Publications by authors named "Laura Rizzi"

51 Publications

Palmitoylethanolamide Modulation of Microglia Activation: Characterization of Mechanisms of Action and Implication for Its Neuroprotective Effects.

Int J Mol Sci 2021 Mar 17;22(6). Epub 2021 Mar 17.

School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.

Palmitoylethanolamide (PEA) is an endogenous lipid produced on demand by neurons and glial cells that displays neuroprotective properties. It is well known that inflammation and neuronal damage are strictly related processes and that microglia play a pivotal role in their regulation. The aim of the present work was to assess whether PEA could exert its neuroprotective and anti-inflammatory effects through the modulation of microglia reactive phenotypes. In N9 microglial cells, the pre-incubation with PEA blunted the increase of M1 pro-inflammatory markers induced by lipopolysaccharide (LPS), concomitantly increasing those M2 anti-inflammatory markers. Images of microglial cells were processed to obtain a set of morphological parameters that highlighted the ability of PEA to inhibit the LPS-induced M1 polarization and suggested that PEA might induce the anti-inflammatory M2a phenotype. Functionally, PEA prevented Ca transients in both N9 cells and primary microglia and antagonized the neuronal hyperexcitability induced by LPS, as revealed by multi-electrode array (MEA) measurements on primary cortical cultures of neurons, microglia, and astrocyte. Finally, the investigation of the molecular pathway indicated that PEA effects are not mediated by toll-like receptor 4 (TLR4); on the contrary, a partial involvement of cannabinoid type 2 receptor (CB2R) was shown by using a selective receptor inverse agonist.
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http://dx.doi.org/10.3390/ijms22063054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002502PMC
March 2021

PET Foams Surface Treated with Graphene Nanoplatelets: Evaluation of Thermal Resistance and Flame Retardancy.

Polymers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Department of Applied Science and Technology, Politecnico di Torino, Alessandria Campus, Viale Teresa Michel 5, 15121 Alessandria, Italy.

In this work, fire-retardant systems consisting of graphene nanoplatelets (GNPs) and dispersant agents were designed and applied on polyethylene terephthalate (PET) foam. Manual deposition from three different liquid solutions was performed in order to create a protective coating on the specimen's surface. A very low amount of coating, between 1.5 and 3.5 wt%, was chosen for the preparation of coated samples. Flammability, flame penetration, and combustion tests demonstrated the improvement provided to the foam via coating. In particular, specimens with PSS/GNPs coating, compared to neat foam, were able to interrupt the flame during horizontal and vertical flammability tests and led to longer endurance times during the flame penetration test. Furthermore, during cone calorimetry tests, the time to ignition (TTI) increased and the peak of heat release rate (pHRR) was drastically reduced by up to 60% compared to that of the uncoated PET foam. Finally, ageing for 48 and 115 h at 160 °C was performed on coated specimens to evaluate the effect on flammability and combustion behavior. Scanning electron microscopy (SEM) images proved the morphological effect of the heat treatment on the surface, showing that the coating was uniformly distributed. In this case, fire-retardant properties were enhanced, even if fewer GNPs were used.
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http://dx.doi.org/10.3390/polym13040501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914555PMC
February 2021

Clinical, demographical characteristics and hospitalisation of 3,010 patients with Covid-19 in Friuli Venezia Giulia Region (Northern Italy). A multivariate, population-based, statistical analysis.

Epidemiol Prev 2020 Sep-Dec;44(5-6 Suppl 2):226-234

Azienda regionale di coordinamento per la salute (ARCS), Udine (Italy).

Objectives: to describe the clinical and demographical characteristics of COVID-19 infected people in the Friuli Venezia Giulia Region (FVG, Northern Italy).

Design: retrospective cohort study with an individual level record linkage procedure of different administrative databases.

Setting And Participants: the cohort included 3,010 patients residing in FVG who tested positive for COVID-19 between 1 March and 15 May 2020, 2020. Regional hospital admissions and deaths without hospital admissions up to June 1st, 2020 were analysed. Determinants of the probability of a highly severe illness were investigated in terms of hospitalisations or death without hospital admission.

