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Adaptive structures are equipped with sensors and actuators to counteract deformations caused by external loads. Concerning railway bridges, previous work has shown that active vibration damping allows to extend the service life. Trains as external loads represent the decisive influencing factor for bridge vibration and has to be taken into account when applying model-based control concepts. This article proposes a state and disturbance estimator (SDE) for bridge structures based on a moving point load train model and estimating the average train axle mass. The model employed for state and disturbance estimation is linear time variant, which allows use of an augmented Kalman filter. Estimability is analyzed based on the Fisher information and the proposed state and disturbance estimator (SDE) is systematically tested through simulations. A linear quadratic regulator is designed and combined with the proposed SDE to evaluate the closed-loop performance for damping the bridge vibrations during train crossing.

Corporate criminal liability enforcement represents the worldwide response to multiple international solicitations that aimed at repressing the crime committed by the legal entities. In the Italian legal system, the issuance of Legislative Decree n° 231 of 8 June 2001 has introduced a specific discipline of corporation criminal liability, that incentivizes – and does not oblige – the adoption of organizational structures aimed at preventing the risk of committing certain crimes. The liability of the corporation requires the existence of four prerequisites: the commission of one of the predicate offences; the qualified relationship of the offender with the corporation; the circumstance that the offence was committed «in the interest» or «to the advantage» of the corporation; finally the failure to adopt a model to prevent the commission of the offences, under the supervising of an ad hoc Supervisory board. The adoption and correct implementation of the MOG 231 entails several forms of exemption from liability for committing crimes, according to the so-called Carrot and Stick Approach. Despite frequent worldwide regulatory measures, the notion of corporate criminal liability continues to be questioned. So, in the Italian legal system the quantitative increase of offences has not always been accompanied by a qualitative improvement in Decree n° 231. Therefore, it would be advisable a systematic revision of the discipline, rethinking the heavy sanctioning system, in order to reaffirm the need for the diffusion of a real “231 culture”.

The life expectancy of bridges depends mainly on the number and amplitude of load cycles experienced. This paper presents an optimal control approach for minimizing the magnitude of train induced vibrations of adaptive bridge structures. The control strategy comprises two parts. First, the a coordinate transformation is carried out for each time step at the equilibrium point to exclude the static displacement resulting from the train weight. Second, a model predictive controller (MPC) with state dependent input constraints is designed, that increases the damping of the structure and thus minimizes its vibration amplitudes by employing limited actuator forces. The presented control approach is tested by means of a simulation study. Results show that a 50% increase in damping is achieved through structural adaptation, which could significantly extend the life expectancy of bridge structures.

Adaptive structures are equipped with sensors and actuators to counteract deformations and vibrations caused by external loads. For railway bridges, active control can be used to reduce vibration amplitudes to extend the service life of the structure, thereby increasing resource and emissions efficiency. Model-based control of bridge structures requires knowledge of the structural state and the external disturbance. This paper compares bridge state estimators (Kalman filters), that get no/full information about the disturbance or include disturbance models of different complexity in the estimation model with respect to the achievable estimation performance. It is shown that the disturbance cannot be neglected, however it is sufficient to take the average train axle weights as average mass (AM)-moving point load (MPL) model into account, while a more complex disturbance model does not improve the estimation performance. Hence, a state and disturbance estimator based on the AM-MPL model is proposed using an Augmented Kalman filter.

ABSTRACTIntroductionParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets.Areas coveredThis review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems.Expert opinionLIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.

The detection of defects in the production of large-scale components is very important for the productivity of a machine, especially in fow production facilities. An effective approach is proposed to automatically detect insufficient layers in the additive manufacturing process of sand formworks for the construction industry. For this a method is introduced to integrate a camera based quality control into the powder bed binder jetting process. Results show the possibility to reduce reject parts by comparing an image of the current layer geometry to the according CAD model.

