More evidence or stronger political will: exploring the feasibility of needle and syringe programs in Ukrainian prisons.

INTRODUCTION: In 2007, the World Health Organization (WHO) recommended for prison authorities to introduce prison needle and syringe programs (PNSP) if they have any evidence that injecting drug use is taking place in prisons. This article presents descriptive evidence that injecting drug use takes place in Ukrainian prisons, it discusses how (denial of) access to injection equipment is regulated in the current system and what changes should be considered in order to implement PNSP. BACKGROUND: Ukrainian prisons still live by the laws and policies adopted in the Soviet Union. Besides laws and regulations, these legacies are replicated through the organization and infrastructure of the prison's physical space, and through "carceral collectivism" as a specific form of living and behaving. Inviolability of the prison order over time helps the prison staff to normalize and routinely rationalize punishment enforcement as a power "over" prisoners, but not a power "for" achieving a specific goal. METHODS: The Participatory Action Research approach was used as a way of involving different actors in the study's working group and research process. The data were gathered through 160 semi-structured interviews with prison health care workers, guards, people who inject drugs (PWID) who served one or several terms and other informants. RESULTS: The "expertise" in drug use among prisoners demonstrated by prison staff tells us two things-they admit that injecting use takes place in prisons, and that the surveillance of prisoner behavior has been carried out constantly since the very beginning as a core function of control. The communal living conditions and prison collectivism may not only produce and reproduce a criminal subculture but, using the same mechanisms, produce and reproduce drug use in prison. The "political will" incorporated into prison laws and policies is essential for the revision of outdated legacies and making PNSP implementation feasible. CONCLUSION: PNSP implementation is not just a question of having evidence of injecting drug use in the hands of prison authorities. For PNSP to be feasible in the prison environment, there is a need for specific changes to transition from one historical period and political leadership to another. And, thus, to make PNSP work requires making power work for change, and not just for reproducing the power itself.

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511.

PURPOSE: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 µSv/MBq). The calculated ED was 24.7 ± 0.8 µSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain.

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [11 C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [11 C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [11 C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [11 C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [11 C]UCB-J in PET studies. In addition, observation of low binding for [11 C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [11 C]UCB-J PET data.

Performance indicator as the main and the only goal: a "dark side" of the intervention aims to accelerate HIV treatment entry among people who inject drugs in Kyiv, Ukraine.

BACKGROUND: To improve healthcare entry and antiretroviral therapy (ART) initiation for HIV-positive people who inject drugs (PWID) in Ukraine, an intervention built upon a successful community-based harm reduction project and the existing best practices was developed. In this article, we present the results of the study conducted in collaboration with one of the recipient organizations of the intervention in Kyiv. The research question was formulated as follows: how does the interaction between different actors work to lead it to a positive outcome (initiation PWIDs into ART) within the limited period of the intervention implementation? METHODS: The central focus of the study was on the work activities of case managers. Their daily routines as well as their interactions with their clients and medical workers were observed and analyzed. Using the institutional ethnography approach, we explore the institutional orders, power imbalances, and social factors that play different roles in coordinating the process of PWIDs entry into healthcare and HIV treatment. RESULTS: The most intriguing result of the study is that the performance indicator that must be completed in order to receive a full salary-as a way to manage the activities of case managers-produces conditions for them to develop their cooperation with medical workers but leaves the clients and their needs out of this "boat" because interaction with them, in fact, does not help to meet case managers' goals. CONCLUSIONS: Accountability of case managers' work assumes the primacy of the result over the process, which makes the process itself less important and the need to achieve the goal becomes the main and the only goal. This can be identified as an unintended consequence of the intervention implementation on the ground, or wider-an unintended consequence of the payment by results practice as a part of the general number-based policy.

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain.

PURPOSE: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design. METHODS: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. RESULTS: The load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding. CONCLUSION: This research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

PURPOSE: [11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain. METHODS: A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches. RESULTS: Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis. CONCLUSIONS: The method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.

BACKGROUND: Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein. METHODS: A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey. RESULTS: The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding. CONCLUSION: Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties.

Brain PET measurement of PDE10A occupancy by TAK-063, a new PDE10A inhibitor, using [11 C]T-773 in nonhuman primates.

