The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac

Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra- and inter-patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P-glycoprotein. The transport of methadone was increased in presence of P-gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.     

Effect of chronic pre‐treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion

Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient’s morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia‐induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia–reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham‐operated animals (n = 11). The effect of ACEi on the non‐ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V_max) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate–malate, succinate and TMPD–ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 ± 2.8 vs. 108 ± 4.19 mmHg; P = 0.01). Ischemia–reperfusion reduced V_max (4.4 ± 0.4 vs. 8.7 ± 0.5 μmol O₂/min/g dry weight, ?49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia‐induced dysfunction (V_max 5.1 ± 0.7 μmol O₂/min/g dry weight) or the non‐ischemic contralateral muscle respiratory rate. Ischemia–reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre‐treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization.     

Binding properties of antagonists to Cannabinoid receptors in intact cells

The implication of the cannabinoid receptor 1 (CB₁ receptor) in several pathophysiological states has sparked the development of selective antagonists. Here we compare binding of the antagonists [³H]‐AZ12491187, [³H]‐taranabant and [³H]‐rimonabant to intact human embryonic kidney cells stably expressing recombinant human CB₁ receptors (CB1r cells). Unlabelled ligands decreased the total binding of the three radioligands with closely the same order of potency: i.e. AZ12288553 ～ AZ12491187 ～ taranabant > rimonabant. Nondisplaceable (i.e. nonspecific) binding to the CB1r cells was the same as total binding to the wells containing untransfected cells and it was more pronounced for [³H]‐AZ12491187 and [³H]‐rimonabant than for [³H]‐taranabant. [³H]‐Rimonabant and (to a lesser extent) [³H]‐AZ12491187 were also prone to bind nonspecifically to the walls of the wells. Compared to the other radioligands, [³H]‐rimonabant displayed lower potency for the CB₁ receptors in saturation binding studies and faster association and dissociation in kinetic experiments. When dissociated, the three radioligands also showed prominent rebinding to the cells in medium only. This could be relieved by the presence of excess of unlabelled ligand and of bovine serum albumin (BSA) but a combination thereof was most efficient. The long ‘residence time’ of AZ12491187 at the CB₁ receptor (because of slow dissociation and prominent rebinding) and its pronounced incorporation into the membranes of the cells could contribute to long‐lasting in vivo CB₁ receptor blockade.     

Mixed-signal template-based reduction scheme for stimulus artifact removal in electrical stimulation

Simultaneous electrical stimulation and recording are used to gain insights into the function of neuronal circuitry. However, artifacts produced by the electrical stimulation pulses prevent the recording of neural responses during, and a short period after, the stimulation duration. In this work, we describe a mixed-signal recording topology with template subtraction for removing the artifact during the stimulation pulse. Emulated artifacts generated from a lumped electrical circuit model and experimental artifacts in cardiac cell cultures are used to evaluate the topology. The simulations show that delays between the emulated artifact and its estimated compensation template represent the largest error source of the analog template subtraction. The quantization error appears like random noise and determines the threshold level for the action potential detection. Simulations show that removal of the artifacts is possible, allowing the detection of action potentials during the stimulation pulsing period, even for high-amplitude saturating artifacts. Measurement results with artifacts elicited in cardiac cell cultures show feasible applications of this topology. The proposed topology therefore promisingly opens up a previously unavailable detection window for improving the analysis of the neuronal activity.     

Arterial spin labeling MR image denoising and reconstruction using unsupervised deep learning

Arterial spin labeling (ASL) imaging is a powerful magnetic resonance imaging technique that allows to quantitatively measure blood perfusion non-invasively, which has great potential for assessing tissue viability in various clinical settings. However, the clinical applications of ASL are currently limited by its low signal-to-noise ratio (SNR), limited spatial resolution, and long imaging time. In this work, we propose an unsupervised deep learning-based image denoising and reconstruction framework to improve the SNR and accelerate the imaging speed of high resolution ASL imaging. The unique feature of the proposed framework is that it does not require any prior training pairs but only the subject's own anatomical prior, such as T1-weighted images, as network input. The neural network was trained from scratch in the denoising or reconstruction process, with noisy images or sparely sampled k-space data as training labels. Performance of the proposed method was evaluated using in vivo experiment data obtained from 3 healthy subjects on a 3T MR scanner, using ASL images acquired with 44-min acquisition time as the ground truth. Both qualitative and quantitative analyses demonstrate the superior performance of the proposed txtc framework over the reference methods. In summary, our proposed unsupervised deep learning-based denoising and reconstruction framework can improve the image quality and accelerate the imaging speed of ASL imaging.     

De novo arteriovenous shunts after endovascular cure of cerebrospinal macro arteriovenous fistulas. A role for the vasa vasorum?

Background and purposeMacro-arteriovenous fistulas (MAVFs) are arteriovenous shunts draining into a giant venous ectasia. They can be treated by surgery or embolisation. Angiographic controls are usually performed rapidly after treatment in order to prove the cure of the lesion but no long term angiographies are generally scheduled. We wanted to control the stabilities of such lesions at follow-up.MethodClinical history and imaging of ninety-five patients with high flow shunts draining into venous ectasias (MAVFs, Vein of Galen malformations and dilatations) were reviewed.ResultsDe novo arteriovenous shunts related to angiogenesis involving vasa vasorum developed in three patients with MAVFs at various intervals. Genetic underlying conditions as HHT or RASA 1 mutations were suspected in each patient.ConclusionsNeo-angiogenesis can occur after cure of MAVFs. Long term imaging follow-ups should be considered as the natural history of such recurrent shunts is currently unknown.