Alterations in the metabolism of iron and its accumulation in the substantia nigra pars compactaaccompany the pathogenesis of Parkinson’s disease (PD). Changes in iron homeostasis also occur during aging, which constitutes a PD major risk factor. As such, mitigation of iron overload via chelation strategies has been considered a plausible disease modifying approach. Iron chelation, however, is imperfect because of general undesired side effects and lack of specificity; more effective approaches would rely on targeting distinctive pathways responsible for iron overload in brain regions relevant to PD and, in particular, the substantia nigra. We have previously demonstrated that the Transferrin/Transferrin Receptor 2 (TfR2) iron import mechanism functions in nigral dopaminergic neurons, is perturbed in PD models and patients, and therefore constitutes a potential therapeutic target to halt iron accumulation. To validate this hypothesis, we generated mice with targeted deletion of TfR2 in dopaminergic neurons. In these animals, we modeled PD with multiple approaches, based either on neurotoxin exposure or alpha-synuclein proteotoxic mechanisms. We found that TfR2 deletion can provide neuroprotection against dopaminergic degeneration, and against PD- and aging-related iron overload. The effects, however, were significantly more pronounced in females rather than in males. Our data indicate that the TfR2 iron import pathway represents an amenable strategy to hamper PD progression. Data also suggest, however, that therapeutic strategies targeting TfR2 should consider a potential sexual dimorphism in neuroprotective response.

ABSTRACTIntroductionLong-term treatment of Parkinson’s disease (PD) with levodopa is hampered by motor complications related to the inability of residual nigrostriatal neurons to convert levodopa to dopamine (DA) and use it appropriately. This generated a tendency to postpone levodopa, favoring the initial use of DA agonists, which directly stimulate striatal dopaminergic receptors. Use of DA agonists, however, is associated with multiple side effects and their efficacy is limited by suboptimal bioavailability.Areas coveredThis paper reviewed the latest preclinical and clinical findings on the efficacy and adverse effects of non-ergot DA agonists, discussing the present and future of this class of compounds in PD therapy.Expert opinionThe latest findings confirm the effectiveness of DA agonists as initial treatment or adjunctive therapy to levodopa in advanced PD, but a more conservative approach to their use is emerging, due to the complexity and repercussions of their side effects. As various factors may increase the individual risk to side effects, assessing such risk and calibrating the use of DA agonists accordingly may become extremely important in the clinical management of PD, as well as the availability of new DA agonists with better profiles of safety and efficacy.

Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson’s disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care.

Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson’s disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care.

Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson’s disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.

ObjectivesGBA1mutations are a frequent risk factor for Parkinson disease (PD). The aim of this study is to evaluate clinical features in a group of GBA1mutation–positive individuals over a 6-year follow-up.MethodsThis is a longitudinal study on a cohort of GBA1-positive carriers. We enrolled 31 patients with Gaucher disease type 1 (GD), 29 GBA1heterozygous carriers (Het GBAgroup) and 30 controls (HC) at baseline and followed them for 6 years. We assessed baseline motor and non-motor signs of PD in all subjects using clinical questionnaires and scales (reduced Unified Multiple System Atrophy Rating Scale (UMSARS), Montreal Cognitive assessment (MoCA), University of Pennsylvania Smell Identification Test (UPSIT), REM Sleep Behavior Disorder screening questionnaire (RBDsq), Movement Disorders Society Unified Parkinson’s Disease Rating Scale motor subscale (MDS-UPDRS III) and Beck Depression Inventory (BDI). We repeated these at the 6-year follow-up alongside venous blood sampling for measurement of glucocerebrosidase enzymatic activity (GCase). We explored whether the GCase activity level was altered in leucocytes of these subjects and how it was related to development of PD.ResultsWe observed a significant worsening in UMSARS, RBDsq, MDS-UPDRS III and BDI scores at the 6-year follow-up compared with baseline in both the GD and Het GBAgroups. Intergroup comparisons showed that GD subjects had significantly worse scores in UPSIT, UMSARS, MoCA and MDS-UPDRS III than HC, while Het GBAdisplayed worse outcomes in UPSIT and MDS-UPDRS III compared with HC. In GBA1mutation–positive individuals (Het GBAand GD), an UPSIT score of 23 at baseline was correlated with worse outcome at 6 years in UPSIT, MoCA, MDS-UPDRS III and BDI.ConclusionIn this 6-year-long longitudinal study, GBA1mutation–positive subjects showed a worsening in motor and non-motor prodromal PD features.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region–specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non–disease-manifesting LRRK2mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient–derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADXassay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

