Challenges in Drug Surveillance: Strengthening the Analysis of New Psychoactive Substances by Harmonizing Drug Checking Services in Proficiency Testing.

BACKGROUND: Drug checking is a proven harm reduction strategy and provides real-time information on the market of new psychoactive substances (NPS). It combines chemical analysis of samples with direct engagement with people who use drugs (PWUD), giving the ability to increase preparedness and responsiveness towards NPS. Next to that, it supports rapid identification of potential unwitting consumption. However, NPS cause a toxicological battle for the researchers, as factors such as the unpredictability and quick shift of the market complicate the detection. METHODS: To evaluate challenges posed towards drug checking services, proficiency testing was set up to evaluate existing analytical techniques and investigate the capability to correctly identify circulating NPS. Twenty blind substances, covering the most common categories of substances, were analyzed according to the existing protocols of the existing drug checking services, including several analytical methods such as gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with diode array detector (LC-DAD). RESULTS: The proficiency test scores range from 80 to 97.5% accuracy. The most common issues and errors are mainly unidentified compounds, presumably due to no up-to-date libraries, and/ or confusion between structural isomers, such as 3- and 4-chloroethcathinone, or structural analogs, such as MIPLA (N-methyl-N-isopropyl lysergamide) and LSD (D-lysergic acid diethylamide). CONCLUSIONS: The participating drug checking services have access to adequate analytical tools to provide feedback to drug users and provide up-to-date information on NPS.

Separating the wheat from the chaff: Observations on the analysis of lysergamides LSD, MIPLA, and LAMPA.

Lysergic acid diethylamide (LSD) is a potent psychoactive substance that has attracted great interest in clinical research. As the pharmacological exploration of LSD analogs continues to grow, some of those analogs have appeared on the street market. Given that LSD analogs are uncontrolled in many jurisdictions, it is important that these analogs be differentiated from LSD. This report presents the analysis of blotters found to contain the N-methyl-N-isopropyl isomer of LSD (MIPLA), and techniques to differentiate it from LSD and the N-methyl-N-propyl isomer (LAMPA) under routine conditions. Gas chromatography (GC)-solid phase infrared spectroscopy was particularly helpful. GC-electron ionization-tandem mass spectrometry of the m/z 72 iminium ion also provided sufficient information to distinguish the three isomers on mass spectral grounds alone, where chromatographic separation proved challenging. Derivatization with 2,2,2-trifluoro-N,N-bis (trimethylsilyl)acetamide (BSTFA) also led to improved GC separation. Liquid chromatography single quadrupole mass spectrometry (LC-Q-MS) and in-source collision-induced dissociation allowed for the differentiation between MIPLA and LAMPA based on distinct m/z 239 ion ratios when co-eluting. An alternative LC-MS/MS method improved the separation between all three lysergamides, but LSD was found to co-elute with iso-LSD. However, a comparison of ion ratios recorded for transitions at m/z 324.2 > 223.2 and m/z 324.2 > 208.2 facilitated their differentiation. The analysis of two blotters by LC-Q-MS revealed the presence of 180 and 186 µg MIPLA per blotter. These procedures may be used to avoid inadvertent misidentification of MIPLA or LAMPA as LSD.

Opt-Out Design for an Observational Toxicology Study Involving Intoxicated Patients at a Dance Music Event.

At electronic dance music events in Belgium in 2013 to 2015, seemingly intoxicated patients were included without their informed consent in an observational toxicology study when the attending physicians determined that they needed treatment with an intravenous line. All included patients received an information letter inviting them to contact the principal investigator (PI) to obtain more information about the study and/or to inform the PI that they wanted to be excluded from it. Overall, 238 patients were included in the study. Nine participants (4%) responded to the information letter, either on their own or through their parent; none of them asked to be excluded from the study. All respondents expressed their gratitude for the information they received. The opt-out study design seemed to be acceptable to the patient-participants, and it provided a fuller picture of the drug-related medical incidents at such music events than what could likely be achieved through a study that includes only people who explicitly choose to participate. These findings may help institutional review boards when evaluating study designs involving recreational drug use, especially at electronic dance music events. Nevertheless, we warn against extrapolation to other settings where informed consent is difficult to obtain.

