Imaging di risonanza magnetica nucleare nello studio del tumore della prostata

Aim of the present study was to evaluate the accuracy of transrectal ultrasound biopsy (TRUS-biopsy) directed to regions with abnormal MRI and/or MRSI (magnetic resonance spectroscopic imaging ) for both the transition (TZ) and the peripheral (PZ) zones in patients who presented with persistent suspect for prostate cancer and with prior negative biopsy. We also evaluated relationship between MRSI results and histopathological findings of biopsy. 54 patients with the aforementioned characteristics underwent MRI/MRSI at least 6 months after prior negative biopsy; interval between MRI/3D-MRSI and the further TRUS-biopsy was less than 3 months. The prostate was divided in 12 regions both for imaging interpretation and biopsy. Moreover one to three cores more were taken from each region with abnormal MRI and/or 3D-MRSI. Twenty-two out of 54 patients presented cancer at MRI/MRSI-directed-TRUS-biopsy. On a patient basis the highest accuracy was obtained by assigning malignancy on a positive finding with MRSI and MRI even though it was not significantly greater than that obtained using MRI alone (area under the ROC curve, AUC: 0.723 vs. 0.676). On a region (n=648) basis the best accuracy was also obtained by considering positive both MRSI and MRI for PZ (0.768) and TZ (0.822). Twenty-eight per cent of cores with prostatitis were false positive findings on MRSI, whereas only 2.7% of benign prostatic hyperplasia was false positive. In conclusion the accuracy of MRI/MRSI-directed biopsies in localization of prostate cancer is good in patient and region analyses. The combination of both MRI and MRSI results makes TRUS-biopsy more accurate particularly in the TZ (0.822) for patients with prior negative biopsies. Histopathological analysis showed that the main limitation of MRSI is the percentage of false positive findings due to prostatitis.

Identificazione e dosaggio di marcatori molecolari dell'endometriosi nel sangue periferico

Purpose: to quantify the mRNA levels of MMP-3, MMP-9, VEGF and Survivin in peripheral blood and the serum levels of CA-125, Ca19-9 in women with and without endometriosis and to investigate the performance of these markers to differentiate between deep and ovarian endometriosis. Methods: a case controls study enrolled a series of 60 patients. Twenty controls have been matched with 20 cases of ovarian and 20 cases of deep endometriosis. Univariable and multivariable performance of serum CA125 and CA19-9, mRNA for Survivin, MMP9, MMP3 and VEGF genes have been evaluated by means of ROC curves and logistic regression respectively. Results: No difference in markers concentration were detected between ovarian and deep endometriosis. In comparison with controls serum CA19 and CA125 yielded the better sensitivity followed by mRNA for Survivin gene (81.5%, 51.9% and 7.5% at 10% false positive rate respectively). Multivariable estimated odds of endometriosis yielded a sensitivity of 87% at the same false positive rate. Conclusions: A combination of serum and molecular markers could allow a better diagnosis of endometriosis.

Expression profiling und rationale Expressionsoptimierung am Beispiel eines prokaryontischen Wirt-,Vektor-Systems