ABSTRACTIntroduction: Prolonged treatment of Parkinson’s disease (PD) with levodopa (L-DOPA) results in motor complications, including motor fluctuations and involuntary movements known as L-DOPA induced dyskinesias (LIDs). LIDs represent an additional cause of disability for PD patients and a major challenge for the clinical neurologist. Preclinical research has provided invaluable insights into the molecular and neural substrates of LIDs, identifying a number of potential targets for new anti-dyskinetic strategies.Areas covered: This review article is centered on drugs currently in Phase I and II clinical trials for LIDs and their relative pharmacological targets, which include glutamate, acetylcholine, serotonin, adrenergic receptors and additional targets of potential therapeutic interest.Expert opinion: LIDs are sustained by complex molecular and neurobiological mechanisms that are difficult to disentangle or target, unless one or more prevalent mechanisms are identified. In this context, the role of the serotonergic system and mGluR5 glutamate receptors seem to stand out. Interesting results have been obtained, for example, with partial 5-HT1A/5-HT1B receptor agonist eltoprazine and mGluR5 negative allosteric modulator dipraglurant. Confirmation of these results through large-scale, Phase III clinical trials will be needed, to obtain new pharmacological tools that may be used to optimize the treatment of PD patients with motor complications.

The underlying relation between Parkinson’s disease (PD) etiopathology and its major risk factor, aging, is largely unknown. In light of the causative link between genome stability and aging, we investigate a possible nexus between DNA damage accumulation, aging, and PD by assessing aging-related DNA repair pathways in laboratory animal models and humans. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that Ercc1mutant mice with mildly compromised NER exhibit typical PD-like pathological alterations, including decreased striatal dopaminergic innervation, increased phospho-synuclein levels, and defects in mitochondrial respiration. Ercc1 mouse mutants are also more sensitive to the prototypical PD toxin MPTP, and their transcriptomic landscape shares important similarities with that of PD patients. Our results demonstrate that specific defects in DNA repair impact the dopaminergic system and are associated with human PD pathology and might therefore constitute an age-related risk factor for PD.

Parkinson’s disease is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiologic assay. Electrically induced and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, whereas acetylcholine levels were assayed in the incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors were assessed by immunohistochemistry or western blot assay. As compared with control rats, at week 4, 6-OHDA–treated animals displayed the following changes: decreased in vivo colonic transit rate, impaired electrically evoked neurogenic cholinergic contractions, enhanced carbachol-induced contractions, decreased basal and electrically stimulated acetylcholine release from colonic tissues, decreased ChAT immunopositivity in the neuromuscular layer, unchanged density of HuC/D immunoreactive myenteric neurons, and increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were also detected at week 8 post 6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate.

Introduction:Prolonged administration of l-3,4-dihydroxyphenylalanine (l–DOPA) for Parkinson's disease (PD) is hampered by motor complications related to the progressive incapacity of residual nigrostriatal neurons to properly utilize the drug. Direct stimulation of dopaminergic (DAergic) receptors with specific compounds (DA agonists) has, therefore, become an additional therapeutic tool for PD.Areas covered:DA agonists have considerable anti-parkinsonian symptomatic efficacy, although they are less potent thanl-DOPA. This review summarizes pre-clinical and clinical data on DA agonists and their role in treating PD. Specific focus was put on second-generation, first-line non-ergolinic DA agonists and their motor, non-motor and putative neuroprotective effects. The anti-parkinsonian potential of recently developed DA agonists that reached Phase II and III clinical trials was also addressed.Expert opinion:DA agonists can be useful along the whole natural course of PD, as monotherapy in the initial phase or combined with l-DOPA in advanced PD. Extended-release formulations have been developed for second-generation DA agonists, which are better appreciated by patients. Neuroprotective properties have been proposed for DA agonists, based on pre-clinical studies, but never convincingly demonstrated in patients. New DA agonists, with better symptomatic efficacy and devoid of the side effects that characterize current compounds, are needed.

Introduction:Parkinson's disease (PD) therapy is still centered on the use of l-3,4-dihydroxyphenylalanine (l-DOPA), which is hampered by numerous side effects, including abnormal involuntary movements known as l-DOPA-induced dyskinesias (LIDs). LIDs are the result of pre- and postsynaptic changes at the corticostriatal level, induced by chronic and pulsatile stimulation of striatal dopaminergic receptors. These changes impact on synaptic plasticity and involve also selected, nondopaminergic receptors expressed by striatal projection neurons.Areas covered:Among nondopaminergic receptors, glutamate receptors – NMDA and mGluR5 subtypes in particular – and adenosine A2Areceptors are those most likely involved in LIDs. The aim of the present review is to summarize results of studies undertaken with specific antagonists of these receptors, first conducted in animal models of LIDs, which in selected cases have been translated into clinical trials.Expert opinion:Selected antagonists of glutamate and adenosine receptors have been proposed as anti-dyskinetic agents. Promising results have been obtained in preclinical investigations and in initial clinical trials, but long-term safety, tolerability and efficacy studies in patients are still required. The current development of novel antagonists, including tools able to act on receptor mosaics, may provide innovative tools for LIDs management in the next future.