Because phosphodiesterase 10A (PDE10A) degrades both cyclic adenosine monophosphate and cyclic guanosine monophosphate and is distributed mainly in the striatum, PDE10A inhibitors have been considered to potentially be useful therapeutic agents for psychiatric and neurodegenerative diseases such as schizophrenia and Huntington's disease. We measured striatal PDE10A occupancy by TAK-063, a newly developed compound with high affinity and selectivity for PDE10A, using PET with [(11)C]T-773 in nonhuman primates. Two 123-min dynamic PET measurements were performed on three female rhesus monkeys, once at baseline and again after intravenous administration of different doses of TAK-063 (0.2-1.6 mg/kg). Total distribution volume (V(T)) was calculated with a two-tissue compartment model using metabolite-corrected plasma input. Although the in vitro autoradiography did not show high specific binding to [(11)C]T-773 in the cerebellum, V(T) in the cerebellum decreased after TAK-063 treatment. The specific binding to PDE10A (V(S)) was calculated as the difference of the V(T) between the target regions and the cerebellum. PDE10A occupancy was calculated as the percent change of V(S). The average PDE10A occupancy of the caudate nucleus and putamen was 35.2% at 0.2 mg/kg and 83.2% at 1.6 mg/kg. In conclusion, this nonhuman primate PET study demonstrated that [(11)C]T-773 is useful to estimate the PDE10A occupancy by TAK-063 in the striatum although there is in vivo interaction of the uptake between [(11)C]T-773 and TAK-063 in the cerebellum. These results warrant further clinical occupancy study for TAK-063.

Dipolar excitation in the third stability region.

Dipole resonant excitation of ions creates instability bands which follow iso-ß lines where ß is the characteristic exponent (stability parameter). Instability bands are exited most effectively on the fundamental frequency π= ßΩ/2. Here π is the angle resonance frequency of the dipolar voltage applied to x or y pair rods of the analyzer, and Ω is the angle frequency of the main drive voltage. Our goal is to study the mass peak shape in the third stability region with dipolar resonance excitation of the instability band with respect to the resonance frequency π and the dipolar potential amplitude. Numerical integration of the ion motion equations with a given ion source emittance is used to investigate peak shapes and ion transmission. We show that it is possible to vary the resolution power at any part of the third stability region. A change of the dipolar potential phase leads to a periodical variation of the resolution with period π.The most effective dipolar excitation in the y direction is along ßy near the stability boundary. The mass peak shape is calculated also for a quadrupole with round rods. The best peak shape (small tails and high resolution) takes place for the rod set with r/r0=1.130. Dipolar excitation increases the transmission by approximately 5-10% at a given resolution.

Thermal Stability of Dopamine Transporters.

The thermal stabilities of the rat and mouse dopamine transporter (DAT) proteins were studied within the temperature range of 0-37°C. The inactivation of the protein was followed by monitoring changes in radioligand-specific binding. We found that the process followed a rate equation with first-order kinetics and was characterized by having a single rate constant k inact. The activation energies (E a) that were calculated from the Arrhenius plots (ln k inact vs. 1/T) were 43 ± 5 and 45 ± 6 kJ/mol for the rat (rDAT) and mouse (mDAT) transporters, respectively, and 44 ± 7 kJ/mol for rDAT from PC-6.3 cell line. These E a values were similar to the E a values of thermal inactivation of the muscarinic receptor from rat brain cortex and to the thermal inactivation of other transmembrane proteins. However, all of these activation energy values were significantly lower than the E a values for soluble single-subunit proteins of similar size. These results therefore suggest that the thermal stability of transmembrane proteins may be governed to a significant extent by cell membrane properties and by interactions between the membrane components and the protein. In contrast, the stability of soluble proteins seems to be mostly governed by protein structure and size, which determine the sum of the stabilizing intramolecular interactions within the protein molecule. It is therefore not surprising that cell membrane properties and composition may have significant effects on the functional properties of transmembrane proteins.

Evaluation of a novel PDE10A PET radioligand, [(11) C]T-773, in nonhuman primates: brain and whole body PET and brain autoradiography.

