Bilateral Implantation of Centromedian‐Parafascicularis Complex and GPi: A New Combination of Unconventional Targets for Deep Brain Stimulation in Severe Parkinson Disease

Objectives. Traditional deep brain stimulation (DBS) at the subthalamic nucleus (STN) has proved to be efficacious on core Parkinsonian symptoms. However, very disabling l ‐dopa–induced abnormal involuntary movements (AIMs) and axial signs are slightly affected, suggesting that we target less conventional targets. Our candidates for DBS were the globus pallidus internus (GPi) plus the intralaminar thalamic complex (Pf or CM), given its extensive functional links with basal ganglia nuclei. Materials and Methods. The routine utilization of our innovative stereotactic apparatus allows us to implant, at the same time, both the CM‐Pf complex together with the GPi in six Parkinson disease patients. Both intraoperative and postoperative neurophysiologic assessments helped us recognize functional subregions while optimizing implantation of electrodes. Unified Parkinson disease rating scale (UPDRS) motor scores, AIMs, and freezing were carefully blindly evaluated for each condition. Results. A significant amelioration of UPDRS scores was achieved by simultaneous activation of both targets. CM‐Pf activation was only slightly effective in reducing rigidity and akinesia, but more efficacious on freezing. Not surprisingly, AIMs were peculiarly decreased by the activation of the permanent electro‐catheter in the posteroventral GPi. Conclusions. These findings confirm that, in selected patients, it is conceivable to target structures other than the conventional STN in order to maximize clinical benefit.     

The role of nitrinergic connections in central cardiovascular responses mediated by physostigmine infused into posterior hypothalamus

In the last few decades, cholinergic connections located into posterior hypothalamus (PH) have been implicated in the central regulation of blood pressure (BP). Here we investigated the role of nitric oxide (NO) in the blood pressure response elicited by infusion of physostigmine into PH of normotensive rats. In freely moving rats, physostigmine (60-200 nM) produced a dose- and time-dependent elevation of BP which was antagonized by the antimuscarinic drug scopolamine (60 nM) and by L-NAME (100 microM), an inhibitor of NO synthase, both infused into the same site. In contrast, L-arginine (L-Arg; 100 microM), the precursor of NO, and glyceryltrinitrate (GTN; 140 nM), an NO donor, infused into the PH did not affect physostigmine-related pressor response. In rats pre-treated with Escherichia coli lipopolisaccharide (LPS; 0.5 microg i.p. 24h beforehand), however, scopolamine, L-Arg and GTN produced a decrease of BP, an effect antagonized by L-NAME. This suggests that NO only slightly modulates physostigmine-related pressor response elicited into PH of LPS-untreated rats. In contrast, the release of large amounts of NO generated by pre-treating rats with LPS, down-regulates cholinergic connections located at the PH, thus contributing in the central dysregulation of BP which can be found when high circulating endotoxin levels may occur.     

The need for patient-focused therapy for children and teenagers with allergic rhinitis: a case-based review of current European practice

Allergic rhinitis is a common problem in childhood and adolescence, with a negative impact on the quality of life of patients and their families. The treatment modalities for allergic rhinitis include allergen avoidance, anti-inflammatory symptomatic treatment and allergen specific immunotherapy. In this review, four cases of children with allergic rhinitis are presented to illustrate how the recently published EAACI Guidelines on Pediatric Allergic Rhinitis can be implemented in clinical practice.     

A novel animal model to evaluate the ability of a drug delivery system to promote the passage through the BBB

The purpose of this investigation was to explore the potentiality of a novel animal model to be used for the in vivo evaluation of the ability of a drug delivery system to promote the passage through the blood–brain barrier (BBB) and/or to improve the brain localization of a bioactive compound. A Tween 80^®-coated poly-l-lactid acid nanoparticles was used as a model of colloidal drug delivery system, able to trespass the BBB. Tacrine, administered in LiCl pre-treated rats, induces electrocorticographic seizures and delayed hippocampal damage. The toxic effects of tacrine-loaded poly-l-lactid acid nanoparticles (5 mg/kg), a saline solution of tacrine (5 mg/kg) and an empty colloidal nanoparticle suspension were compared following i.p. administration in LiCl-pre-treated Wistar rats. All the animals treated with tacrine-loaded nanoparticles showed an earlier outcome of CNS adverse symptoms, i.e. epileptic onset, with respect to those animals treated with the free compound (10 min vs. 22 min respectively). In addition, tacrine-loaded nanoparticles administration induced damage of neuronal cells in CA1 field of the hippocampus in all treated animals, while the saline solution of tacrine only in 60% of animals. Empty nanoparticles provided similar results to control (saline-treated) group of animals. In conclusion, the evaluation of time-to-onset of symptoms and the severity of neurodegenerative processes induced by the tacrine–lithium model of epilepsy in the rat, could be used to evaluate preliminarily the capability of a drug delivery system to trespass (or not) the BBB in vivo.     

Neurobiological mediators of neuronal apoptosis in experimental neuroAIDS

Neuronal loss has often been described at post-mortem in the brain neocortex of patients suffering from AIDS. Neuroinvasive strains of HIV infect macrophages, microglial cells and multinucleated giant cells but not neurones. Processing of the virus by cells of the myelomonocytic lineage yields viral products that, in conjunction with potentially neurotoxic molecules generated by the host, might initiate a complex network of events which leads neurones to death. In particular, the HIV-1 coat glycoprotein gp120 has been proposed as a likely aetiologic agent of the described neuronal loss because it causes death of neurones in culture. More recently, it has been shown that brain neocortical cell death is caused in rat by intracerebroventricular injection of a recombinant gp120 coat protein and this occurs via apoptosis. The latter observation broadens our knowledge in the pathophysiology of the reported neuronal cell loss and opens a new lane of experimental research for the development of novel therapeutic strategies to limit damage to the brain of patients suffering from HIV associated dementia.     

Neuronal vulnerability following inhibition of mitochondrial complex II: a possible ionic mechanism for Huntington's disease

An impaired complex II (succinate dehydrogenase, SD) striatal mitochondrial activity is one of the prominent metabolic alterations in Huntington's disease (HD), and intoxication with 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, mimics the motor abnormalities and the pathology of HD. We found that striatal spiny neurons responded to this toxin with an irreversible membrane depolarization/inward current, while cholinergic interneurons showed a hyperpolarization/outward current. Both these currents were sensitive to intracellular concentration of ATP. The 3-NP-induced depolarization was associated with an increased release of endogenous GABA, while acetylcholine levels were reduced. Moreover, 3-NP induced a higher depolarization in presymptomatic R6/2 HD transgenic mice compared to wild-type (WT) mice, showing an increased susceptibility to SD inhibition. Conversely, the hyperpolarization did not significantly differ from the one recorded in WT mice. The diverse membrane changes induced by SD inhibition may contribute to the cell-type-specific neuronal death in HD.