In vivo detection of short- and long-term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain

The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [¹¹C](+)McN 5652, a potent 5-HT transporter ligand, as well as [¹¹C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [¹¹C](+)McN5652, [¹¹C](−)McN5652 (the inactive enantiomer of the active enantiomer [¹¹C](+)McN5652) and [¹¹C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [¹¹C](+)McN 5652, but not with [¹¹C](−)McN5652 or [¹¹C]RTI-55. Reductions in specific [¹¹C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (−)[¹¹C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [¹¹C](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [¹¹C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects. Synapse 29:183–192, 1998. © 1998 Wiley-Liss, Inc.     

Combining cardiac magnetic resonance and computed tomography coronary calcium scoring: added value for the assessment of morphological coronary disease?

To investigate prospectively, in patients with suspicion of coronary artery disease (CAD), the added value of coronary calcium scoring (CS) as adjunct to cardiac magnetic resonance (CMR) for the diagnosis of morphological coronary stenosis in comparison to catheter angiography (CA). Sixty consecutive patients (8 women; 64 ± 10 years) referred to CA underwent CMR (1.5 T) including perfusion and late gadolinium-enhancement imaging as well as CS with computed tomography. Diagnostic performance was evaluated for CMR and CS separately, and for both methods combined, with CA as reference standard. Best CS threshold combined with a specificity >90% to predict significant stenosis in patients without abnormalities on CMR was determined from receiver operator characteristics (ROC) analysis. Abnormal CMR results were considered to indicate significant stenosis regardless of CS; CS above threshold reclassified patients to have CAD regardless of CMR. CA identified 104/960 (11%) coronary segments with coronary artery stenosis >50% in 36/60 (60%) patients. ROC revealed an area-under-the-curve of 0.83 (95%CI: 0.68-0.99) with the best CS threshold of 495 Agatston score (sensitivity 50%). CMR depicted 128/960 (13%) myocardial segments with abnormalities in 31/60 (52%) patients. Sensitivity, specificity, negative (NPV) and positive predictive value (PPV) of CMR were 78, 88, 72 and 90%. When adding CS to CMR, sensitivity and NPV increased to 89 and 83%, while specificity and PPV slightly decreased to 83 and 89%. Accuracy of the combined approach (87%) was significantly (P < 0.05) higher than that of CMR (82%) alone. Adding CS to CMR improves the accuracy for the detection of morphological CAD.     

CD14 and TRIF govern distinct responsiveness and responses in mouse microglial TLR4 challenges by structural variants of LPS

Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co-receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14^−/− microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF (cd14^−/−, myd88^−/−, and trif^lps2), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges.     

(11)C]-GR89696, a potent kappa opiate receptor radioligand; in vivo binding of the R and S enantiomers.

The R and S enantiomers of [(11)C]GR89696, [(11)C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate, were synthesized from their appropriate chiral precursors and [(11)C]methyl chloroformate. The [(11)C]-labeled R enantiomer of GR89696, also known as GR103545, demonstrated high affinity in mouse brain with region to cerebellar ratios at 90 minutes of 11.4 and 8.7 for the hypothalamus and olfactory tubercle, respectively. The [(11)C]-labeled S enantiomer showed low affinity and region to cerebellar ratios of 1 for all brain regions. The [(11)C]-labeled GR103545 exhibited a selective and saturable binding for the kappa opioid receptor.     

HTLV-III serology in hemophilia: relationship with immunologic abnormalities

We investigated the relationship of the presence of antibodies to HTLV-III and immunologic abnormalities in patients with hemophilia. Serum antibodies to HTLV-III were analyzed by ELISA assay, immunoprecipitation of labeled cell extracts, and immunoprecipitation of purified HTLV-III p24. Thirty-four (61%) of the total group (n = 56) had antibody to HTLV-III; 34 (76%) of 45 patients given commercial factor VIII preparations were seropositive, compared with none of 11 patients treated exclusively with cryoprecipitate obtained from volunteer blood donors. Of patients who were seropositive for HTLV-III antibody, 94% had abnormal T4/T8 ratios, and 33% of those whose serum was antibody negative had abnormal T4/T8 ratios; five patients, each antibody positive, have lymphadenopathy syndrome. Sequential studies in a subset of patients indicate that there is a changing pattern of antibody production to HTLV-III antigens after seroconversion.     

Sympathetic tone assessed by washout of iodine 125-labeled metaiodobenzylguanidine from the murine left ventricle-influence of immobilization stress and inhibition of the renin-angiotensin system

Background  

Because it is not metabolized as is norepinephrine (NE), most of the metaiodobenzylguanidine (MIBG) taken up by the heart is considered to be lost subsequently by release concomitant with sympathetic stimulation. Therefore we examined whether the washout of MIBG is influenced by sympathetic tone, which we modulated by using immobilization stress or activation of the renin-angiotensin system (RAS).