Analytical characterization of "etonitazepyne," a new pyrrolidinyl-containing 2-benzylbenzimidazole opioid sold online.

This paper reports on the identification and full chemical characterization of the substance colloquially called "etonitazepyne" or "N-pyrrolidino etonitazene" (2-(4-ethoxybenzyl)-5-nitro-1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazole), a potent NPS opioid of the 5-nitrobenzimidazole class. Identification of etonitazepyne was performed, on a sample purchased during routine monitoring of the drug market, using GC-MS, HRAM LC-MS/MS, 1 H NMR, and FTIR. The chromatographic data, together with the FTIR data, indicated the presence of a highly pure compound and already indicated a benzimidazole structure. The specific benzimidazole regio-isomer was confirmed using 1 H NMR spectroscopy, resulting in the unambiguous identification of etonitazepyne.

Report on a New Opioid NPS: Chemical and In Vitro Functional Characterization of a Structural Isomer of the MT-45 Derivative Diphenpipenol.

In this paper, the identification and full characterization of a novel non-fentanyl opioid sourced online, which is a member of the 1-substituted-4-(1,2-diphenylethyl)piperazine derivatives related to MT-45, is reported. The sample was sold under the name "diphenpipenol," (3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylethyl]phenol), although extensive NMR analysis showed that the product obtained was actually a diphenpipenol structural isomer, (2-[4-(2-methoxyphenyl)piperazin-1-yl]-1,2-diphenylethanol). Liquid chromatography time-of-flight mass spectrometry identified an exact mass for the protonated molecule of m/z 389.2264, with two prominent fragment ions (m/z 91.0567 and 150.0937), which were not reported in earlier literature describing MT-45 derivatives. The chemical characterization was finalized by gas chromatography-mass spectrometry, high-performance liquid chromatography diode array detector and Fourier-transform infrared spectroscopy analyses. This product is a clear example of the trend that new non-fentanyl opioids are reappearing on the recreational drug market to escape the recent changes in (inter)national legislation concerning fentanyl analogues. Although in this particular case, the product's potency and efficacy were relatively low, other new non-fentanyl opioids might possess stronger potencies and therefore pose greater health risks for ignorant users. The fact that the product was sold under the wrong name further demonstrates the well-known problematic issue of a mismatch between the adverted and true identity, confirming the irregularities of the online new psychoactive substances market.

An infrared spectroscopic approach to characterise white powders, easily applicable in the context of drug checking, drug prevention and on-site analysis.

More and more events, such as the summer music festivals, are considering the possibilities for implementing on-site testing of psychoactive drugs in the context of prevention and harm reduction. Although the on-site identification is already implemented by plenty of drug checking services, the required rapid quantitative dosing of the composition of illicit substances is still a missing aspect for a successful harm reduction strategy at events. In this paper, an approach is presented to identify white powders as amphetamine, cocaine, ketamine or others and to estimate the purity of the amphetamine, cocaine and ketamine samples using spectroscopic techniques hyphenated with partial least squares (PLS) modelling. For identification purposes, it was observed that mid-infrared spectroscopy hyphenated with PLS-discriminant analysis allowed the distinction between amphetamine, cocaine, ketamine and other samples and this with a correct classification rate of 93.1% for an external test set. For quantitative estimation, near-infrared spectroscopy was more performant and allowed the estimation of the dosage/purity of the amphetamine, cocaine and ketamine samples with an error of more or less 10% w/w. An easily applicable, practical and cost-effective approach for on-site characterisation of the majority of the psychoactive samples encountered in Belgian nightlife settings based on IR spectroscopy was proposed.

Awareness of users and motivational factors for using new psychoactive substances in Belgium.

BACKGROUND: Few data on motivations for using new psychoactive substances (NPS) are available. However, the cost, the legal status, and their accessibility through channels like internet contributed to the popularity of NPS. The objective of this article are first to gain a deeper understanding of the culture surrounding NPS in Belgium and second to define the awareness of the users concerning the content of the NPS they are consuming. METHODS: Snowball sampling and partners in the drug demand reduction field were used as a gateway in order to reach a heterogeneous study population. In total, 45 users were recruited and in-depth interviews were conducted. The personal experiences of NPS users and their needs for support along the continuum of care were explored through an interview guideline, while subjects were given the opportunity to deposit a NPS sample for forensic analysis in a recognized laboratory. RESULTS: A diversity of profiles was found among NPS users but also a wide diversity in the motives to consume NPS: personal reasons such as pleasure, mind exploration, being connected to others, or out of curiosity, but also external reasons such as price, accessibility or the specific effects procured by certain NPS. The results showed as well that a majority of NPS users seem to be aware of the substances they are using. CONCLUSION: Understanding the motivations of use is of importance to determine which type of NPS targeted interventions are adapted to different profiles of users.