Durch globale Expressionsprofil-Analysen auf Transkriptom-, Proteom- oder Metabolom-Ebene können biotechnologische Produktionsprozesse besser verstanden und die Erkenntnisse für die zielgerichtete, rationale Optimierung von Expressionssystemen genutzt werden. In der vorliegenden Arbeit wurde die Überexpression einer Glukose-Dehydrogenase (EC 1.1.5.2), die von der Roche Diagnostics GmbH für die diagnostische Anwendung optimiert worden war, in Escherichia coli untersucht. Die Enzymvariante unterscheidet sich in sieben ihrer 455 Aminosäuren vom Wildtyp-Enzym und wird im sonst isogenen Wirt-/Vektor-System in signifikant geringeren Mengen (Faktor 5) gebildet. Das prokaryontische Expressionssystem wurde auf Proteom-Ebene charakterisiert. Die 2-dimensionale differenzielle Gelelektrophorese (DIGE) wurde zuvor unter statistischen Aspekten untersucht. Unter Berücksichtigung von technischen und biologischen Variationen, falsch-positiven (α-) und falsch-negativen (β-) Fehlern sowie einem daraus abgeleiteten Versuchsdesign konnten Expressionsunterschiede als signifikant quantifiziert werden, wenn sie um den Faktor ≥ 1,4 differierten. Durch eine Hauptkomponenten-Analyse wurde gezeigt, dass die DIGE-Technologie für die Expressionsprofil-Analyse des Modellsystems geeignet ist. Der Expressionsstamm für die Enzymvariante zeichnete sich durch eine höhere Variabilität an Enzymen für den Zuckerabbau und die Nukleinsäure-Synthese aus. Im Expressionssystem für das Wildtyp-Enzym wurde eine unerwartet erhöhte Plasmidkopienzahl nachgewiesen. Als potenzieller Engpass in der Expression der rekombinanten Glukose-Dehydrogenase wurde die Löslichkeitsvermittlung identifiziert. Im Expressionsstamm für das Wildtyp-Enzym wurden viele Proteine für die Biogenese der äußeren Membran verstärkt exprimiert. Als Folge dessen wurde ein sog. envelope stress ausgelöst und die Zellen gingen in die stationäre Wuchsphase über. Die Ergebnisse der Proteomanalyse wurden weiterführend dazu genutzt, die Produktionsleistung für die Enzymvariante zu verbessern. Durch den Austausch des Replikationsursprungs im Expressionsvektor wurde die Plasmidkopienzahl erhöht und die zelluläre Expressionsleistung für die diagnostisch interessantere Enzymvariante um Faktor 7 - 9 gesteigert. Um die Löslichkeitsvermittlung während der Expression zu verbessern, wurde die Plasmidkopienzahl gesenkt und die Coexpression von Chaperonen initiiert. Die Ausbeuten aktiver Glukose-Dehydrogenase wurden durch die Renaturierung inaktiven Produkts aus dem optimierten Expressionssystem insgesamt um einen Faktor von 4,5 erhöht. Somit führte im Rahmen dieser Arbeit eine proteombasierte Expressionsprofil-Analyse zur zielgerichteten, rationalen Expressionsoptimierung eines prokaryontischen Modellsystems.

Oligomerization and protein-protein interactions of the sensory histidine kinase DcuS in Escherichia coli

DcuS is a membrane-integral sensory histidine kinase involved in the DcuSR two-component regulatory system in Escherichia coli by regulating the gene expression of C4-dicarboxylate metabolism in response to external stimuli. How DcuS mediates the signal transduction across the membrane remains little understood. This study focused on the oligomerization and protein-protein interactions of DcuS by using quantitative Fluorescence Resonance Energy Transfer (FRET) spectroscopy. A quantitative FRET analysis for fluorescence spectroscopy has been developed in this study, consisting of three steps: (1) flexible background subtraction to yield background-free spectra, (2) a FRET quantification method to determine FRET efficiency (E) and donor fraction (fD = [donor] / ([donor]+[acceptor])) from the spectra, and (3) a model to determine the degree of oligomerization (interaction stoichiometry) in the protein complexes based on E vs. fD. The accuracy and applicability of this analysis was validated by theoretical simulations and experimental systems. These three steps were integrated into a computer procedure as an automatic quantitative FRET analysis which is easy, fast, and allows high-throughout to quantify FRET accurately and robustly, even in living cells. This method was subsequently applied to investigate oligomerization and protein-protein interactions, in particular in living cells. Cyan (CFP) and yellow fluorescent protein (YFP), two spectral variants of green fluorescent protein, were used as a donor-acceptor pair for in vivo measurements. Based on CFP- and YFP-fusions of non-interacting membrane proteins in the cell membrane, a minor FRET signal (E = 0.06 ± 0.01) can be regarded as an estimate of direct interaction between CFP and YFP moieties of fusion proteins co-localized in the cell membrane (false-positive). To confirm if the FRET occurrence is specific to the interaction of the investigated proteins, their FRET efficiency should be clearly above E = 0.06. The oligomeric state of DcuS was examined both in vivo (CFP/YFP) and in vitro (two different donor-acceptor pairs of organic dyes) by three independent experimental systems. The consistent occurrence of FRET in vitro and in vivo provides the evidence for the homo-dimerization of DcuS as full-length protein for the first time. Moreover, novel interactions (hetero-complexes) between DcuS and its functionally related proteins, citrate-specific sensor kinase CitA and aerobic dicarboxylate transporter DctA respectively, have been identified for the first time by intermolecular FRET in vivo. This analysis can be widely applied as a robust method to determine the interaction stoichiometry of protein complexes for other proteins of interest labeled with adequate fluorophores in vitro or in vivo.