Main Outcome Measures: COVID-19 patients were identified from regional epidemiological data warehouse. Demographical and clinical variables such as gender, age, patient's comorbidities, vaccinations, ARBs/sartans prescriptions, and geographical residence variables were collected by linking different databases. Descriptive analyses were performed. Logistic multivariate regressions were used to estimate the probability of hospitalisation or death, whichever came first. Model coefficients and odds ratios (OR) were reported.

Results: COVID-19 population in FVG had a mean age of 60 years and 59% were females. The study found that 37% had hypertension while patients with cardiologic diseases, diabetes, and cancer were around 15%; 22% of the cases were residing in retirement homes. Approximately 30% received flu or pneumococcal vaccination and a similar proportion of patients had at least one prescription of ARBs /sartans in the previous 6 months. Statistical models showed a higher probability of a worst course of disease for males, elderly, highly complicated (in terms of resource use) subjects, in the presence of cardiologic diseases, diabetes, and pneumococcal vaccination. People living in retirement homes had a lower probability of hospitalisation/death without hospital admission. The cohort was divided into two groups: COVID-19 patients infected in the territory and infected in retirement homes. Among COVID-19 patients infected in the territory, the probability of hospitalisation/death was higher for males, for older individuals, and for those with comorbidities. Diabetes resulted to be a risk factor (OR 1.79; 95%CI 1.23-2.62), as well as pneumococcal vaccination (OR 1.64; 95%CI: 1.18-2.29), which is a likely proxy of fragile patients with pulmonary disease. The flu vaccination showed a potential protective effect with a 40% lower probability of hospitalisation or death (OR 0.62; 95%CI 0.44-0.85). Among the retirement homes cohort group, a higher probability of a bad course of disease emerged for males and for more complex patients.

Conclusions: the greatest risk of hospitalisation/death as a measure of more severe illness was confirmed for males, elderly, and for individuals with comorbidities. Flu vaccination seemed to have had a protective effect while pneumococcal vaccination likely identified a group of high-risk patients to be actively monitored. For patients infected in the territory, different hospitalisation strategies were implemented by the regional health districts.
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http://dx.doi.org/10.19191/EP20.5-6.S2.122DOI Listing
January 2021

Characterization of Synovial Cytokine Patterns in Bucket-Handle and Posterior Horn Meniscal Tears.

Mediators Inflamm 2020 22;2020:5071934. Epub 2020 Oct 22.

Orthopedic Department, San Gerardo Hospital, Monza, Italy.

The specific etiology of meniscal tears, including the mechanism of lesion, location, and orientation, is considered for its contribution to subsequent joint cytokine responsiveness, healing outcomes, and by extension, appropriate lesion-specific surgical remediation. Meniscal repair is desirable to reduce the probability of development of posttraumatic osteoarthritis (PTOA) which is strongly influenced by the coordinate generation of pro- and anti-inflammatory cytokines by the injured cartilage. We now present biochemical data on variation in cytokine levels arising from two particular meniscal tears: bucket-handle (BH) and posterior horn (PH) isolated meniscal tears. We selected these two groups due to the different clinical presentations. We measured the concentrations of TNF-, IL-1, IL-6, IL-8, and IL-10 in knee synovial fluid of 45 patients with isolated meniscal lesions (BH tear, = 12; PH tear, = 33). TNF- levels were significantly ( < 0.05) greater in the BH group compared with the PH group, whereas IL-1 levels were significantly greater ( < 0.05) in the PH group compared with the BH group. Both BH and PH groups were consistent in presenting a positive correlation between concentrations of IL-6 and IL-1. A fundamental difference in IL-10 responsiveness between the two groups was noted; specifically, levels of IL-10 were positively correlated with IL-6 in the BH group, whereas in the PH group, levels of IL-10 were positively correlated with IL-1. Collectively, our data suggest a possible influence of the meniscal tear pattern to the articular cytokine responsiveness. This differential expression of inflammatory cytokines may influence the risk of developing PTOA in the long term.
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http://dx.doi.org/10.1155/2020/5071934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599409PMC
October 2020

Androgen Therapy in Neurodegenerative Diseases.

J Endocr Soc 2020 Nov 21;4(11):bvaa120. Epub 2020 Aug 21.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvement in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.
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http://dx.doi.org/10.1210/jendso/bvaa120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568521PMC
November 2020

Graphene Nanoplatelets for the Development of Reinforced PLA-PCL Electrospun Fibers as the Next-Generation of Biomedical Mats.