When clozapine appears at a dance event .

Objectives: The content of substances sold and consumed as party drugs is often unknown. They may contain inactive, contaminated or unexpected ingredients, and the dosage of the active components may vary considerably. Obviously, these phenomena increase the chances of a wrong or delayed therapy. To illustrate this point, we report 3 cases of clozapine intoxication at a dance event where most likely clozapine tablets were sold as party drugs.Methods: The three cases were part of a prospective toxicology study at a nocturnal indoor dance event.Results: One patient had to be intubated after obstructive breathing with desaturation and bradycardia, while the 2 other patients presented with syncope and altered mental status. All patients recovered after 20 minutes to 8 hours. Systematic toxicological analysis of the blood samples revealed the presence of clozapine (73-244 ng/ml) and its metabolite norclozapine (9-59 ng/ml). A pill, found in a pocket of one patient, was identified as Leponex® 100 mg (clozapine). This neuroleptic drug is mainly prescribed for treatment-resistant schizophrenia. In clozapine-naive subjects, orthostatic hypotension, bradycardia and syncope have been reported with a single 25 mg oral dose. Serum clozapine concentrations of the 3 cases were below the defined therapeutic range (350-600ng/ml) and the clozapine:norclozapine ratios were suggestive for recent drug intake.Conclusion: Routine drug screening may be unable to detect the toxic agent(s) involved. Whenever unusual symptoms are observed in an intoxicated patient, blood and urine samples should be sent to a reference toxicology laboratory.

Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene.

This paper reports on the identification and full chemical characterization of isotonitazene (N,N-diethyl-2-[5-nitro-2-({4-[(propan-2-yl)oxy]phenyl}methyl)-1H-benzimidazol-1-yl]ethan-1-amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS), the latter identifying an exact-mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio-isomer was performed using 1 H and 13 C NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier-transform (FT-IR) spectra. A live cell-based reporter assay to assess the in vitro biological activity at the µ-opioid receptor (MOR) revealed that isotonitazene has a high potency (EC50 of 11.1 nM) and efficacy (Emax 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder.

Lessons to be learned from toxicological analyses in intoxicated patients and seized materials at an electronic music dance festival.

Medical problems related to illicit drug use are frequently encountered at electronic dance music (EDM) events. In this prospective study, the medical problems and toxicological analyses on intoxicated persons and seized materials are described jointly. The aim of this study is to find out to what extent these efforts may assist in developing prevention strategies and organising on-site care at EDM events. The most frequently encountered clinical presentation in the 121 included patients was: agitation/aggression (26%), drunkenness (25%), depressed level of consciousness (24%) and hallucinations (9%). Only five patients were transported by ambulance to a hospital. In 100 of the 121 included patients (83%) an ethanolemia of at least 0.50 g/L was measured (with ethanol as the only drug found in 47 cases). 3,4-methylenedioxymethamphetamine (MDMA) was detected in 54% of the blood samples, cocaine in 11%, gamma-hydroxybutyric acid (GHB) in 11%, amphetamine in 7%, ketamine in 6% and a new psychoactive substance (NPS) in 4%. Except for 8 MDMA-users poly drug use was found in all these cases. The 178 seized samples most frequently contained MDMA (31%), cannabis (28%) or no active substance (15%). In 11 samples (6%) an NPS was detected. Of particular interest was a tablet containing 4-chloromethamphetamine (a previously unknown neurotoxic NPS), 4-chloroamphetamine, para-methoxyamphetamine, para-methoxymethamphetamine and ethylone. Our data show that at EDM events ethanol and MDMA are still the party drugs causing most health hazards and that NPS only play a minor role. Regarding the toxicological efforts, we recommend to analyse all seized materials from an EDM event, but only blood samples from the most severely intoxicated patients.

