nucleon resonances, is unphysical. Extensive studies for the suitability of silicon photomultipliers as read out devices for a scintillating fiber tracking detector, with potential applications in both positive and negative arms of the spectrometer, will be presented as well.

Etablierung eines high content imaging-basierten in vitro Testsystems zur Evaluierung genotoxischer Substanzen

Zur Registrierung von Pharmazeutika ist eine umfassende Analyse ihres genotoxischen Potentials von Nöten. Aufgrund der Vielzahl genotoxischer Mechanismen und deren resultierenden Schäden wird ein gestaffeltes Testdesign durch die ICH-Richtlinie S2(R1) „Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use S2(R1)“ definiert, um alle genotoxischen Substanzen zu identifizieren. Die Standardtestbatterie ist in der frühen Phase der Arzneimittelentwicklung aufgrund des geringen Durchsatzes und des Mangels an verfügbarer Substanzmenge vermindert anwendbar. Darüber hinaus verfügen in vitro Genotoxizitätstests in Säugerzellen über eine relativ geringe Spezifität. Für eine vollständige Sicherheitsbeurteilung wird eine in vivo Testung auf Kanzerogenität benötigt. Allerdings sind diese Testsysteme kosten- und zeitintensiv. Aufgrund dessen zielen neue Forschungsansätze auf die Verbesserung der Prädiktivität und die Erfassung des genotoxischen Potentials bereits in der frühen Phase der Arzneimittelentwicklung ab. Die high content imaging (HCI)-Technologie offeriert einen Ansatz zur Verbesserung des Durchsatzes verglichen mit der Standardtestbatterie. Zusätzlich hat ein Zell-basiertes Modell den Vorteil Daten relativ schnell bei gleichzeitig geringem Bedarf an Substanzmenge zu generieren. Demzufolge ermöglichen HCI-basierte Testsysteme eine Prüfung in der frühen Phase der pharmazeutischen Arzneimittelentwicklung. Das Ziel dieser Studie ist die Entwicklung eines neuen, spezifischen und sensitiven HCI-basierten Testsytems für Genotoxine und Progenotoxine in vitro unter Verwendung von HepG2-Zellen gewesen. Aufgrund ihrer begrenzten metabolischen Kapazität wurde ein kombiniertes System bestehend aus HepG2-Zellen und einem metabolischen Aktivierungssystem zur Testung progenotoxischer Substanzen etabliert. Basierend auf einer vorherigen Genomexpressionsprofilierung (Boehme et al., 2011) und einer Literaturrecherche wurden die folgenden neun unterschiedlichen Proteine der DNA-Schadensantwort als putative Marker der Substanz-induzierten Genotoxizität ausgewählt: p-p53 (Ser15), p21, p-H2AX (Ser139), p-Chk1 (Ser345) p-ATM (Ser1981), p-ATR (Ser428), p-CDC2 (Thr14/Tyr15), GADD45A und p-Chk2 (Thr68). Die Expression bzw. Aktivierung dieser Proteine wurde 48 h nach Behandlung mit den (pro-) genotoxischen Substanzen (Cyclophosphamid, 7,12-Dimethylbenz[a]anthracen, Aflatoxin B1, 2-Acetylaminofluoren, Methylmethansulfonat, Actinomycin D, Etoposid) und den nicht-genotoxischen Substanzen (D-Mannitol, Phenforminhydrochlorid, Progesteron) unter Verwendung der HCI-Technologie ermittelt. Die beste Klassifizierung wurde bei Verwendung der folgenden fünf der ursprünglichen neun putativen Markerproteine erreicht: p-p53 (Ser15), p21, p-H2AX (Ser139), p-Chk1 (Ser345) und p-ATM (Ser1981). In einem zweiten Teil dieser Arbeit wurden die fünf ausgewählten Proteine mit Substanzen, welche von dem European Centre for the Validation of Alternative Methods (ECVAM) zur Beurteilung der Leistung neuer oder modifizierter in vitro Genotoxizitätstests empfohlen sind, getestet. Dieses neue Testsystem erzielte eine Sensitivität von 80 % und eine Spezifität von 86 %, was in einer Prädiktivität von 84 % resultierte. Der synergetische Effekt dieser fünf Proteine ermöglicht die Identifizierung von genotoxischen Substanzen, welche DNA-Schädigungen durch eine Vielzahl von unterschiedlichen Mechanismen induzieren, mit einem hohen Erfolg. Zusammenfassend konnte ein hochprädiktives Prüfungssystem mit metabolischer Aktivierung für ein breites Spektrum potenziell genotoxischer Substanzen generiert werden, welches sich aufgrund des hohen Durchsatzes, des geringen Zeitaufwandes und der geringen Menge benötigter Substanz zur Substanzpriorisierung und -selektion in der Phase der Leitstrukturoptimierung eignet und darüber hinaus mechanistische Hinweise auf die genotoxische Wirkung der Testsubstanz liefert.