Stem cells have been increasingly recognized as a potential tool to replace or support cells damaged by the neurodegenerative process that underlies Parkinson's disease (PD). In this frame, human adult mesenchymal stem cells (hMSCs) have been proposed as an attractive alternative to heterologous embryonic or neural precursor cells. To address this issue, in this study we implanted undifferentiated hMSCs into the striatum of rats bearing a lesion of the nigrostriatal pathway induced by local injection of 6-hydroxydopamine (6-OHDA), a widely recognized rodent model of PD. Before grafting, cultured hMSCs expressed markers of both undifferentiated and committed neural cells, including nestin, GAP-43, NSE, β-tubulin III, and MAP-2, as well as several cytokine mRNAs. No glial or specific neuronal markers were detected. Following transplantation, some hMSCs acquired a glial-like phenotype, as shown by immunoreactivity for glial fibrillary acid protein (GFAP), but only in animals bearing the nigrostriatal lesion. More importantly, rats that received the striatal graft showed increased survival of both cell bodies and terminals of dopaminergic, nigrostriatal neurons, coupled with a reduction of the behavioral abnormalities (apomorphine-induced turning behavior) associated with the lesion. No differentiation of the MSCs toward a neuronal (dopaminergic) phenotype was observed in vivo. In conclusion, our results suggest that grafted hMSCs exert neuroprotective effects against nigrostriatal degeneration induced by 6-OHDA. The mechanisms underlying this effect remain to be clarified, although it is likely that the acquisition of a glial phenotype by grafted hMSCs may lead to the release of prosurvival cytokines within the lesioned striatum.

"The Glass Dome", a frameless structural glass shell spanning 8,5 m, has been designed and built with the aim of exploiting the structural efficiency as well as the aesthetical quality that can be achieved by combining structural use of glass with adhesives as joining system. The joint, developed by the author, permits to accommodate gaps between the panes, allowing forces to be transmitted and tolerances to be adjusted. Tensile, shear and bending tests, designed and carried out under different temperatures and loading times, demonstrated the validity of such a joining system. FE parametric analyses were carried out on an imperfect shell model to verify and optimise the structural behaviour of the prototype. In the opinion of the author, the Glass Dome, being the first glass shell in the world which makes no use of metallic frames or clamping systems, will open new dimensions to glass design with its fully transparent continuous curved skin.

“The Glass Dome”, a frameless structural glass shell spanning 8,5 m, has been designed and built with the aim of exploiting the structural efficiency as well as the aesthetical quality that can be achieved by combining structural use of glass with adhesives as joining system. The joint, developed by the author, permits to accommodate gaps between the panes, allowing forces to be transmitted and tolerances to be adjusted. Tensile, shear and bending tests, designed and carried out under different temperatures and loading times, demonstrated the validity of such a joining system. FE parametric analyses were carried out on an imperfect shell model to verify and optimise the structural behaviour of the prototype. In the opinion of the author, the Glass Dome, being the first glass shell in the world which makes no use of metallic frames or clamping systems, will open new dimensions to glass design with its fully transparent continuous curved skin.

Defects of the ubiquitin-proteasome (UP) system, a multicatalytic complex degrading polyubiquitinated proteins, may intervene in the pathogenesis of neurodegenerative disorders characterized by intracellular formation of protein aggregates such as Parkinson disease (PD) and Alzheimer disease (AD) by inducing proapoptotic conditions.