Activity-Based Detection and Bioanalytical Confirmation of a Fatal Carfentanil Intoxication.

Carfentanil, one of the most potent opioids known, has recently been reported as a contaminant in street heroin in the United States and Europe, and is associated with an increased number of life-threatening emergency department admissions and deaths. Here, we report on the application of a novel in vitro opioid activity reporter assay and a sensitive bioanalytical assay in the context of a fatal carfentanil intoxication, revealing the highest carfentanil concentrations reported until now. A 21-year-old male was found dead at home with a note stating that he had taken carfentanil with suicidal intentions. A foil bag and plastic bag labeled "C.50" were found at the scene. These bags were similar to a sample obtained by the Belgian Early Warning System on Drugs from a German darknet shop and to those found in the context of a fatality in Norway. Blood, urine and vitreous, obtained during autopsy, were screened with a newly developed in vitro opioid activity reporter assay able to detect compounds based on their µ-opioid receptor activity rather than their chemical structure. All extracts showed strong opioid activity. Results were confirmed by a bioanalytical assay, which revealed extremely high concentrations for carfentanil and norcarfentanil. It should be noted that carfentanil concentrations are typically in pg/mL, but here they were 92 ng/mL in blood, 2.8 ng/mL in urine, and 23 ng/mL in vitreous. The blood and vitreous contained 0.532 and 0.300 ng/mL norcarfentanil, respectively. No norcarfentanil was detected in urine. This is the first report where a novel activity-based opioid screening assay was successfully deployed in a forensic case. Confirmation and quantification using a validated bioanalytical procedure revealed the, to our knowledge, highest carfentanil concentrations reported in humans so far.

Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy - a risk to public health.

This paper reports the structure elucidation and full characterization of 4-chloromethamphetamine (4-CMA), a compound which was never reported previously outside of laboratory settings in seized drug samples, or samples actively being used at large dance festivals. Identification of 4-CMA was obtained by liquid chromatography with diode array detector (HPLC-PDA) and gas chromatography mass spectrometry (GC-MS). Further structure elucidation was performed by fragment pattern analysis of the trimethylsilyl and trifluoroacetyl derivatives with GC-MS. The region-isomeric form was confirmed by 1H nuclear magnetic resonance spectroscopy (1H NMR). HPLC-PDA was used for quantitation of 4-CMA in the seized tablet to obtain an indication of the potency. A literature review of the toxic effects of 4-CMA was performed, and mechanisms for serotonin neurotoxicity were proposed and discussed. Finally the risks for potential widespread harm to the public in events where similar substances or tablets start appearing and circulating on a larger scale in the general population is discussed.

Medical Emergencies Related to Ethanol and Illicit Drugs at an Annual, Nocturnal, Indoor, Electronic Dance Music Event.

Introduction Medical problems are frequently encountered during electronic dance music (EDM) events. Problem There are uncertainties about the frequencies and severity of intoxications with different types of recreational drugs: ethanol, "classical" illicit party drugs, and new psychoactive substances (NPS). METHODS: Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening. RESULTS: In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n=171), headache (n=36), gastro-intestinal problems (n=44), and intoxication (n=160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4-methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found. CONCLUSIONS: At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events. Calle P , Sundahl N , Maudens K , Wille SMR , Van Sassenbroeck D , De Graeve K , Gogaert S , De Paepe P , Devriese D , Arno G , Blanckaert P . Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event. Prehosp Disaster Med. 2018;33(1):71-76.

Identification of a new tert-leucinate class synthetic cannabinoid in powder and "spice-like" herbal incenses: Methyl 2-[[1-(5-fluoropentyl)indole-3-carbonyl]amino]-3,3-dimethyl-butanoate (5F-MDMB-PICA).

A brown powder and different product packages of "spice-like" herbal incenses were analyzed using a systematic identification approach based on liquid chromatography with diode array detector (HPLC-PDA) and gas chromatography mass spectrometry (GC-MS) with computer based library search against spectral libraries. However, the most predominant compound in the methanolic sample solutions could not be identified. In order to elucidate the chemical structure, a more extensive analysis of the material was initiated using liquid chromatography mass spectrometry (LC-MS), electrospray high resolution mass spectrometry (ESI-HRMS) and 1H, 13C and 19F nuclear magnetic resonance spectroscopy (NMR), which allowed the identification and characterization of the major compound as methyl 2-[[1-(5-fluoropentyl)indole-3-carbonyl]amino]-3,3-dimethyl-butanoate (5F-MDMB-PICA). The goal of this study is to provide analytical information for the identification of this new tert-leucinate class synthetic cannabinoid by various analytical methods.