Imaging and modeling of pore scale processes in porous media using X-ray computed tomography and lattice Boltzmann solver

In der Erdöl– und Gasindustrie sind bildgebende Verfahren und Simulationen auf der Porenskala im Begriff Routineanwendungen zu werden. Ihr weiteres Potential lässt sich im Umweltbereich anwenden, wie z.B. für den Transport und Verbleib von Schadstoffen im Untergrund, die Speicherung von Kohlendioxid und dem natürlichen Abbau von Schadstoffen in Böden. Mit der Röntgen-Computertomografie (XCT) steht ein zerstörungsfreies 3D bildgebendes Verfahren zur Verfügung, das auch häufig für die Untersuchung der internen Struktur geologischer Proben herangezogen wird. Das erste Ziel dieser Dissertation war die Implementierung einer Bildverarbeitungstechnik, die die Strahlenaufhärtung der Röntgen-Computertomografie beseitigt und den Segmentierungsprozess dessen Daten vereinfacht. Das zweite Ziel dieser Arbeit untersuchte die kombinierten Effekte von Porenraumcharakteristika, Porentortuosität, sowie die Strömungssimulation und Transportmodellierung in Porenräumen mit der Gitter-Boltzmann-Methode. In einer zylindrischen geologischen Probe war die Position jeder Phase auf Grundlage der Beobachtung durch das Vorhandensein der Strahlenaufhärtung in den rekonstruierten Bildern, das eine radiale Funktion vom Probenrand zum Zentrum darstellt, extrahierbar und die unterschiedlichen Phasen ließen sich automatisch segmentieren. Weiterhin wurden Strahlungsaufhärtungeffekte von beliebig geformten Objekten durch einen Oberflächenanpassungsalgorithmus korrigiert. Die Methode der „least square support vector machine” (LSSVM) ist durch einen modularen Aufbau charakterisiert und ist sehr gut für die Erkennung und Klassifizierung von Mustern geeignet. Aus diesem Grund wurde die Methode der LSSVM als pixelbasierte Klassifikationsmethode implementiert. Dieser Algorithmus ist in der Lage komplexe geologische Proben korrekt zu klassifizieren, benötigt für den Fall aber längere Rechenzeiten, so dass mehrdimensionale Trainingsdatensätze verwendet werden müssen. Die Dynamik von den unmischbaren Phasen Luft und Wasser wird durch eine Kombination von Porenmorphologie und Gitter Boltzmann Methode für Drainage und Imbibition Prozessen in 3D Datensätzen von Böden, die durch synchrotron-basierte XCT gewonnen wurden, untersucht. Obwohl die Porenmorphologie eine einfache Methode ist Kugeln in den verfügbaren Porenraum einzupassen, kann sie dennoch die komplexe kapillare Hysterese als eine Funktion der Wassersättigung erklären. Eine Hysterese ist für den Kapillardruck und die hydraulische Leitfähigkeit beobachtet worden, welche durch die hauptsächlich verbundenen Porennetzwerke und der verfügbaren Porenraumgrößenverteilung verursacht sind. Die hydraulische Konduktivität ist eine Funktion des Wassersättigungslevels und wird mit einer makroskopischen Berechnung empirischer Modelle verglichen. Die Daten stimmen vor allem für hohe Wassersättigungen gut überein. Um die Gegenwart von Krankheitserregern im Grundwasser und Abwässern vorhersagen zu können, wurde in einem Bodenaggregat der Einfluss von Korngröße, Porengeometrie und Fluidflussgeschwindigkeit z.B. mit dem Mikroorganismus Escherichia coli studiert. Die asymmetrischen und langschweifigen Durchbruchskurven, besonders bei höheren Wassersättigungen, wurden durch dispersiven Transport aufgrund des verbundenen Porennetzwerks und durch die Heterogenität des Strömungsfeldes verursacht. Es wurde beobachtet, dass die biokolloidale Verweilzeit eine Funktion des Druckgradienten als auch der Kolloidgröße ist. Unsere Modellierungsergebnisse stimmen sehr gut mit den bereits veröffentlichten Daten überein.