Abstract: In this study, we measured the lymphocyte levels of proteins involved in apoptosis regulation, such as Bcl‐2, the peripheral benzodiazepine receptor (PBR), caspase‐3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with Parkinson's disease (PD), either untreated or under therapy with dopaminergic agents (l‐Dopa alone or l‐dopa + dopamine agonists) and in healthy volunteers. All PD groups showed increased activity of caspase‐3, compared to controls, particularly those under treatment only with l‐Dopa. In this latter group, the increase in caspase‐3 activity was also paralleled by an increase in the concentration of Cu/Zn SOD. In addition, patients taking l‐Dopa + dopamine agonists showed marked decrease in Bcl‐2 levels and increased PBR expression, which seems in keeping with the hypothesis that PBR may be functionally related to Bcl‐2. In conclusion, we found clear modifications in the levels of proteins involved in the control of apoptosis in lymphocytes of PD patients. These changes were disease related but also modulated by the pharmacological treatment, which confirms the potential role of apoptosis in PD pathogenesis and the modulatory influence of dopaminergic agents.

Abstract: Dopamine (DA) modulates apoptosis in neuronal and non‐neuronal cells, and dopaminergic pathways contribute to neurodegenerative disease. Human lymphocytes express dopaminergic receptors and DA transporters, and synthesize endogenous catecholamines, which may modulate apoptosis in these cells. In the present study, dopaminergic modulation of apoptosis was investigated in human peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. Twenty‐four‐hour DA reduced at 0.1–5 × 3 10−6M and enhanced at 1–5 × 310−4M spontaneous apoptosis. DA 1 × 310−6M was inhibited by the D1‐like receptor antagonist SCH 23390 1 × 310−6M, but not by the D2‐like receptor antagonists domperidone 1 × 3 10−6M or haloperidol 1 × 3 10−6M, while the effect of DA 5 × 3 10−4M was prevented by the antioxidants glutathione 5–10 mM or N‐acetyl‐l‐cysteine 1–10 mM. Intracellular reactive oxygen species were respectively reduced and increased by 1–3 h incubation with DA 0.1–10 × 3 10−6M and 1–5×310−4M. Twenty‐four‐hour DA 1 × 3 10−6M or 5 × 3 10−4M had no effect on PBMC expression of Cu/Zn superoxide dismutase or Bcl‐2; however, DA 5 × 3 10−4M decreased caspase‐3 activity. In human PBMCs, DA seems to promote apoptosis through oxidative mechanisms but may also result in cell rescue from apoptotic death possibly through activation of D1‐like receptors. The dual effect of DA on human PBMCs closely resembles that on striatal neurons. Lymphocytes of patients with Parkinson's disease may show reduced DA content and impaired DA transporter immunoreactivity. Human PBMCs may thus represent a simple and readily accessible model to study DA‐related mechanisms relevant for neurodegenerative disease.

Using permanent cannulas connected to subcutaneous pumps, we infused selective glutamate antagonists into the subthalamic nucleus of rats. Pumps were implanted immediately after the intrastriatal injection of 6‐hydroxydopamine and delivered micro‐quantities of the N‐methyl‐D‐aspartate antagonist MK‐801 or the α‐amino‐3‐hydroxy‐5‐methylisoxazole antagonist NBQX for 4 weeks. Subthalamic infusion of MK‐801, but not of NBQX, prevented the basal ganglia metabolic changes and motor abnormalities caused by nigrostriatal lesion. Animals treated with MK‐801 also exhibited marked reduction of nigral cell loss. We conclude that pharmacological modulation of subthalamic activity may have both symptomatic and neuroprotective effects in Parkinson's disease. Ann Neurol 2001;49:525–529

Inactivation of the subthalamic nucleus (STN) has attracted interest as a therapeutic tool in Parkinson's disease. The functional consequences of the inactivation, however, are uncertain. In this study definition of the pattern of changes of cerebral functional activity associated with lesion of the STN and dopaminergic stimulation, by using the [14C]deoxyglucose method, was sought. Six or 7 days following unilateral lesion of the STN, the animals were divided into two groups: One group (n = 10) was administered apomorphine (1 mg/kg) subcutaneously; the second group (n = 10) received saline. The [14C]deoxyglucose procedure was initiated 10 minutes following the drug or saline injection. The results show that systemic administration of apomorphine to rats with unilateral lesion of the STN causes ipsiversive rotational behavior and asymmetries of glucose utilization of defined brain areas, including the substantia nigra reticulata, globus pallidus, and entopeduncular nucleus. These nuclei are the main targets of the subthalamic excitatory projections. Lesion of the nucleus per se (without challenge with apomorphine) has no significant consequences on glucose utilization. The findings indicate that the STN is involved in the activation of the basal ganglia output nuclei induced by systemic dopaminergic stimulation.