Phosphodiesterase 10A (PDE10A) is considered to be a key target for the treatment of several neuropsychiatric diseases. The characteristics of [(11) C]T-773, a novel positron emission tomography (PET) radioligand with high binding affinity and selectivity for PDE10A, were evaluated in autoradiography and in nonhuman primate (NHP) PET. Brain PET measurements were performed under baseline conditions and after administration of a selective PDE10A inhibitor, MP-10. Total distribution volume (VT ) and binding potential (BPND ) were calculated using various kinetic models. Whole body PET measurements were performed to calculate the effective dose of [(11) C]T-773. Autoradiography studies in postmortem human and monkey brain sections showed high accumulation of [(11) C]T-773 in the striatum and substantia nigra which was blocked by MP-10. Brain PET showed high accumulation of [(11) C]T-773 in the striatum, and the data could be fitted using a two tissue compartment model. BPND was approximately 1.8 in the putamen when the cerebellum was used as the reference region. Approximately 70% of PDE10A binding was occupied by 1.8 mg/kg of MP-10. Whole body PET showed high accumulation of [(11) C]T-773 in the liver, kidney, heart, and brain in the initial phase. The radioligand was partly excreted via bile and the gastrointestinal tract, and partly excreted through the urinary tract. The calculated effective dose was 0.007 mSv/MBq. In conclusion, [(11) C]T-773 was demonstrated to be a promising PET radioligand for PDE10A with favorable brain kinetics. Dosimetry results support multiple PET measurements per person in human studies. Further research is required with [(11) C]T-773 in order to test the radioligand's potential clinical applications.

Development of a series of novel carbon-11 labeled PDE10A inhibitors.

Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon-11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3-(1H-pyrazol-5-yl)pyridazin-4(1H)-one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)-LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT-1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon-11 employing O-methylation on the hydroxyl moiety using [(11)C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [(11)C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon-11 labeled KIT-5 and KIT-6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [(11)C]KIT-6, named [(11)C]T-773, is a promising PET tool for further examination of PDE10A in human brain.

Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain.

Only recently the first successful serotonin 2A (5-HT2A) receptor agonist PET radioligands have been described, with [(11)C]Cimbi-36 reported as the most promising in the pig brain so far. Agonist radioligands may target specifically the G protein-coupled state of the receptors and thereby provide a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET measurements were conducted after intravenous injection of [(11)C]Cimbi-36 during baseline conditions and after intravenous infusion of the 5-HT2 receptor antagonist ketanserin (n=3) or the 5-HT2C receptor antagonist SB 242084 (n=2). On four of the experimental days an additional baseline PET measurement was conducted after injection of [(11)C]MDL 100907. All PET measurements were performed for 2h in a HRRT PET system and arterial blood was obtained for measurement of the [(11)C]Cimbi-36 input function. Quantification of [(11)C]Cimbi-36 receptor binding was performed using kinetic and graphical analysis. After injection of [(11)C]Cimbi-36 the regional distribution of radioactivity in brain was in accordance with the known 5-HT2 receptor distribution. The two-tissue compartment model was superior for the description of the time-radioactivity curves of all examined brain regions. BPND values obtained with reference tissue models correlated with corresponding values obtained with kinetic modeling. Administration of ketanserin decreased the binding in all brain regions but did not affect the cerebellar distribution volume. The BPND of [(11)C]Cimbi-36 was 56±8% of [(11)C]MDL 100907 across cortical regions, but higher in other brain regions including choroid plexus. After administration of SB 242084, [(11)C]Cimbi-36 binding was nearly completely inhibited in the choroid plexus, partly reduced in several subcortical regions (e.g. hippocampus), but not affected in the cortical regions. In conclusion, the receptor binding of [(11)C]Cimbi-36 can be quantified using kinetic modeling and the cerebellum was found to be a suitable reference region. The difference between [(11)C]Cimbi-36 and [(11)C]MDL 100907 binding in the choroid plexus is related to 5-HT2C receptor binding of [(11)C]Cimbi-36. [(11)C]Cimbi-36 is the first agonist radioligand suitable for examination of 5-HT2A receptors in the cortical regions and of 5-HT2C receptors in the choroid plexus of the primate brain.

Amphetamine decreases α2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain.

BACKGROUND: The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands. METHODS: We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys. RESULTS: Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata. CONCLUSIONS: Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.

(e)Managing the uncertainty of tuberculosis in the post-Soviet limbo: Tracking prisoners' coerced mobility for treatment in Ukrainian prisons.