Graph-based analysis of brain resting-state fMRI data in nocturnal frontal lobe epileptic patients

Il lavoro che ho sviluppato presso l'unità di RM funzionale del Policlinico S.Orsola-Malpighi, DIBINEM, è incentrato sull'analisi dati di resting state - functional Magnetic Resonance Imaging (rs-fMRI) mediante l'utilizzo della graph theory, con lo scopo di valutare eventuali differenze in termini di connettività cerebrale funzionale tra un campione di pazienti affetti da Nocturnal Frontal Lobe Epilepsy (NFLE) ed uno di controlli sani. L'epilessia frontale notturna è una peculiare forma di epilessia caratterizzata da crisi che si verificano quasi esclusivamente durante il sonno notturno. Queste sono contraddistinte da comportamenti motori, prevalentemente distonici, spesso complessi, e talora a semiologia bizzarra. L'fMRI è una metodica di neuroimaging avanzata che permette di misurare indirettamente l'attività neuronale. Tutti i soggetti sono stati studiati in condizioni di resting-state, ossia di veglia rilassata. In particolare mi sono occupato di analizzare i dati fMRI con un approccio innovativo in campo clinico-neurologico, rappresentato dalla graph theory. I grafi sono definiti come strutture matematiche costituite da nodi e links, che trovano applicazione in molti campi di studio per la modellizzazione di strutture di diverso tipo. La costruzione di un grafo cerebrale per ogni partecipante allo studio ha rappresentato la parte centrale di questo lavoro. L'obiettivo è stato quello di definire le connessioni funzionali tra le diverse aree del cervello mediante l'utilizzo di un network. Il processo di modellizzazione ha permesso di valutare i grafi neurali mediante il calcolo di parametri topologici che ne caratterizzano struttura ed organizzazione. Le misure calcolate in questa analisi preliminare non hanno evidenziato differenze nelle proprietà globali tra i grafi dei pazienti e quelli dei controlli. Alterazioni locali sono state invece riscontrate nei pazienti, rispetto ai controlli, in aree della sostanza grigia profonda, del sistema limbico e delle regioni frontali, le quali rientrano tra quelle ipotizzate essere coinvolte nella fisiopatologia di questa peculiare forma di epilessia.