Characterization of the Caspr2 and NLGN2 ligands: a proteomic and biochemical approach

Autism Spectrum Disorder (ASD) is a range of early-onset conditions classified as neurodevelopmental disorders, characterized by deficits in social interactions and communication, as well as by restricted interest and repetitive behaviors. Among the proteins associated with this spectrum of disease there are Caspr2, α-NRXN1, NLGN1-4. Caspr2 is involved in the clustering of K+ channels at the juxtaparanodes, where it is proposed to bind TAG-1. Recent works reported a synaptic localization of Caspr2, but little is know on its role in this compartment. NRXNs and their ligand NLGNs, instead, have a well-defined role in the formation and maintenance of synapses. Among the neuroligins, NLGN2 binds NRXNs with the lowest affinity, suggesting that it could have other not yet characterized ligands. The aim of this work was to better characterize the binding of Caspr2 to TAG-1 and to identify new potential binding partner for Caspr2 and NLGN2. Unexpectedly, using Isothermal Titration Calorimetry and co-immunoprecipitation experiments the direct association of the first two proteins could not be verified and the results indicate that the first evidences reporting it were biased by false-positive artifacts. These findings, together with the uncharacterized synaptic localization of Caspr2, made the identification of new potential binding partners for this protein necessary. To find new proteins that associate with Caspr2 and NLGN2, affinity chromatography in tandem with mass spectrometry experiments were performed. Interestingly, about 25 new potential partners were found for these two proteins and NLGN1, that was originally included as a control: 5 of those, namely SFRP1, CLU, APOE, CNTN1 and TNR, were selected for further investigations. Only the association of CLU to NLGN2 was confirmed. In the future, screenings of the remaining candidates have to be carried out and the functional role for the proposed NLGN2-CLU complex has to be studied.

Vergleich der Elastographie-gesteuerten Biopsie mit der Systembiopsie bei der Detektion von Prostatakarzinomen

Hintergrund: Die Systembiopsie gilt als Goldstandard zum Nachweis eines Prostatakarzinoms, obwohl ein relevanter Anteil an Prostatakarzinomen nicht diagnostiziert wird. Wir wollten mit unserer Arbeit die Frage beantworten, ob mittels elastographisch gezielter Biopsien die Prostatakarzinom-Detektion im Vergleich zur Goldstandard-Systembiopsie verbessert werden kann. Material und Methode: 152 Patienten wurden in einer prospektiven Studie einer 12-fachen Prostata-Systembiopsie unterzogen. In Linksseitenlagerung wurde dabei aus jedem der vordefinierten 6 Prostatasegmente je 1 laterale und 1 mediale Stanze entnommen. Elastographisch suspekte Areale wurden zusätzlich gezielt biopsiert. Als statistisch signifikant wurde p<0,05 angenommen. Ergebnisse: Bei 62 der 152 Patienten (40,8%) wurde ein Prostatakarzinom diagnostiziert. Die Detektionsrate der Systembiopsie betrug 39,5% (60/152), die Detektionsrate der Elastographie 29,6% (45/152). Somit war die Systembiopsie der elastographisch gezielten Biopsie signifikant überlegen (p=0,039).Jedoch war die Wahrscheinlichkeit mit einer Prostatastanze ein Karzinomherd zu entdecken, für die elastographischen Biopsien 3,7-fach höher als für die Systembiopsien. Die Sensitivität der Elastographie betrug 72,6% und die Spezifität 66,6%. Der positive Vorhersagewert für die Elastographie war 60%, der negative Vorhersagewert 78%. Die Kombination von Systembiopsie und elastographisch gezielten Biopsien bot die höchste Detektionsrate. In der rechten Prostatahälfte (48%) verzeichneten wir doppelt so viele elastographisch falsch-positive Befunde wie in der linken Prostatahälfte (25%). Desweiteren fanden sich am häufigsten falsch-positive Befunde im Prostata-Apex (46%) und am seltensten in der Prostata-Basis (29%). Schlussfolgerung: In unserer Studie war die elastographisch gezielte Biopsie der Systembiopsie signifikant unterlegen (p=0,039). Die Kombination von Systembiopsie mit elastographisch gezielten Biopsien bot die höchste Detektionsrate und kann daher empfohlen werden. Die Auffälligkeiten in der Segment-bezogenen Auswertung und ein möglicher Einfluss der Patienten-Lagerung müssen durch weitere Studien überprüft werden.rn