The collapse of the Soviet Union triggered an escalation of the tuberculosis (TB) epidemic in many post-Soviet countries, including Ukraine. The main reasons for this situation include both the approach to TB care and the concentration of TB cases in prisons. The neoliberal approach to TB care system reform promises the optimization of treatment terms, "dehospitalization" and "despecialization" of the system of care, and a different type of control, established through digital technologies. One such technology is the "e-TB Manager", which was designated as a national TB registry, including in the prison system in 2012. In prison, where everyone "is to be fixed" and isolated, the uncertainty of patients' movements seems to be avoided by pre-existing conditions. In practice, however, the vertically aligned, centralized organizational structure of the post-Soviet prison implies a constant need to link its elements together through "coerced" mobility carried out in secrecy. Treatment in exile may not be the primary goal of such a practice, but it becomes the result when prisoners from numerous prison facilities are sent to a limited number of prison TB hospitals. The integration of the e-TB Manager as a tool to enable the tracking of patient movements and, consequently, improve the efficiency of diagnostic and treatment processes in prison, can be seen as both a purely technical measure and a "magic bullet". In this article, we argue that, in the case of Ukrainian prisons, the neoliberal approach and the Soviet socialist approach to gaining control over TB indeed adapt and reinforce each other but fail to compete meaningfully. The fragmented implementation of one is absorbed by the fundamental and resilient nature of the other to produce and reproduce the state of "post-Soviet limbo". We use the "post-Soviet limbo" as an overall framework aimed at conceptualizing the post-Soviet transformation as a combination of efforts to avoid and manage the uncertainty of TB treatment, especially in prison. We examine the empirical case of coerced mobility of prisoners who require TB treatment, seeking to trace how this process is reflected in the e-TB Manager. We provide a more in-depth picture of this journey with details gathered from qualitative research materials to situate numbers and variables in their contexts, deconstructing the way the data are recorded according to the logic of the system in which they are produced.

Agent-based models under uncertainty.

Background: Monte Carlo (MC) is often used when trying to assess the consequences of uncertainty in agent-based models (ABMs). However, this approach is not appropriate when the uncertainty is epistemic rather than aleatory, that is, when it represents a lack of knowledge rather than variation. The free-for-all battleship simulation modelled here is inspired by the children's battleship game, where each battleship is an agent. Methods: The models contrast an MC implementation against an interval implementation for epistemic uncertainty. In this case, our epistemic uncertainty is in the form of an imperfect radar. In the interval method, the approach occludes the status of the agents (ships) and precludes an analyst from making decisions about them in real-time. Results: In a highly uncertain environment, after many time steps, there can be many ships remaining whose status is unknown. In contrast, any MC simulation invariably tends to conclude with a small number of the remaining ships after many time steps. Thus, the interval approach misses the quantitative conclusion. However, some quantitative results are generated by the interval implementation, e.g. the identities of the surviving ships, which are revealed to be nearly mutual with the MC implementation, though with fewer identities in total compared to MC. Conclusions: We have demonstrated that it is possible to implement intervals in an ABM, but the results are broad, which may be useful for generating the overall bounds of the system but do not provide insight on the expected outcomes and trends.

Cowper's Glands Abscess with Spreading to Adjacent Organs and Tissues with Development of Septic Shock: An Extremely Rare Case.

BACKGROUND: We present here the first case of Cowper's gland abscess complicated by septic shock and breakthrough of the abscess into the paraurethral region, cavernous body, scrotum, and pararectal tissue. CASE PRESENTATION: A 63-year-old patient was admitted with complaints of temperature increase up to 39°C, pain and enlargement of the perineum and the right half of the scrotum, frequent and difficulty urination, weakness, dizziness, dry mouth, and a sharp deterioration of the general condition. Clinical-laboratory data showed the presence of septic shock with unstable haemodynamics and many concomitant diseases. From the history, it is known that the patient for more than 20 years suffered from urinary tract infection and urinary disorders. Six months earlier, the patient underwent a puncture of a bulbourethral abscess. According to the ultrasound of the scrotum, TRUS, and MRI, bulbourethral abscess with spread to the right half of the scrotum, a part of the cavernous body, and the cellular tissue of the left sciatic-rectal fossa was diagnosed. Purulent cavities were opened with two incisions and drained. A cystostomy was installed. In the intensive care unit, according to a microbiological study (Escherichia coli, Klebsiella pneumoniae, and Klebsiella pneumoniae), antibacterial, detoxification, and symptomatic therapy of concomitant diseases were carried out together with a resuscitator and therapist. The patient was discharged on the 30th day with a negative analysis of urine culture, with a cystostomy, which was removed six months after the independent restoration of urination and closure of the fistulous passage between the urethra and Cowper's glands. CONCLUSION: Untimely treatment of the very rare abscess of the Cowper's gland can lead to serious complications, up to the spread of a purulent process to neighbouring organs and tissues, and the development of septic shock, which will require urgent and intensive therapy with the involvement of experts from interdisciplinary fields.

Correction: Is no test better than a bad test: Impact of diagnostic uncertainty on the spread of COVID-19.

[This corrects the article DOI: 10.1371/journal.pone.0240775.].