Performance analysis of reconstruction algorithms for breast microwave imaging

The problem of localizing a scatterer, which represents a tumor, in a homogeneous circular domain, which represents a breast, is addressed. A breast imaging method based on microwaves is considered. The microwave imaging involves to several techniques for detecting, localizing and characterizing tumors in breast tissues. In all such methods an electromagnetic inverse scattering problem exists. For the scattering detection method, an algorithm based on a linear procedure solution, inspired by MUltiple SIgnal Classification algorithm (MUSIC) and Time Reversal method (TR), is implemented. The algorithm returns a reconstructed image of the investigation domain in which it is detected the scatterer position. This image is called pseudospectrum. A preliminary performance analysis of the algorithm vying the working frequency is performed: the resolution and the signal-to-noise ratio of the pseudospectra are improved if a multi-frequency approach is considered. The Geometrical Mean-MUSIC algorithm (GM- MUSIC) is proposed as multi-frequency method. The performance of the GMMUSIC is tested in different real life computer simulations. The performed analysis shows that the algorithm detects the scatterer until the electrical parameters of the breast are known. This is an evident limit, since, in a real life situation, the anatomy of the breast is unknown. An improvement in GM-MUSIC is proposed: the Eye-GMMUSIC algorithm. Eye-GMMUSIC algorithm needs no a priori information on the electrical parameters of the breast. It is an optimizing algorithm based on the pattern search algorithm: it searches the breast parameters which minimize the Signal-to-Clutter Mean Ratio (SCMR) in the signal. Finally, the GM-MUSIC and the Eye-GMMUSIC algorithms are tested on a microwave breast cancer detection system consisting of an dipole antenna, a Vector Network Analyzer and a novel breast phantom built at University of Bologna. The reconstruction of the experimental data confirm the GM-MUSIC ability to localize a scatterer in a homogeneous medium.

Tomographic 3D reconstruction through linear inversion for breast microwave imaging

In the present thesis we address the problem of detecting and localizing a small spherical target with characteristic electrical properties inside a volume of cylindrical shape, representing female breast, with MWI. One of the main works of this project is to properly extend the existing linear inversion algorithm from planar slice to volume reconstruction; results obtained, under the same conditions and experimental setup are reported for the two different approaches. Preliminar comparison and performance analysis of the reconstruction algorithms is performed via numerical simulations in a software-created environment: a single dipole antenna is used for illuminating the virtual breast phantom from different positions and, for each position, the corresponding scattered field value is registered. Collected data are then exploited in order to reconstruct the investigation domain, along with the scatterer position, in the form of image called pseudospectrum. During this process the tumor is modeled as a dielectric sphere of small radius and, for electromagnetic scattering purposes, it's treated as a point-like source. To improve the performance of reconstruction technique, we repeat the acquisition for a number of frequencies in a given range: the different pseudospectra, reconstructed from single frequency data, are incoherently combined with MUltiple SIgnal Classification (MUSIC) method which returns an overall enhanced image. We exploit multi-frequency approach to test the performance of 3D linear inversion reconstruction algorithm while varying the source position inside the phantom and the height of antenna plane. Analysis results and reconstructed images are then reported. Finally, we perform 3D reconstruction from experimental data gathered with the acquisition system in the microwave laboratory at DIFA, University of Bologna for a recently developed breast-phantom prototype; obtained pseudospectrum and performance analysis for the real model are reported.

A Fully Automatic Calibration Framework for Navigated Ultrasound Imaging

Navigated ultrasound (US) imaging is used for the intra-operative acquisition of 3D image data during imageguided surgery. The presented approach includes the design of a compact and easy to use US calibration device and its integration into a software application for navigated liver surgery. User interaction during the calibration process is minimized through automatic detection of the calibration process followed by automatic image segmentation, calculation of the calibration transform and validation of the obtained result. This leads to a fast, interaction-free and fully automatic calibration procedure enabling intra-operative