Climate change in Libya and desertification of Jifara Plain

The study was arranged to manifest its objectives through preceding it with an intro-duction. Particular attention was paid in the second part to detect the physical settings of the study area, together with an attempt to show the climatic characteristics in Libya. In the third part, observed temporal and spatial climate change in Libya was investigated through the trends of temperature, precipitation, relative humidity and cloud amount over the peri-ods (1946-2000), (1946-1975), and (1976-2000), comparing the results with the global scales. The forth part detected the natural and human causes of climate change concentrat-ing on the greenhouse effect. The potential impacts of climate change on Libya were ex-amined in the fifth chapter. As a case study, desertification of Jifara Plain was studied in the sixth part. In the seventh chapter, projections and mitigations of climate change and desertification were discussed. Ultimately, the main results and recommendations of the study were summarized. In order to carry through the objectives outlined above, the following methods and approaches were used: a simple linear regression analysis was computed to detect the trends of climatic parameters over time; a trend test based on a trend-to-noise-ratio was applied for detecting linear or non-linear trends; the non-parametric Mann-Kendall test for trend was used to reveal the behavior of the trends and their significance; PCA was applied to construct the all-Libya climatic parameters trends; aridity index after Walter-Lieth was shown for computing humid respectively arid months in Libya; correlation coefficient, (after Pearson) for detecting the teleconnection between sun spot numbers, NAOI, SOI, GHGs, and global warming, climate changes in Libya; aridity index, after De Martonne, to elaborate the trends of aridity in Jifara Plain; Geographical Information System and Re-mote Sensing techniques were applied to clarify the illustrations and to monitor desertifi-cation of Jifara Plain using the available satellite images MSS, TM, ETM+ and Shuttle Radar Topography Mission (SRTM). The results are explained by 88 tables, 96 figures and 10 photos. Temporal and spatial temperature changes in Libya indicated remarkably different an-nual and seasonal trends over the long observation period 1946-2000 and the short obser-vation periods 1946-1975 and 1976-2000. Trends of mean annual temperature were posi-tive at all study stations except at one from 1946-2000, negative trends prevailed at most stations from 1946-1975, while strongly positive trends were computed at all study stations from 1976-2000 corresponding with the global warming trend. Positive trends of mean minimum temperatures were observed at all reference stations from 1946-2000 and 1976-2000, while negative trends prevailed at most stations over the period 1946-1975. For mean maximum temperature, positive trends were shown from 1946-2000 and from 1976-2000 at most stations, while most trends were negative from 1946-1975. Minimum tem-peratures increased at nearly more than twice the rate of maximum temperatures at most stations. In respect of seasonal temperature, warming mostly occurred in summer and au-tumn in contrast to the global observations identifying warming mostly in winter and spring in both study periods. Precipitation across Libya is characterized by scanty and sporadically totals, as well as high intensities and very high spatial and temporal variabilities. From 1946-2000, large inter-annual and intra-annual variabilities were observed. Positive trends of annual precipi-tation totals have been observed from 1946-2000, negative trends from 1976-2000 at most stations. Variabilities of seasonal precipitation over Libya are more strikingly experienced from 1976-2000 than from 1951-1975 indicating a growing magnitude of climate change in more recent times. Negative trends of mean annual relative humidity were computed at eight stations, while positive trends prevailed at seven stations from 1946-2000. For the short observation period 1976-2000, positive trends were computed at most stations. Annual cloud amount totals decreased at most study stations in Libya over both long and short periods. Re-markably large spatial variations of climate changes were observed from north to south over Libya. Causes of climate change were discussed showing high correlation between tempera-ture increasing over Libya and CO2 emissions; weakly positive correlation between pre-cipitation and North Atlantic Oscillation index; negative correlation between temperature and sunspot numbers; negative correlation between precipitation over Libya and Southern Oscillation Index. The years 1992 and 1993 were shown as the coldest in the 1990s result-ing from the eruption of Mount Pinatubo, 1991. Libya is affected by climate change in many ways, in particular, crop production and food security, water resources, human health, population settlement and biodiversity. But the effects of climate change depend on its magnitude and the rate with which it occurs. Jifara Plain, located in northwestern Libya, has been seriously exposed to desertifica-tion as a result of climate change, landforms, overgrazing, over-cultivation and population growth. Soils have been degraded, vegetation cover disappeared and the groundwater wells were getting dry in many parts. The effect of desertification on Jifara Plain appears through reducing soil fertility and crop productivity, leading to long-term declines in agri-cultural yields, livestock yields, plant standing biomass, and plant biodiversity. Desertifi-cation has also significant implications on livestock industry and the national economy. Desertification accelerates migration from rural and nomadic areas to urban areas as the land cannot support the original inhabitants. In the absence of major shifts in policy, economic growth, energy prices, and con-sumer trends, climate change in Libya and desertification of Jifara Plain are expected to continue in the future. Libya cooperated with United Nations and other international organizations. It has signed and ratified a number of international and regional agreements which effectively established a policy framework for actions to mitigate climate change and combat deserti-fication. Libya has implemented several laws and legislative acts, with a number of ancil-lary and supplementary rules to regulate. Despite the current efforts and ongoing projects being undertaken in Libya in the field of climate change and desertification, urgent actions and projects are needed to mitigate climate change and combat desertification in the near future.

