Primary dural lymphoma: A novel concept of heterogeneous disease

Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well‐documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an additional case of spinal PDL that, similarly to our previous case, was grade 1–2 follicular B‐cell PDL. Our two cases were diagnosed over a 3‐year interval in a 72‐year‐old female and a 74‐year‐old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B‐cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B‐cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site‐specific lymphoma‐type predilection phenomenon, well‐recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification.     

Pre-marital predictors of marital violence in the WHO World Mental Health (WMH) Surveys

Social Psychiatry and Psychiatric Epidemiology - Intimate partner violence (IPV) is a pervasive public health problem. Existing research has focused on reports from victims and few studies have...     

One‐step radiosynthesis of [18F]LBT‐999: a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3‐beta‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2‐beta‐carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (K_D : 9 nM for the DAT and IC₅₀ > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine‐18‐labelling of LBT‐999 was based on the robust and reliable two‐step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene followed by a N‐alkylation reaction with the appropriate nor‐tropane moiety. In the present work, a simple one‐step fluorine‐18‐labelling of LBT‐999 is reported, based on a chlorine‐for‐fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high‐performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[¹⁸F]F–Kryptofix^®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C‐18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Typically, 3.70–5.92 GBq of [¹⁸F]LBT‐999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep‐Pak‐based formulation included), starting from a 37.0 GBq [¹⁸F]fluoride batch (overall radiochemical yields: 10–16%, non‐decay‐corrected). Copyright © 2007 John Wiley & Sons, Ltd.     

Discrepancies in the P-glycoprotein-Mediated Transport of 18F-MPPF: A Pharmacokinetic Study in Mice and Non-human Primates

Purpose

Several in vivo studies have found that the 5-HT_1A PET radioligand ¹⁸F-MPPF is a substrate of rodent P-glycoprotein (P-gp). However, in vitro assays suggest that MPPF is not a substrate of human P-gp. We have now tested the influence of inhibiting P-gp on the brain kinetics of ¹⁸F-MPPF in mice and non-human primates.

Methods

We measured the peripheral kinetics (arterial input function, metabolism, free fraction in plasma (f_P)) during ¹⁸F-MPPF brain PET scanning in baboons with or without cyclosporine A (CsA) infusion. We measured ³H-MPPF transport at the mouse BBB using in situ brain perfusion in P-gp/Bcrp deficient mice and after inhibiting P-gp with PSC833.

Results

There was an unexpected 1.9-fold increase in brain area under the curve in CsA-treated baboons (n?=?4), with no change in radiometabolite-corrected arterial input. However, total volume of distribution corrected for f_P (V_T/f_P) remained unchanged. In situ brain perfusion showed that P-gp restricted the permeability of the mouse BBB to ³H-MPPF while Bcrp did not.

Conclusion

These and previous in vitro results suggest that P-gp may not influence the permeability of human BBB to ¹⁸F-MPPF. However, CsA treatment increased ¹⁸F-MPPF free fraction, which is responsible for a misleading, P-gp unrelated enhanced brain uptake.     

18F]FPhEP and [18F]F2PhEP, two new epibatidine-based radioligands: evaluation for imaging nicotinic acetylcholine receptors in baboon brain

The radioligand 2-[(18)F]fluoro-A-85380 has been developed for imaging alpha(4)beta(2) nAChRs with PET. However, it has slow kinetics and a large fraction of bound activity is nondisplaceable. In an attempt to address these problems, two epibatidine-based alpha(4)beta(2) nicotinic antagonists, coded FPhEP and F(2)PhEP, were evaluated in vivo in baboons. They were radiolabeled with fluorine-18 from the corresponding N-Boc-protected bromo-derivatives and the no-carrier-added K[(18)F]F-Kryptofix(222) complex. Radiochemically pure [(18)F]FPhEP or [(18)F]F(2)PhEP was obtained in 80 min in amounts of 1.11-2.22 GBq (111-185 GBq/micromol). After injection of 215 MBq of [(18)F]FPhEP or [(18)F]F(2)PhEP, dynamic PET data were acquired. Thalamic radioactivity peaked at 20 min (4.9% +/- 0.2% ID/100 mL tissue) for [(18)F]FPhEP. For [(18)F]F(2)PhEP, the peak was at 45 min (3.3% +/- 0.1% ID/100 mL tissue). Regional distribution of both radiotracers was in accordance with the known distribution of nAChRs. In presaturation experiments, nicotine, cytosine, or FPhEP reduced brain radioactivity of [(18)F]FPhEP. In a displacement experiment with nicotine only a small amount of [(18)F]F(2)PhEP was dislodged. In spite of a moderate to high in vitro affinity, both ligands do not fulfill the widely adopted criteria for a PET radioligand.     