Treatment for substance use disorders: the Belgian Treatment Demand Indicator registration protocol.

BACKGROUND: Registration of patients with substance use disorders is of key importance to get insights and to study trends in patients characteristics and substance use patterns. The Treatment Demand Indicator (TDI) is gathering this information at European level since 2000. In Belgium, this registration started at national level in 2011 and an increasing number of facilities of different types are participating in this data collection since then. METHODS/DESIGN: This surveillance register collects information on every treatment episode started by patients for their substance use disorder. Information is collected on socio-demographic characteristics of the patient, treatment history and substance use patterns. Patients are identified uniquely using their national identification number in order identify multiple episodes followed by a same person. A large range of treatment facilities have the possibility to participate in this registration to allow a wide coverage of the population. DISCUSSION: The objective of the paper is to facilitate the use of data by authorities or researchers by correctly describing all aspects of the indicator. The case definition, the variables collected and the way data should be reported are of key importance to use and interpret the data correctly. An overview of the data registered in 2014 gives also an idea of the content of the database. The article also pictures the strengths and limitations of the register and foresees some future improvements.

A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700).

A 30-year old man was found dead in his home after inhaling fumes of a powder burned on aluminum foil. Blood and urine were taken by the medical examiner during the external body examination and submitted to the laboratory for a comprehensive systematic toxicological analysis. A toxic fentanyl level of 10.9µg/L was measured in the subclavian blood. Police investigation revealed that the man searched the internet for information on new psychotropic substances, among others including U-47700. A powder found in the victims' home was transferred to the laboratory for analysis, in which trace amounts of fentanyl (0.0035%, m/m) and U-47700 (0.0012%, m/m) were identified by gas chromatography mass spectrometry. U-47700 is an opioid analgesic drug, considered to have a potency of approximately 7.5 times that of morphine. A target analysis on U-47700 was performed using liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry operating in multiple reaction monitoring mode. The method validation was based on the Scientific Working Group of Forensic Toxicology document 'Standard Practices of Method Validation in Forensic Toxicology'. In blood and urine the U-47700 concentration was 13.8 and 71.0µg/L, respectively. To the author's knowledge, this is the first case report of a fatal intoxication involving U-47700 abused as a new psychotropic substance.

Assessment of tumor vascularization in pancreatic adenocarcinoma using 128-slice perfusion computed tomography imaging.

OBJECTIVE: Computed tomography (CT) perfusion studies can provide valuable information regarding tumor vascularization. We report on a study assessing CT perfusion characteristics in the normal pancreas and in patients with pancreatic adenocarcinoma. METHODS: Twenty healthy subjects and 20 patients with histologically confirmed pancreatic adenocarcinoma were included in the study after written informed consent and approval by our institutional review board. All subjects underwent perfusion CT imaging of the pancreas using 128-slice dual-source CT. The scanning sequence included 18 scans. Parametric maps of blood volume (BV), blood flow (BF), and permeability surface area product (PS) were generated and compared with density measurements. RESULTS: In normal pancreas, no significant difference in perfusion values was observed between head, body, and tail of the pancreas. Mean organ values were 76.76 (SD, 15.6) mL/100 g/min, 15.80 (SD, 2.40) mL/100 g, and 27.74 (SD, 16.8) mL/100 g/min for BF, BV, and PS, respectively. Compared with the normal pancreas, a 60% reduction in BF and BV was observed in the tumor tissue. Perfusion values gradually increased toward the tumor rim. Necrotic tumor areas were identified in 25% of patients. No significant differences were observed when comparing normal pancreas and healthy pancreatic tissue in adenocarcinoma patients. CONCLUSIONS: The feasibility of whole-tumor perfusion imaging using 128-slice CT was demonstrated in patients with pancreatic adenocarcinoma. Perfusion CT provides additional information compared with image assessment based on density measurements (Hounsfield units) and allows noninvasive assessment of vascularization in the tumor tissue.

