Multimodal investigation of dopamine D2/D3 receptors,default mode network suppression,and cognitive control in cocaine-use disorder

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [¹¹C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.Subject terms: Addiction, Cognitive control     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Implication of emergency departments in the regulation of public hospitalizations

PURPOSE: Emergency departments become a useful way to access to hospital care. Since these last years difficulties of hospitalization, mainly of the elderly, after visit to the emergency department, are on the increase. CURRENT KNOWLEDGE AND KEY POINTS: Emergency departments are an important mode of recruitment for hospital units, 4 patients to 10 are hospitalized from emergency departments. The difficulties of hospitalization starting at the emergency department are more important for the elderly. Actually, there are 2 type of hospital care, planed and non planed care. The development of observation units specific to the emergency departments allowed to resolve some of these difficulties. But they are limited by their small number of beds and the duration of hospitalization below to 36 h. Some hospitals developed polyvalent emergency short stay unit to hospitalize patients who visited emergency department without necessity to give them a specialized care. FUTURE PROSPECTS AND PROJECTS: This situation must allow us to purpose a better regulation of hospitalizations which includes emergency departments in a network system including the different hospital ways of taking care. A downstream way of care adapted to the emergency hospitalizations would be developed. This could include the emergency department, the observation unit and the emergency short stay unit in interface with internal medicine and general medicine units, geriatric unit and specialized units, all of them will be included in a town-hospital care network.     

Tracer kinetic modeling of [11C]AFM,a new PET imaging agent for the serotonin transporter

[¹¹C]AFM, or [¹¹C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [¹¹C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [¹¹C]AFM binding potential (BP_ND) matched well with the known regional SERT densities. For routine use of [¹¹C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [¹¹C]AFM is a suitable PET radioligand to image and quantify SERT in humans.     

Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy

The first case of cobalamin deficiency with megaloblastic anaemia in a patient under long-term omeprazole therapy is presented. This patient received omeprazole at a daily dose of 40–60 mg for 4 years as treatment for a gastro-oesophagal reflux complicated by peptic oesophagitis. Seric vitamin B12 was dramatically decreased at 80 pmol L^-1. The Schilling test was normal (13%) with crystalline [⁵⁷Co] cobalamin and it was at 0% with [⁵⁷Co] cobalamin-labelled trout meat. All other assimilation tests were normal except an expiratory hydrogen breath test performed with lactulose. The haematological status was restored after intramuscular treatment with cobalamin. In conclusion, prolonged omeprazole therapy can be responsible for a cobalamin deficiency due to protein-bound cobalamin malabsorption.     

Thermo-sensitive microparticles of PNIPAM-grafted ethylcellulose by spray-drying method

The thermo-sensitive polymer, PNIPAM-grafted ethylcellulose, was synthesized and it was confirmed by FTIR spectroscopy that PNIPAM was successfully grafted onto ethylcellulose. Microparticles were prepared by the spray-drying method using a B-191 Mini Spray Dryer. Their morphology, observed by scanning electron microscopy (SEM), showed irregular spheres with rugged surfaces, and narrow size distribution. In a model delivery system, ethylcelullose-g-PNIPAM was used as the polymer wall material and allopurinol was used as the model drug. The release rate of allopurinol from ECGPN8 microparticles was slower at 40 degrees C (above the LCST) than that of 25 degrees C (below the LCST), probably due to the collapse of PNIPAM chains by temperature. Although PNIPAM was the large part of wall material, the thermo-sensitive release behavior was not so obvious. It is believed that the release of allopurinol from the microparticles is more dependent on the porous structure of microparticles than the conformational change of PNIPAM, created by the rapid evaporation of solvent during the spray-drying process.     

Increased morbidity from nasopharyngeal carcinoma and chronic pharyngitis or sinusitis among workers at a newspaper printing company

Objectives: To determine the association between printing works and nasopharygeal carcinoma as well as other diseases.

Methods: Demographic data were obtained for those who had worked in a particular newspaper company since its establishment in 1950. Through access to the data bank of the hospital records of the Labor Insurance Bureau for 1985–94, all workers were identified who had been admitted to hospital during their employment in the newspaper company. Multiple logistic regressions were performed to estimate the adjusted morbidity odds ratio (OR) for various diseases among the printing workers with cardiovascular diseases as the reference diseases. Biopsy specimens from patients with nasopharyngeal carcinoma were all subjected to in situ hybridisation of Epstein-Barr virus (EBV), and colocalisation of EBV and secretor component protein.

Results: Of the 1564 people who had worked in this company, 579 of them were admitted to hospital at least once. Five out of 144 printing workers admitted to hospital were diagnosed with nasopharyngeal carcinoma compared with none of the other 435 non-printing workers admitted to hospital. The morbidity OR for nasopharyngeal carcinoma in printing workers was 57.0 (95% confidence interval (95% CI) 2.8 to 1155.3). The morbidity OR for benign skin tumours was 28.0 (95% CI 2.7 to 293.1). Chronic pharyngitis or sinusitis also showed significant relations with printing works with a morbidity OR 29.4 (95% CI 1.7 to 514.7). Using all other diseases as the reference diseases for calculation of morbidity ORs still showed a similar trend. In situ hybridisation of EBV encoded small nuclear RNA-1 (EBER-1) showed tumour cells free of the EBV in each biopsy specimen. Colocalisation of EBER-1 and secretor component showed that some tumour cells contained both secretor component and EBV signal in each case.

Conclusion: Printing works are associated with an increased risk of nasopharyngeal carcinoma, benign skin tumours, chronic pharyngitis or sinusitis, chronic liver diseases, and mechanical injuries. Induction of the development of nasopharyngeal carcinoma is probably not related to EBV infection in these patients.