Association of perceived stigma and mood and anxiety disorders: results from the World Mental Health Surveys

Objective: We assessed the prevalence of perceived stigma among persons with mental disorders and chronic physical conditions in an international study. Method: Perceived stigma (reporting health‐related embarrassment and discrimination) was assessed among adults reporting significant disability. Mental disorders were assessed with Composite International Diagnostic Interview (CIDI) 3.0. Chronic conditions were ascertained by self‐report. Household‐residing adults (80 737) participated in 17 population surveys in 16 countries. Results: Perceived stigma was present in 13.5% (22.1% in developing and 11.7% in developed countries). Suffering from a depressive or an anxiety disorder (vs. no mental disorder) was associated with about a twofold increase in the likelihood of stigma, while comorbid depression and anxiety was even more strongly associated (OR 3.4, 95%CI 2.7–4.2). Chronic physical conditions showed a much lower association. Conclusion: Perceived stigma is frequent and strongly associated with mental disorders worldwide. Efforts to alleviate stigma among individuals with comorbid depression and anxiety are needed.     

Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling Part I: PET studies

BackgroundLBT-999 (E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane is a dopamine transporter (DAT) ligand. [¹⁸F]LBT-999 was first labelled with carbon-11; we will now describe its in vivo behaviour in comparison to that of [¹¹C]LBT-999.Methods/ResultsPositron emission tomography (PET) experiments (baboons) confirmed the high affinity/specificity of [¹⁸F]LBT-999 for DAT. The brain regional distribution was in accordance with that of DAT. Pre-treatment with LBT-999 (1 mg/kg iv), but not with desipramine, a norepinephrine (NET) antagonist, reduced the striatum-to-cerebellum ratio by 96%, confirming the specificity for DAT vs. NET. The parent compound decreased rapidly and represented 24.3±5.0% of plasma radioactivity at 30 min pi. Whole-body scans showed an important bone uptake of free fluorine following metabolism of [¹⁸F]LBT-999. In the cerebellum and striatum, distribution volumes increased by 30–40% between 80 and 230 min, suggesting the polluting role of a radiometabolite(s). [¹¹C]LBT-999 exhibited a 40% higher standardized uptake value in the striata. This difference is likely due to N-dealkylation followed by [¹⁸F]fluoride release. 2β-Carbomethoxy-3β-(4′-tolyl) nortropane is then formed, while [¹¹C]2β-carbomethoxy-3β-(4′-tolyl) nortropane is formed following injection of [¹¹C]LBT-999. This metabolite has high affinity for the DAT. In one specific PET experiment, intravenous injection of this metabolite induced a strong displacement of [¹⁸F]LBT-999 in the striata, confirming that this metabolite readily crosses the blood–brain barrier (BBB) and binds to DAT.Conclusions[¹⁸F]LBT-999 is N-dealkylated in vivo to yield (1) a nonradioactive metabolite that crosses the BBB and has a high affinity for the DAT and (2) a [¹⁸F]fluoro-alkyl chain which is further defluorinated. The temporal changes in distribution volumes are consistent with the accumulation of a radiometabolite(s) in the brain. Therefore, the quantification of DAT density with [¹⁸F]LBT-999 is rather difficult.     

Multiinjection approach for D2 receptor binding quantification in living rats using [11C]raclopride and the beta-microprobe: crossvalidation with in vitro binding data.

The purpose of this study was to quantify D2 receptors density and affinity in living rats using [11C]raclopride and to validate the multiinjection modelling approach. To this aim, we used an intracerebral beta+-sensitive probe as a highly sensitive system to quantify the radioligand activity using a single three-injection experimental paradigm. The study was divided into three main parts: (i) [11C]raclopride catabolism evaluation without and with cimetidine pretreatment (cytochrome P450 inhibitor); (ii) quantification of kinetics parameters in the striatum, enthorinal cortex, and cerebellum of living rats using a three-compartment model with an arterial input function; (iii) correlation study of in vivo and in vitro binding density and affinity values in the same striatal tissues. (i) raclopride catabolism was very reproducible between individuals; cimetidine pre-treatment resulted in a 30% reduction of raclopride metabolites. (ii) D2 striatal B'max and KdVr estimates obtained by compartmental modelling were 19.87+/-6.45 and 6.2+/-3.3 nmol/L, respectively. Cerebellum is the best candidate as a reference region with no specific binding detectable in vivo. (iii) When comparing density (Bmax/B'max) and affinity (Kd/KdVr) values in vivo and in vitro for each striatum, a high strict correlation was found (r2=0.90 and 0.72, for density and affinity, respectively). These results validate the multi-injection modelling approach coupled to beta-microprobe acquisitions as a mean to provide accurate and separate estimates of dopamine D2-receptor density and affinity, in the living rodent striatum.