Assessment of neovascular permeability in a pancreatic tumor model using dynamic contrast-enhanced (DCE) MRI with contrast agents of different molecular weights.

OBJECT: We evaluated the relationship of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters and contrast agents with different molecular weights (MW) in a pancreatic tumor mouse model. MATERIALS AND METHODS: Panc02 tumors were induced in mice at the hind leg. DCE-MRI was performed using Gadolinium (Gd)-based contrast agents with different MW: Gd-DOTA (0.5 kDa), P846 (3.5 kDa), and P792 (6.47 kDa). Quantitative vascular parameters (AUC, K(trans), V(e), and V(p)) were calculated according to a modified Tofts two-compartment model. Values for all contrast groups were compared for tumor and control (muscle) tissues. RESULTS: Values for K(trans) and V(e) were significantly higher in tumor tissue than in muscle tissue. When comparing contrast agents, lowest absolute K(trans) values were observed using P792. The relative increase in K(trans) in tumor tissue compared with normal tissue was highest after the use of P792. In both tumor and normal tissues, K(trans) decreased with increasing molecular weight of the contrast agent used. CONCLUSION: It was demonstrated that values for the different DCE-MRI vascular (permeability) parameters are highly dependent on the contrast agent used. Due to their potential to better differentiate tumor from muscle tissue, higher molecular weight contrast agents show promise when evaluating tumors using DCE-MRI.

The impact of HF-rTMS treatment on serotonin(2A) receptors in unipolar melancholic depression.

BACKGROUND: Currently, the underlying neurobiological mechanism as to how repetitive transcranial magnetic stimulation (rTMS) can alter depressive states remains unclear. Animal data suggest that its influence could occur at the neurotransmitter level, such as modulation of the serotonin system. METHODS: Twenty-one antidepressant-free medication-resistant unipolar depressed patients, and 21 age- and gender-matched healthy subjects were studied. We examined the neurobiologic impact of 10 high-frequent (HF)-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) on postsynaptic 5-HT(2A) receptor binding indices (BI) measured with ¹²³I-5-I-R91150 single photon emission computed tomography (SPECT) only in patients. RESULTS: Compared with the control group, patients displayed significantly less bilateral dorsolateral prefrontal cortical and significantly higher left hippocampal baseline 5-HT(2A) receptor BI. Successful HF-rTMS treatment correlated positively with 5-HT(2A) receptor BI in the DLPFC bilaterally and correlated negatively with right hippocampal 5-HT(2A) receptor uptake values. CONCLUSIONS: Our results indicate that HF-rTMS treatment affect the serotonergic system. Our data also suggest that this kind of treatment affects 5-HT(2A) receptor BI in the DLPFC and in the hippocampus in different ways.

Variability of CT contrast enhancement in the pancreas: a cause for concern?

BACKGROUND: Multidetector CT is a valuable technique for diagnosis/staging in several pancreatic pathologies. Diagnosis is usually based on tissue density measurements. Recently, newer functional CT techniques have been introduced. The aim of this study was to assess variability in perfusion and dual-energy CT data, and to compare these data with density measurements in the pancreas of a healthy population. METHODS: Two groups were included: 20 patients underwent perfusion CT imaging, and 10 patients were scanned using a dual-energy protocol. In both groups, tissue density [Hounsfield units (HU)] was measured in the pancreatic head, body and tail. Functional data were calculated (blood flow/blood volume in the perfusion CT group, iodine concentration in the dual-energy group), and variability was assessed. RESULTS: Density measurements were comparable for the perfusion and dual-energy CT groups, and ranged from 14 to 60 HU. Maximal enhancement differences between the head/body/tail of the pancreas ranged between 2 and 21 HU. Considerable variability was observed, both in density measurements (ranging from 3 to 34%) and in functional parameters (mean variability in perfusion CT parameters blood flow and blood volume was 21.3 and 10% respectively; mean variability in dual-energy iodine-mapping results was 24.4%). CONCLUSION: This study demonstrated the presence of important intraindividual variability in pancreatic tissue contrast enhancement, regardless of the CT technique used. Considering the variability observed in this study, the use of cut-off values to characterize pancreatic pathologies seems troublesome, and morphologic primary and secondary changes will remain important, even when using novel functional imaging techniques. and IAP.