Tor network forensics and hidden service deanonymization

The cybernetics revolution of the last years improved a lot our lives, having an immediate access to services and a huge amount of information over the Internet. Nowadays the user is increasingly asked to insert his sensitive information on the Internet, leaving its traces everywhere. But there are some categories of people that cannot risk to reveal their identities on the Internet. Even if born to protect U.S. intelligence communications online, nowadays Tor is the most famous low-latency network, that guarantees both anonymity and privacy of its users. The aim of this thesis project is to well understand how the Tor protocol works, not only studying its theory, but also implementing those concepts in practice, having a particular attention for security topics. In order to run a Tor private network, that emulates the real one, a virtual testing environment has been configured. This behavior allows to conduct experiments without putting at risk anonymity and privacy of real users. We used a Tor patch, that stores TLS and circuit keys, to be given as inputs to a Tor dissector for Wireshark, in order to obtain decrypted and decoded traffic. Observing clear traffic allowed us to well check the protocol outline and to have a proof of the format of each cell. Besides, these tools allowed to identify a traffic pattern, used to conduct a traffic correlation attack to passively deanonymize hidden service clients. The attacker, controlling two nodes of the Tor network, is able to link a request for a given hidden server to the client who did it, deanonymizing him. The robustness of the traffic pattern and the statistics, such as the true positive rate, and the false positive rate, of the attack are object of a potential future work.