In Parkinson's disease, the functional architecture of the basal ganglia nuclei undergoes profound alterations, one of the most important of which is overactivity of the basal ganglia output nuclei. This phenomenon seems to be intimately related to pathological overactivity of the subthalamic nucleus, which directly modulates the basal ganglia output through its glutamatergic projections. In this study, we investigated the effects of unilateral subthalamic nucleus lesions on the activities of succinate dehydrogenase and cytochrome oxidase, two markers of neuronal activity, in rats with prior unilateral lesions of the nigrostriatal tract. We also explored the effect of subthalamic nucleus lesions on the rotational response to systemic apomorphine. Rats with unilateral lesions of the nigrostriatal tract showed ipsilateral increases in enzyme activity in the basal ganglia output nuclei, entopeduncular nucleus and substantia nigra pars reticulata. Selective subthalamic nucleus destruction completely reversed this phenomenon. In addition, subthalamic nucleus lesions abolished the rotational response to apomorphine. These results confirm that overactivity of the subthalamic nucleus plays a pivotal role in the functional alterations of basal ganglia associated with Parkinson's disease. They also shed further light on the neural mechanisms through which manipulations of subthalamic activity can ameliorate Parkinson's disease symptoms

Summary—It has been suggested that the excitatory amino acid glutamate, acting as both a neurotoxin and a neurotransmitter, might play a central role in the pathophysiology of Parkinson's disease (PD). Intrinsic energetic defects of the neurons of the substantia nigra pars compacta, the brain area where the degenerative process of PD takes place, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. Degeneration of dopamine nigral neurons and striatal dopaminergic denervation cause a cascade of functional modifications in the activity of basal ganglia nuclei. Due to the close relationship that links dopaminergic and glutamatergic neurotransmission, glutamate is directly involved in the functional alterations of basal ganglia circuitry that lead to the development of parkinsonian motor symptoms. Drugs counteracting the effects of glutamate might therefore provide new protective and symptomatic strategies for therapy of PD.

The subthalamic nucleus (STN) plays a major role in the control of basal ganglia output, and its overactivity may be central to the symptoms of Parkinson's disease. In order to elucidate the functional relationship between STN and its projection nuclei, we studied the short-term (1 week) effect of a selective lesion of STN on the activity of succinate dehydrogenase (SDH) and cytochrome oxidase (CO), two markers of neuronal activity, in the basal ganglia of rats. STN ablation induced a discrete reduction of oxidative metabolism, ipsilaterally to the lesion, in substantia nigra pars reticulata and globus pallidus, the rodent homologue of lateral globus pallidus. Such changes, ascribable to the interruption of the STN excitatory output to these nuclei, were present after 24 h and remained stable, or increased, throughout the observation period. A transitory, ipsilateral decrease was also observed in the caudate-putamen and the somato-sensory cortex, likely due to involvement of polysynaptic pathways. SDH and CO activity were always altered in the same areas, but SDH changes were more pronounced and occurred more rapidly. These results shed further light on the role played by STN in the control of basal ganglia output.

We have developed an assay for the binding of [3H]dihydrorotenone ([3H]DHR), an analogue of the pesticide rotenone, to the mitochondrial enzyme, complex I, in intact human platelets. The highly hydrophobic nature of dihydrorotenone, which diffuses easily through biological membranes, rendered the isolation of mitochondrial fractions unnecessary. This allowed us to reduce the amount of blood required and to shorten the processing of samples considerably. [3H]DHR binding was saturable, specific, and highly reproducible. We also found that MPP+(1-methyl-4-phenylpyridinium species), which is accumulated actively by platelets, inhibited [3H]DHR specific binding in a concentration-dependent manner. This method could provide a simple tool for the study of complex I in those disorders, such as Parkinson′s disease (PD), in which a defect of this enzyme has been suggested.

Neuropeptide Y, one of the most abundant polypeptides within the nervous system, is co-stored with catecholamines, especially norepinephrine (NE), thus suggesting its possible involvement in pathologies characterized by a noradrenergic impairment. In Parkinson's disease (PD), as well as in multiple system atrophy (MSA), a central noradrenergic deficit has been demonstrated, and in the dementia of Alzheimer type (DAT) an impaired noradrenergic transmission has been postulated. In this study we determined CSF NE and MHPG levels in 29 PD, 15 MSA, 22 DAT patients and in 36 controls, while CSF NPY-immunoreactivity (NPY-ir) levels were measured in 10 PD, 7 MSA, 10 DAT patients and 20 controls. PD, MSA, and DAT patients showed a significant reduction in CSF NPY-ir and NE levels compared with controls, while CSF MHPG levels resulted in a reduction in only the MSA group.

