Redox sensitivity of tyrosine hydroxylase activity and expression in dopaminergic dysfunction

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson’s disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression. The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.peer-reviewe

Techniques in Neuroscience

Microdialysis cerebral technique has been widely employed in order to study neurotransmitter release. This technique presents numerous advantages such as it allows work with sample in vivo from freely moving animals. Different drugs in different points implanted probes in several brain areas can be infused simultaneously by means of microdialysis. Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopamine (DA) neurons in the nigrostriatal system, which in turn produces profound neurochemical changes within the basal ganglia, representing the neural substrate for Parkinsonian motor symptoms. Over the years, a broad variety of experimental models of the disease have been developed and applied in diverse animal species. The two most common toxin models used employ 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenilpyridinium ion (MPTP/MPP+), either given systemically or locally applied into the nigrostriatal pathway, to resemble PD features in animals. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, although with different mechanisms. Since in vivo microdialysis coupled to high-performance liquid chromatography (HPLC) is an established technique for studying physiological, pharmacological, and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid, here we describe a rapid and simple microdialysis technique that allows the direct quantitative study of the damage produced by 6-OHDA and MPP+ toxins on dopaminergic (DAergic) striatal terminals of rat brain.peer-reviewe

Clinical significance of the buccal fat pad: how to determine the correct surgical indications based on preoperative analysis

Background: Despite the multitude of clinical and aesthetic uses, the correct surgical indications for buccal fat pad (BFP) removal have yet to be fully elucidated. Although the procedure is widely performed and promoted for aesthetic purpose, literature lacks of studies accounting for a proper evaluation of patients undergoing BFP removal. Methods: Between 2012 and 2016 patients seeking an improvement of the malar contour by reduction of the submalar prominence have been visited at the Department of Plastic Surgery of the Institution. A preoperative MRI was requested in order to correctly identify the volume of the BFP and the presence of a masseter muscle (MM) hypertrophy. Results: According to clinical examination and the results of the preoperative imaging, patients were offered different treatment options: patients with BFP hypertrophy underwent BFP removal through an itraoral approach; patients with MM hypertrophy received injection of 50 UI of botulinum toxin (BTX). No complications were observed in the postoperative period and all patients were satisfied with the results. Conclusions: According to the experience, midface contouring procedures should take account of both surgeons’ experience, patients’ expectations and anatomical evaluation. As such, there is no given approach suitable for all cases. Suggested visual criteria, clinical examination and imaging analysis are useful in establishing patient’s condition and determining the appropriate methods of treatment to enhance the facial profile

Crossmodal Links between Vision and Touch in Spatial Attention: A Computational Modelling Study

Many studies have revealed that attention operates across different sensory modalities, to facilitate the selection of relevant information in the multimodal situations of every-day life. Cross-modal links have been observed either when attention is directed voluntarily (endogenous) or involuntarily (exogenous). The neural basis of cross-modal attention presents a significant challenge to cognitive neuroscience. Here, we used a neural network model to elucidate the neural correlates of visual-tactile interactions in exogenous and endogenous attention. The model includes two unimodal (visual and tactile) areas connected with a bimodal area in each hemisphere and a competition between the two hemispheres. The model is able to explain cross-modal facilitation both in exogenous and endogenous attention, ascribing it to an advantaged activation of the bimodal area on the attended side (via a top-down or bottom-up biasing), with concomitant inhibition towards the opposite side. The model suggests that a competitive/cooperative interaction with biased competition may mediate both forms of cross-modal attention

Diverging effects of postextrasystolic potentiation on left ventricular segmental wall motion in coronary heart disease.