Polymers (Basel) 2020 Jun 21;12(6). Epub 2020 Jun 21.

Department of Drug Sciences, University of Pavia, V.le Taramelli 12-27100 Pavia, Italy.

Electrospun scaffolds made of nano- and micro-fibrous non-woven mats from biodegradable polymers have been intensely investigated in recent years. In this field, polymer-based materials are broadly used for biomedical applications since they can be managed in high scale, easily shaped, and chemically changed to tailor their specific biologic properties. Nonetheless polymeric materials can be reinforced with inorganic materials to produce a next-generation composite with improved properties. Herein, the role of graphene nanoplatelets (GNPs) on electrospun poly-l-lactide-co-poly-ε-caprolactone (PLA-PCL, 70:30 molar ratio) fibers was investigated. Microfibers of neat PLA-PCL and with different amounts of GNPs were produced by electrospinning and they were characterized for their physicochemical and biologic properties. Results showed that GNPs concentration notably affected the fibers morphology and diameters distribution, influenced PLA-PCL chain mobility in the crystallization process and tuned the mechanical and thermal properties of the electrospun matrices. GNPs were also liable of slowing down copolymer degradation rate in simulated physiological environment. However, no toxic impurities and degradation products were pointed out up to 60 d incubation. Furthermore, preliminary biologic tests proved the ability of the matrices to enhance fibroblast cells attachment and proliferation probably due to their unique 3D-interconnected structure.
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http://dx.doi.org/10.3390/polym12061390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362196PMC
June 2020

Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease.

Stem Cells Transl Med 2020 09 4;9(9):1068-1084. Epub 2020 Jun 4.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

The critical role of neuroinflammation in favoring and accelerating the pathogenic process in Alzheimer's disease (AD) increased the need to target the cerebral innate immune cells as a potential therapeutic strategy to slow down the disease progression. In this scenario, mesenchymal stem cells (MSCs) have risen considerable interest thanks to their immunomodulatory properties, which have been largely ascribed to the release of extracellular vesicles (EVs), namely exosomes and microvesicles. Indeed, the beneficial effects of MSC-EVs in regulating the inflammatory response have been reported in different AD mouse models, upon chronic intravenous or intracerebroventricular administration. In this study, we use the triple-transgenic 3xTg mice showing for the first time that the intranasal route of administration of EVs, derived from cytokine-preconditioned MSCs, was able to induce immunomodulatory and neuroprotective effects in AD. MSC-EVs reached the brain, where they dampened the activation of microglia cells and increased dendritic spine density. MSC-EVs polarized in vitro murine primary microglia toward an anti-inflammatory phenotype suggesting that the neuroprotective effects observed in transgenic mice could result from a positive modulation of the inflammatory status. The possibility to administer MSC-EVs through a noninvasive route and the demonstration of their anti-inflammatory efficacy might accelerate the chance of a translational exploitation of MSC-EVs in AD.
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http://dx.doi.org/10.1002/sctm.19-0327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445021PMC
September 2020

JMV5656, a short synthetic derivative of TLQP-21, alleviates acid-induced lung injury and fibrosis in mice.

Pulm Pharmacol Ther 2020 06 20;62:101916. Epub 2020 Mar 20.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

TLQP-21, a peptide encoded by the prohormone VGF, is expressed in neuroendocrine cells and can modulate inflammatory processes. Since TLQP-21 can bind the complement 3a receptor 1 on macrophages, interest has risen in this peptide as a potential drug for the treatment of Acute Respiratory Distress Syndrome (ARDS), whose hospital mortality can reach 35-46%. Since no effective pharmacologic therapies are available, our aim was to exploit the potential of a short analog of TLQP-21(JMV5656) in order to modulate the inflammatory process in ARDS and the progression to pulmonary fibrosis in an experimental model of unilateral acid aspiration in mice. Mice were divided in 2 treatment groups. In the acute protocol, mice received intra-peritoneal injection of either vehicle or 0.6 mg/kg JMV5656 on experimental days 1 and 2, and ARDS was induced on day 3 under deep anesthesia by instillation of HCl (1.5 ml/kg of 0.1 M HCl in 0.9% NaCl) into the right lung; all measurements were performed 24 h later. In the subacute protocol, mice were treated as previously, but treatment with vehicle or JMV5656 was repeated also on day 4 and measurements were made 2 weeks later. Twenty-four hours after acid instillation, the total number of immune cell in the BAL rose sharply due primarily to an increase in the PMN population which increased from 1% up to 58% of total cell numbers. JMV5656 significantly reduced PMN recruitment into the alveolar space, but had no effects on cytokine levels in BAL. Two weeks after acid injury, static compliance of the right lung was significantly higher in the JMV5656-treated group compared to vehicle-treated group. Treatment with JMV5656 also blunted the acid-induced collagen deposition in the right lung. These results suggest that JMV5656 can ameliorate mechanical compliance, and reduce collagen deposition in acid-injured lungs in mice. This effect was likely due to the ability of JMV5656 to inhibit PMN recruitment in the injured lung.
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http://dx.doi.org/10.1016/j.pupt.2020.101916DOI Listing
June 2020