Pros and cons of post-mortem CT imaging on aspiration diagnosis

Recently, the field of forensics has experienced a rapid increase in the use of modern cross-sectional imaging in forensic investigations. We examined the value of post-mortem computed tomography (CT) imaging relative to autopsy for distinguishing aspiration into the lungs from airways, from lung alterations due to other causes, and for identifying the aspirated material. We selected 54 bodies submitted to whole-body CT scanning prior to autopsy. All cases had autopsy findings of blood (31 cases), fresh water (12 cases), or gastric content (11 cases) aspiration. The radiological images were retrospectively analyzed for airway and lung aspiration. In all cases, CT imaging detected pulmonary abnormalities suggestive of aspiration. Nevertheless, analysis of the CT images alone was not able to identify the aspirated material or to distinguish pulmonary findings of aspiration from lung changes due to other causes, except for a few cases of hemo-aspiration. However, due to its ability to visualize the entire parenchyma, CT imaging was superior to autopsy in providing additional data about the distribution and severity of the aspiration as well as in detecting small abnormalities. Post-mortem CT imaging should be considered as a superior tool for forensic investigations of aspiration due to its ability to document diagnostic conclusions and to guide the forensic pathologist during lung tissue examination.

Blood aspiration as a vital sign detected by postmortem computed tomography imaging

Blood aspiration is a significant forensic finding. In this study, we examined the value of postmortem computed tomography (CT) imaging in evaluating findings of blood aspiration. We selected 37 cases with autopsy evidence of blood in the lungs and/or in the airways previously submitted to total-body CT scanning. The CT-images were retrospectively analyzed. In one case with pulmonary blood aspiration, biopsy specimens were obtained under CT guide for histological examination. In six cases, CT detected pulmonary abnormalities suggestive of blood aspiration, not mentioned in the autopsy reports. CT reconstructions provided additional data about the distribution and extent of aspiration. In one needle-biopsied case, the pulmonary specimens showed blood in the alveoli. We suggest the use of CT imaging as a tool complementary to traditional techniques in cases of blood aspiration to avoid misdiagnosis, to guide the investigation of lung tissue, and to allow for more evidence-based inferences on the cause of death.

Diffusion-weighted MR imaging of the placenta in fetuses with placental insufficiency

PURPOSE: To evaluate diffusion-weighted magnetic resonance (MR) imaging of the human placenta in fetuses with and fetuses without intrauterine growth restriction (IUGR) who were suspected of having placental insufficiency. MATERIALS AND METHODS: The study was approved by the local ethics committee, and written informed consent was obtained. The authors retrospectively evaluated 1.5-T fetal MR images from 102 singleton pregnancies (mean gestation ± standard deviation, 29 weeks ± 5; range, 21-41 weeks). Morphologic and diffusion-weighted MR imaging were performed. A region of interest analysis of the apparent diffusion coefficient (ADC) of the placenta was independently performed by two observers who were blinded to clinical data and outcome. Placental insufficiency was diagnosed if flattening of the growth curve was detected at obstetric ultrasonography (US), if the birth weight was in the 10th percentile or less, or if fetal weight estimated with US was below the 10th percentile. Abnormal findings at Doppler US of the umbilical artery and histopathologic examination of specimens from the placenta were recorded. The ADCs in fetuses with placental insufficiency were compared with those in fetuses of the same gestational age without placental insufficiency and tested for normal distribution. The t tests and Pearson correlation coefficients were used to compare these results at 5% levels of significance. RESULTS: Thirty-three of the 102 pregnancies were ultimately categorized as having an insufficient placenta. MR imaging depicted morphologic changes (eg, infarction or bleeding) in 27 fetuses. Placental dysfunction was suspected in 33 fetuses at diffusion-weighted imaging (mean ADC, 146.4 sec/mm(2) ± 10.63 for fetuses with placental insufficiency vs 177.1 sec/mm(2) ± 18.90 for fetuses without placental insufficiency; P < .01, with one false-positive case). The use of diffusion-weighted imaging in addition to US increased sensitivity for the detection of placental insufficiency from 73% to 100%, increased accuracy from 91% to 99%, and preserved specificity at 99%. CONCLUSION: Placental dysfunction associated with growth restriction is associated with restricted diffusion and reduced ADC. A decreased ADC used as an early marker of placental damage might be indicative of pregnancy complications such as IUGR.

Deposition, imaging, and clearance: what remains to be done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.