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.     

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.     

Corticostriatal LTP requires combined mGluR1 and mGluR5 activation

Metabotropic glutamate receptors (mGluRs) have been demonstrated to play a role in synaptic plasticity. It has been recently shown that mGluR1 is involved in corticostriatal long-term depression, by means of pharmacological approach and by using mGluR1-knockout mice. Here, we report that both mGluR1 and mGluR5 are involved in corticostriatal long-term potentiation (LTP). In particular, the mGluR1 antagonist LY 367385, as well as the mGluR5 antagonist MPEP, reduce LTP amplitude. Moreover, blockade of both mGluR1 and mGluR5 by LY 367385 and MPEP co-administration fully suppresses LTP. Accordingly, group II and group III mGluRs antagonists fail to affect LTP induction. Interestingly, LTP amplitude is also significantly reduced in both mGluR1- and mGluR5-knockout mice.The differential function of mGluR1 and mGluR5 in corticostriatal synaptic plasticity may play a role in the modulation of the motor activity mediated by the basal ganglia, thus providing a substrate for the pharmacological treatment of motor disorders involving the striatum.     

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.     

Removal of tattoos by CO2 laser and acetic acid]

The Authors pay attention to small tattoo removal by means of the utilization of the CO2 laser. Moreover, the Authors emphasize the drawback of double treatment which, usually, the patient suffers in tattoo removal by CO2 laser. Then, the pressure of the Authors is small sized tattoo removal in only one sitting achieving so an excellent esthetic result. Besides, the Authors, in this medical study, explains two methods for tattoo removal. In the study's results, the Authors describes the manner and the time of the two lesion recovery by the different manners of treatment. Finally, the Authors affirms the great consequence of the surgical CO2 laser, they don't fail, however, to affirm that the laser and acetic acid combination is an excellent procedure for small tattoo removal.     

Characteristics of Early Transient, Persistent, and Late Onset Wheezers at 9 to 11 Years of Age

Study objective. To investigate the early determinants and characteristics of different phenotypes of wheeze in children on the basis of questionnaire data, lung function, and prick tests. Design. Cross-sectional survey. Setting. Rome and Fiumicino municipalities in Lazio region, Italy, within the ISAAC phase II project. Subjects. Sample of 2107 9-11 year old schoolchildren (response rate 83.5%). Results. We divided children into four mutually exclusive groups according to onset of wheeze: 154 early transient (birth to age 2), 51 persistent (birth to age 2 and current), 66 late onset (current only), and 1,446 control subjects (no early or current wheeze). Logistic regression models have shown that a family history of asthma and allergies is strongly associated with persistent and late onset wheezing; exposure to parental smoking—both during pregnancy and during the child's first year of life—is related to persistent wheezing; all children with wheezing show a significantly greater risk to have current respiratory symptoms other than wheeze compared with control subjects; current allergic rhinoconjunctivitis symptoms and atopy are related with both persistent and late onset wheeze. Multiple linear regression models show that forced expiratory rates at 25% to 75% of vital capacity (FEF_25-75) and the ratio between forced expiratory volume in 1 second and forced vital capacity (FEV₁/FVC) are significantly lower both in early transient (-305 mL/s, -1.7%) and persistent (-298 mL/s, -3.2%) wheezers; FEV₁/FVC is significantly reduced in late onset wheezers too (-2.0%). Conclusions. The strength of the association of family history and exposure to parental smoking varies with the three wheezing phenotypes. Moreover, early, persistent and late onset wheezers have different clinical characteristics in terms of their respiratory health and atopic status.     

Choline pivaloyl ester enhances brain expression of both nerve growth factor and high-affinity receptor TrkA, and reverses memory and cognitive deficits, in rats with excitotoxic lesion of nucleus basalis magnocellularis

The aim of present work was the evaluation of the effects on brain levels of nerve growth factor (NGF) and of its high-affinity tyrosine kinase A receptor (TrkA), induced in rats unilaterally lesioned at nucleus basalis magnocellularis (NBM), by treatment with choline pivaloyl ester (CPE). CPE was daily administered (60 micromol/Kg ip) during 3 weeks to rats selectively lesioned by AMPA infusion into right NBM; the intact left NBM serving as control. NGF levels were determined in cerebral cortex and hippocampus by Elisa assay. TrkA receptor expression was evaluated in right NBM by Western blotting analysis. CPE treatment significantly increased NGF levels in both hippocampus and neocortex in right NBM, compared with intact left counter-part and controls. Western blotting showed an evident enhancement in TrkA receptor expression in lesioned right NBM in comparison with intact left counter-part and controls. CPE treatment was also able to restore, in bilaterally NBM-lesioned rats, the disrupted cortical EEG and HVS activities as well as to reverse deficits in learning and memory in spatial navigation and probe trials, and cognitive capacities in object recognition task.