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Department of Pharmacy-Drug Sciences, University of Bari, 70125 Bari, Italy.

Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.
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http://dx.doi.org/10.3390/ijms21041242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072891PMC
February 2020

TLQP-21, A VGF-Derived Peptide Endowed of Endocrine and Extraendocrine Properties: Focus on In Vitro Calcium Signaling.

Int J Mol Sci 2019 Dec 24;21(1). Epub 2019 Dec 24.

School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.

VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca. This effect relies both on Ca release from the endoplasmic reticulum (ER) and extracellular Ca entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca entry, the activation of outward K-Ca-dependent currents, mainly the K currents, provides a membrane polarizing influence which offset the depolarizing action of Ca elevation and indirectly maintains the driving force for optimal Ca increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions.
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http://dx.doi.org/10.3390/ijms21010130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982260PMC
December 2019

Effect of nutrition on neurodegenerative diseases. A systematic review.

Nutr Neurosci 2019 Nov 4:1-25. Epub 2019 Nov 4.

Molecular Biology, School of Medicine and Surgery, University of Milano-Bicocca, Monza Brianza, Italy.

Neurodegenerative diseases are characterized by the progressive functional loss of neurons in the brain, causing cognitive impairment and motoneuron disability. Although multifactorial interactions are evident, nutrition plays an essential role in the pathogenesis and evolution of these diseases. A systematic literature search was performed, and the prevalence of studies evaluated the effect of the Mediterranean diet (MeDiet), nutritional support, EPA and DHA, and vitamins on memory and cognition impairment. The data showed that malnutrition and low body mass index (BMI) is correlated with the higher development of dementia and mortality. MeDiet, nutritional support, and calorie-controlled diets play a protective effect against cognitive decline, Alzheimer's disease (AD), Parkinson disease (PD) while malnutrition and insulin resistance represent significant risk factors. Malnutrition activates also the gut-microbiota-brain axis dysfunction that exacerbate neurogenerative process. Omega-3 and -6, and the vitamins supplementation seem to be less effective in protecting neuron degeneration. Insulin activity is a prevalent factor contributing to brain health while malnutrition correlated with the higher development of dementia and mortality.
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http://dx.doi.org/10.1080/1028415X.2019.1681088DOI Listing
November 2019

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle.

Int J Mol Sci 2019 Sep 5;20(18). Epub 2019 Sep 5.

School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia-reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.
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http://dx.doi.org/10.3390/ijms20184361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769538PMC
September 2019

miRNA-218 Targets Lipin-1 and Glucose Transporter Type 4 Genes in 3T3-L1 Cells Treated With Lopinavir/Ritonavir.

Front Pharmacol 2019 30;10:461. Epub 2019 Apr 30.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.
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http://dx.doi.org/10.3389/fphar.2019.00461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524698PMC
April 2019

Angiotensin-(1-7) exerts a protective action in a rat model of ventilator-induced diaphragmatic dysfunction.

Intensive Care Med Exp 2019 Jan 18;7(1). Epub 2019 Jan 18.

Department of Medicine, University of Milano-Bicocca, Monza, Italy.