Factors affecting bony impingement in hip arthroplasty

Computer modeling of 10 patients' computed tomographic scans was used to study the variables affecting hip arthroplasty range of motion before bony impingement (ROMBI) including acetabular offset and height, femoral offset, height and anteversion, and osteophyte removal. The ROMBI was compared with the ROM before component impingement and the native hip ROM. The ROMBI decreased with decreased total offset and limb shortening. Acetabular offset and height had a greater effect on ROMBI than femoral offset and height. The ROMBI lost with decreased acetabular offset was not fully recoverable with an increase in femoral offset or osteophyte removal. Bony impingement increased and component impingement decreased with decreased acetabular offset and increased head diameter.

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.

Nonlinear three-dimensional noise filter with low-dose CT angiography: effect on the detection of small high-contrast objects in a phantom model

To study the effect of a nonlinear noise filter on the detection of simulated endoleaks in a phantom with 80- and 100-kVp multidetector computed tomographic (CT) angiography.

Effect of beam hardening on arterial enhancement in thoracoabdominal CT angiography with increasing patient size: an in vitro and in vivo study

To assess the effect of beam hardening on arterial enhancement in thoracoabdominal computed tomographic (CT) angiography in various body sizes in a phantom and in a clinical study.

Detection of pancreatic tumors, image quality, and radiation dose during the pancreatic parenchymal phase: effect of a low-tube-voltage, high-tube-current CT technique--preliminary results

To intraindividually compare a low-tube-voltage (80 kVp), high-tube-current (675 mA) computed tomographic (CT) technique with a high-tube-voltage (140 kVp) CT protocol for the detection of pancreatic tumors, image quality, and radiation dose during the pancreatic parenchymal phase.

High-throughput procedure for tick surveys of tick-borne encephalitis virus and its application in a national surveillance study in Switzerland

Tick-borne encephalitis (TBE), a viral infection of the central nervous system, is endemic in many Eurasian countries. In Switzerland, TBE risk areas have been characterized by geographic mapping of clinical cases. Since mass vaccination should significantly decrease the number of TBE cases, alternative methods for exposure risk assessment are required. We established a new PCR-based test for the detection of TBE virus (TBEV) in ticks. The protocol involves an automated, high-throughput nucleic acid extraction method (QIAsymphony SP system) and a one-step duplex real-time reverse transcription-PCR (RT-PCR) assay for the detection of European subtype TBEV, including an internal process control. High usability, reproducibility, and equivalent performance for virus concentrations down to 5 x 10(3) viral genome equivalents/microl favor the automated protocol compared to the modified guanidinium thiocyanate-phenol-chloroform extraction procedure. The real-time RT-PCR allows fast, sensitive (limit of detection, 10 RNA copies/microl), and specific (no false-positive test results for other TBEV subtypes, other flaviviruses, or other tick-transmitted pathogens) detection of European subtype TBEV. The new detection method was applied in a national surveillance study, in which 62,343 Ixodes ricinus ticks were screened for the presence of TBE virus. A total of 38 foci of endemicity could be identified, with a mean virus prevalence of 0.46%. The foci do not fully agree with those defined by disease mapping. Therefore, the proposed molecular test procedure constitutes a prerequisite for an appropriate TBE surveillance. Our data are a unique complement of human TBE disease case mapping in Switzerland.

Dopaminergic modulation of rapid reality adaptation in thinking

Dopamine has long held a prominent role in the interpretation of schizophrenia and other psychoses. Clinical studies on confabulation and disorientation, disorders marked by a confusion of reality in thinking, indicated that the ability to keep thinking in phase with reality depends on a process suppressing the interference of upcoming memories that do not refer to ongoing reality. A host of animal studies and a recent clinical study suggested that this suppression might correspond to the phasic inhibition of dopaminergic neurons in response to the absence of expected outcomes. In this study, we tested healthy subjects with a difficult version of a memory paradigm on which confabulating patients had failed. Subjects participated in three test sessions, in which they received in double-blind, randomized fashion L-dopa, risperidone, or placebo. We found that l-dopa, in comparison with risperidone, impaired performance in a highly specific way, which corresponded to the pattern of patients with reality confusion. Specifically, they had an increase of false positive responses, while overall memory performance and reaction times were unaffected. We conclude that dopaminergic transmission influences the ability to rapidly adapt thinking to ongoing reality.