The effects of postextrasystolic potentiation (PESP) on regional left ventricular (LV) wall motion were evaluated in 40 coronary artery disease (CAD) patients. Of the 40 CAD patients, 20 had a prior myocardial infarction and 20 had a history of angina pectoris. PESP was obtained by applying programmed atrial stimulation during LV angiography, in a way that basal cycle length, premature beat, and postextrasystolic pause were almost identical in all patients. Segmental wall motion was evaluated by calculating regional ejection fraction (EF) of 5 different areas with a computerized method before and after the premature beat. The results were compared to those obtained in a group of 8 normal subjects. LV areas were classified as normokinetic, mildly hypokinetic, severely hypokinetic, and hyperkinetic, on the basis of their regional EF in respect to normals, and classified as "responder" (R) and "nonresponder" on the basis of the magnitude of the increase of regional EF with PESP. Of a total of 200 areas 129 were normokinetic (68% R), 45 were mildly hypokinetic (78% R), 17 severely hypokinetic (76% R), and 9 were hyperkinetic (78% R). Infarcted patients had a higher percentage of hypokinetic areas in basal conditions (p<0.001), however, the percentage of hypokinetic areas that responded to PESP was not significantly different from noninfarcted patients. In CAD patients, as a whole, a significant direct correlation was found between basal regional EF and regional EF after PESP (r=0.88, p<0.01). In conclusion, the results indicate: (1) normokinetic LV areas do not always respond to PESP; (2) while infarcted patients have a higher proportion of myocardial segments that are hypokinetic, the number of these areas that respond to PESP does not differ between infarcted and noninfarcted patients; (3) in CAD patients there is a direct relationship between the degree of basal regional function and the magnitude of the response to PESP

Parachute emergency landing simulation and enhanced composite material characterization for General Aviation aircraft

General Aviation (GA) aircraft crashworthiness of the vehicle when it hits the ground after the parachute deployment is an important issue. The current dynamic emergency landing regulation (CS 23.562) defines the maximum human tolerant accelerations under both vertical and horizontal directions. This article aims to compare two different aircraft configurations: metal low-wing and composite high-wing ones. Both are two-seats and single-engine GA aircraft. The purpose of the analysis is to check whether the seats and restraint systems met human injury tolerance standards and to determine the possible impact on passengers in the cabin space due to shock loads. Finite element analysis of the fuselage sections for both configurations is performed using the commercial LS-Dyna solver. An extensive campaign of experimental tests has been performed on the composite samples for tuning and validating the model and to find the transition from an undamaged up to totally collapsed sample. The material of the composite fuselage has been characterized through experimental tests. The adopted material model has been refined to match with the performed experimental analysis, allowing high-fidelity modeling. A parametric analysis has been performed to determine the optimal impact angle in terms of lumbar injuries and loads transmitted by the seat belt due to aircraft contact with the ground, thereby increasing the level of safety. The investigations carried out may be an important indicator of the design of the parachute system

Acquired ptosis associated with oculomotor and contralateral facial nerve synkinesis: the first reported case

Evidence of oculomotor nerve (ON) synkinesis is a common occurrence following both acquired and congenital III nerve palsy. It is generally accepted that aberrant regeneration is the likely aetiology of synkinesis in acquired III nerve palsy, following intracranial aneurysm, trauma, compressive neoplasms, cavernous sinus thrombosis and basilar meningitis

Episodic ataxia type 1

Clinical characteristics: Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other findings can include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence. Diagnosis/testing: Diagnosis is based on clinical findings, an electrophysiologic test of axonal superexcitability and threshold electrotonus, and/or molecular genetic testing of KCNA1, the only gene in which pathogenic variants are known to cause EA1. Management: Treatment of manifestations: Acetazolamide (ACTZ), a carbonic-anhydrase (CA) inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Antiepileptic drugs (AEDs) may significantly reduce the frequency of the attacks in some individuals.peer-reviewe

5-HT2 receptors-mediated modulation of voltage-gated K+ channels and neurophysiopathological correlates

The activity of voltage-gated K(+) channels (Kv) can be dynamically modulated by several events, including neurotransmitter stimulated biochemical cascades mediated by G protein-coupled receptors such as 5-HT2 receptors (5-HT2Rs). Activation of 5-HT2A/CR inhibits the Shaker-like K(+) channels Kv1.1 and Kv1.2, and this modulation involves the dual coordination of both RPTPα and distinct tyrosine kinases coupled to this receptor; 5-HT2Rs-mediated modulation of Kv channels controls glutamate release onto prefrontal cortex neurons that might play critical roles in neurophysiological, neurological, and psychiatric conditions. Noticeably, hallucinogens modulate Kv channel activity, acting at 5-HT2R. Hence, comprehensive knowledge of 5-HT2R signaling through modulation of distinct K(+) channels is a pivotal step in the direction that will enable scientists to discover novel 5-HT functions and dysfunctions in the brain and to identify original therapeutic targets.peer-reviewe