Background: Ventilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction. Recent data show that renin-angiotensin system is involved in diaphragmatic skeletal muscle atrophy after MV. In particular, angiotensin-II can induce marked diaphragm muscle wasting, whereas angiotensin-(1-7) (Ang-(1-7)) could counteract this activity. This study was designed to evaluate the effects of the treatment with Ang-(1-7) in a rat model of VIDD with neuromuscular blocking agent infusion. Moreover, we studied whether the administration of A-779, an antagonist of Ang-(1-7) receptor (Mas), alone or in combination with PD123319, an antagonist of AT2 receptor, could antagonize the effects of Ang-(1-7).

Methods: Sprague-Dawley rats underwent prolonged MV (8 h), while receiving an iv infusion of sterile saline 0.9% (vehicle) or Ang-(1-7) or Ang-(1-7) + A-779 or Ang-(1-7) + A-779 + PD123319. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis, quantitative real-time PCR, and Western blot analysis.

Results: MV resulted in a significant reduction of diaphragmatic contractility in all groups of treatment. Ang-(1-7)-treated rats showed higher muscular fibers cross-sectional area and lower atrogin-1 and myogenin mRNA levels, compared to vehicle treatment. Treatment with the antagonists of Mas and Ang-II receptor 2 (AT2R) caused a significant reduction of muscular contractility and an increase of atrogin-1 and MuRF-1 mRNA levels, not affecting the cross-sectional fiber area and myogenin mRNA levels.

Conclusions: Systemic Ang-(1-7) administration during MV exerts a protective role on the muscular fibers of the diaphragm preserving muscular fibers anatomy, and reducing atrophy. The involvement of Mas and AT2R in the mechanism of action of Ang-(1-7) still remains controversial.
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http://dx.doi.org/10.1186/s40635-018-0218-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338614PMC
January 2019

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: Relationship between the electrode trajectory and cognitive decline.

Parkinsonism Relat Disord 2019 04 8;61:45-49. Epub 2018 Dec 8.

Department of Psychology, University of Turin, Via Verdi, 8 - 10124, Turin, Italy.

Introduction: It remains to be clarified whether penetration of the caudate nucleus increases the risk of cognitive decline in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN).

Methods: A retrospective analysis of pre/postoperative neuropsychological changes was performed with 46 consecutive patients with PD who underwent DBS of the STN. In particular, to evaluate the possible relationship between cognitive changes and DBS lead trajectories, repeated-measures ANCOVAs were conducted to analyze the effects of group (23 patients with vs 23 patients without penetration of the caudate nucleus) and time (T0 vs T1) for each neuropsychological test.

Results: A statistically significant main effect of time was observed in the Trail Making Test - Part B (TMT-B), as well as in both the phonemic and semantic (F [1, 44] = 35.59, p < 0.001, PrtEta = 0.447) verbal fluency tasks, and the results suggested postoperative cognitive decline. However, no significant interaction effects of time and group were observed. The results indicated that the extent of the decline was comparable between the caudate and non-caudate penetration groups, and no relationship was found between cognitive changes and caudate penetration.

Conclusion: Although postoperative cognitive decline was observed in some attentional-executive functions, which were assessed by the verbal fluency and TMT-B tasks, the trajectory passing through the caudate appeared not to increase the risk of cognitive decline in patients with PD undergoing DBS of the STN.
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http://dx.doi.org/10.1016/j.parkreldis.2018.12.005DOI Listing
April 2019

STIM Proteins and Orai Ca Channels Are Involved in the Intracellular Pathways Activated by TLQP-21 in RAW264.7 Macrophages.

Front Pharmacol 2018 27;9:1386. Epub 2018 Nov 27.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

TLQP-21 is a neuropeptide which has been implicated in regulation of nociception and other relevant physiologic functions. Although recent studies identified C3a and gC1q receptors as targets for TLQP-21, its intracellular molecular mechanisms of action remain largely unidentified. Our aim was (i) to explore the intracellular signaling pathway(s) activated by JMV5656, a novel derivative of TLQP-21, in RAW264.7 macrophages, and (ii) to assess linkages of these pathways with its purported receptors. JMV5656 stimulated, in a dose-dependent fashion, a rapid and transient increase in intracellular Ca concentrations in RAW264.7 cells; repeated exposure to the peptide resulted in a lower response, suggesting a possible desensitization mechanism of the receptor. In particular, JMV5656 increased cytoplasmic Ca levels by a PLC-dependent release of Ca from the endoplasmic reticulum. STIM proteins and Orai Ca channels were activated and played a crucial role. In fact, treatment of the cells with U73122 and thapsigargin modulated the increase of intracellular Ca levels stimulated by JMV5656. Moreover, in RAW264.7 cells intracellular Ca increases did not occur through the binding of JMV5656 to the C3a receptor, since the increase of intracellular Ca levels induced by JMV5656 was not affected by specific siRNA against C3aR. In summary, our study provides new indications for the downstream effects of JMV5656 in macrophages, suggesting that it could activate receptors different from the C3aR.
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http://dx.doi.org/10.3389/fphar.2018.01386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277904PMC
November 2018