An impairment of the monoaminergic systems has frequently been reported for Alzheimer's disease (AD) as well as an overactivity of cerebral monoamineoxidase B (MAO-B).

We present our 17 years of experience in using a sliding axial musculocutaneous flap from the nasal dorsum in the repair of 53 nasal lobular defects followup 3 to 212 months, mean 47.3 months. This flap is a modification of the classic Rintala flap but is based on a greater understanding of surgical anatomy, the biomechanical properties of skin, and the physiology of flaps, all of which allow a more aesthetically satisfactory closure of very distal nasal lobular defects. After excising the tumor, two parallel incisions are made along the sides of the nasal dorsum, and the flap is raised in the gliding plane deep to the fibromuscular layer of the nose and superficial to the cartilage and bone and then advanced over the defect, which can be as large as the entire nasal lobule.

Activity of mitochondrial enzyme complex I (NADH‐ubiquinone oxidoreductase) is reduced in the substantia nigra of patients with Parkinson's disease (PD). A less pronounced decrease in the activity of this enzyme has also been reported in platelets of PD patients. To obtain quantitative information on platelet complex I in PD, we studied platelet complex I in 16 PD patients and 16 age‐matched controls by using a newly developed technique based on the binding of [3H]dihydrorotenone ([3H]DHR), an analog of the pesticide rotenone, to complex I. We also investigated the inhibitory effect of MPP+(1‐methyl‐4‐phenyl‐pyridinium) on [3H]DHR specific binding to platelet complex I. PD patients and controls showed similar levels of [3H]DHR specific binding; preincubation of platelets with MPP+caused the same degree of inhibition of [3H]DHR specific binding in the two groups. In PD patients, we observed a direct correlation between MPP+‐induced inhibition of [3H]DHR specific binding and the daily intake of levodopa, which may be related to drug‐induced changes in the transport of MPP+into the platelet or in its binding to complex I. These findings demonstrate that the reported reduction in complex I activity in platelets of PD patients can not be accounted for by an abnormality at the level of the rotenone binding site (putatively the ND‐1 gene product), although they do not exclude differences in complex I activity between PD patients and controls.

The skin stretching device was designed to harness the biomechanical properties of the skin in order to close large cutaneous defects by direct closure, without the need of other more complicated techniques such as skin grafts or flaps. The authors present their experience with 31 patients in whom the device was used to repair defects produced by excision of lesions of different nature, size, and body areas, six cases are presented. The main defect of the method, i.e. the increase of intraoperative time to allow for tissue stretching, should be avoidable most of the time by applying the device preoperatively under local anesthesia. The importance of not undermining during this procedure is stressed; the objective parameters to evaluate are analyzed, such as colour and tension of the skin. The complication rate was very acceptable, there was only one infection and one marginal necrosis that healed without further interventions. The described technique appears safe and easy to perform, and produces a good short-term result.

We studied the levels of free plasma noradrenaline (norepinephrine, NE), adrenaline (epinephrine, E), and dopamine (DA) in 143 normal subjects, either basally or, in a part of them, in response to tour tests stimulating the sympathoadrenomedullary activity: the tilt-table test (TTT), the cold-pressor test (CPT), the mental-arithmetic test (MAT), and the insulin tolerance test (ITT). In both cases we evaluated the influence of age, which is considered the main physiological variable affecting the peripheral sympathetic activity. A normal distribution of values was observed, in the basal study, only for NE, while E and particularly, DA levels were distributed in an non-homogeneous fashion; a direct correlation was observed between age of subjects and NE levels, while neither E, nor DA levels showed any correlation with the aging process; sex did not influence any of the catecholamines.In the dynamic study, CPT, ITT and, above all, TTT elicited a significant rise in NE levels, while the E release was greatly stimulated by the insulin-induced hypoglycaemia. Neither NE, nor E levels rose after the MAT stimulation. Also in this case, the elderly showed an increased noradrenergic responsiveness when compared with the young subjects, confirming the existence of an 'up-regulation' of the peripheral sympathetic tone in old people.