Study of the Tissue Distribution of TLQP-21 in Mice Using [F]JMV5763, a Radiolabeled Analog Prepared via [F]Aluminum Fluoride Chelation Chemistry.

Front Pharmacol 2018 13;9:1274. Epub 2018 Nov 13.

School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.

TLQP-21 is a neuropeptide that is involved in the control of several physiological functions, including energy homeostasis. Since TLQP-21 could oppose the early phase of diet-induced obesity, it has raised a huge interest, but very little is known about its mechanisms of action on peripheral tissues. Our aim was to investigate TLQP-21 distribution in brain and peripheral tissues after systemic administration using positron emission tomography. We report here the radiolabeling of NODA-methyl phenylacetic acid (MPAA) functionalized JMV5763, a short analog of TLQP-21, with [F]aluminum fluoride. Labeling of JMV5763 was initially performed manually, on a small scale, and then optimized and implemented on a fully automated radiosynthesis system. In the first experiment, mice were injected in the tail vein with [F]JMV5763, and central and peripheral tissues were collected 13, 30, and 60 min after injection. Significant uptake of [F]JMV5763 was found in stomach, intestine, kidney, liver, and adrenal gland. In the CNS, very low uptake values were measured in all tested areas, suggesting that the tracer does not efficiently cross the blood-brain barrier. Pretreatment with non-radioactive JMV5763 caused a significant reduction of tracer uptake only in stomach and intestine. In the second experiment, PET analysis was performed 10-120 min after i.v. [F]JMV5763 administration. Results were consistent with those of the determinations. PET images showed a progressive increase of [F]JMV5763 uptake in intestine and stomach reaching a peak at 30 min, and decreasing at 120 min. Our results demonstrate that F-labeling of TLQP-21 analogs is a suitable method to study its distribution in the body.
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http://dx.doi.org/10.3389/fphar.2018.01274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277862PMC
November 2018

Correction to: Parma consensus statement on metabolic disruptors.

Environ Health 2017 12 6;16(1):130. Epub 2017 Dec 6.

Department of Biology, University of Massachusetts, Amherst, MA, USA.

Correction: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".
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http://dx.doi.org/10.1186/s12940-017-0343-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719727PMC
December 2017

Neurotrophic and Neuroregenerative Effects of GH/IGF1.

Int J Mol Sci 2017 Nov 17;18(11). Epub 2017 Nov 17.

Molecular Biology, School of Medicine and Surgery, University of Milano-Bicocca, via Cadore, 48-20900 Monza Brianza, Italy.

Introduction: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects.

Methods: In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: "GH/IGF-1" associated with "neuroregeneration", "amyotrophic lateral sclerosis", "Alzheimer disease", "Parkinson's disease", "brain", and "neuron".

Results: Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results.

Conclusions: Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.
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http://dx.doi.org/10.3390/ijms18112441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713408PMC
November 2017

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia.

Sci Rep 2017 10 12;7(1):13017. Epub 2017 Oct 12.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "A. Moro", Bari, Italy.

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.
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http://dx.doi.org/10.1038/s41598-017-13504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638899PMC
October 2017

Pharmacological and Biochemical Characterization of TLQP-21 Activation of a Binding Site on CHO Cells.

Front Pharmacol 2017 30;8:167. Epub 2017 Mar 30.

Department of Medicine and Surgery, University of Milano-BicoccaMonza, Italy.

VGF is a propeptide of 617 amino acids expressed throughout the central and the peripheral nervous system. VGF and peptides derived from its processing have been found in dense core vesicles and are released from neuronal and neuroendocrine cells via the regulated secretory pathway. Among VGF-derived neuropeptides, TLQP-21 (VGF) has raised a huge interest and is one of most studied. TLQP-21 is a multifunctional neuropeptide involved in the control of several physiological functions, potentially including energy homeostasis, pain modulation, stress responsiveness and reproduction. Although little information is available about its receptor and the intracellular mechanisms mediating its biological effects, recent reports suggest that TLQP-21 may bind to the complement receptors C3aR1 and/or gC1qR. The first aim of this study was to ascertain the existence and nature of TLQP-21 binding sites in CHO cells. Secondly, we endeavored to characterize the ligand binding to these sites by using a small panel of VGF-derived peptides. And finally, we investigated the influence of TLQP-21 on selected intracellular signaling pathways. We report that CHO cells express a single class of saturable and specific binding sites for TLQP-21 with an affinity and capacity of = 0.55 ± 0.05 × 10 M and 81.7 ± 3.9 fmol/mg protein, respectively. Among the many bioactive products derived from the C-terminal region of VGF that we tested, TLQP-21 was the most potent in stimulating intracellular calcium mobilization in CHO cells; this effect is primarily due to its C-terminal fragment (HFHH-10). TLQP-21 induced rapid and transient dephosphorylation of phospholipase Cγ1 and phospholipase A2. Generation of IP and diacylglycerol was crucial for TLQP-21 bioactivity. In conclusion, our results suggest that the receptor stimulated by TLQP-21 belongs to the family of the G-coupled receptors, and its activation first increases membrane-lipid derived second messengers which thereby induce the mobilization of Ca from the endoplasmic reticulum followed by a slower store-operated Ca entry from outside the cell.
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http://dx.doi.org/10.3389/fphar.2017.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371653PMC
March 2017

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia.

J Cachexia Sarcopenia Muscle 2017 Jun 10;8(3):386-404. Epub 2017 Mar 10.

Department of Pharmacy - Drug Sciences, University of Bari, Via Orabona 4, 70125, Bari, Italy.

Background: Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose-limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium-dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS-R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood.

Methods: By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast-twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin-induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention.

Results: Cisplatin-treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up-regulation of atrogin1/Murf-1 genes and a down-regulation of Pgc1-a gene, all indexes of muscle atrophy, and by a two-fold increase in resting intracellular calcium, [Ca ] , compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store-operated calcium entry were ~50% significantly reduced in cisplatin-treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin-induced alteration of calcium homeostasis by both common as well as drug-specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis.

Conclusions: Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin-induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin-induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy-associated cachexia.
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http://dx.doi.org/10.1002/jcsm.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703021PMC
June 2017

JMV5656, A Novel Derivative of TLQP-21, Triggers the Activation of a Calcium-Dependent Potassium Outward Current in Microglial Cells.

Front Cell Neurosci 2017 23;11:41. Epub 2017 Feb 23.

Department of Medicine and Surgery, University of Milano-Bicocca Monza, Italy.

TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca in the N9 microglia cells, and whether this Ca elevation is coupled with the activation Ca-sensitive K channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca-activated potassium (K) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that K3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca, and, following extracellular Ca entry, the opening of K3.1 channels.
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http://dx.doi.org/10.3389/fncel.2017.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322282PMC
February 2017

JMV2894, a novel growth hormone secretagogue, accelerates body mass recovery in an experimental model of cachexia.

Endocrine 2017 Oct 28;58(1):106-114. Epub 2016 Nov 28.

Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Oncologic patients subjected to chemotherapy frequently present aphagia, malnutrition, and cachexia. The purpose of this study was to investigate whether selected growth hormone secretagogues including hexarelin, JMV2894 and JMV2951 could antagonize body weight loss and wasting induced by cisplatin administration in rats. The three growth hormone secretagogues behaved as full agonists of the growth hormone secretagogues receptor both in terms of ability to stimulate calcium mobilization in Chinese hamster ovary cells and stimulation of growth hormone release in neonatal rats. Adult rats were (i) treated with vehicle throughout (controls), or (ii) treated with cisplatin (days 1-3) and a growth hormone secretagogues or vehicle, (days 1-12). Body weight and food consumption were measured daily. Although all growth hormone secretagogues caused initial transient acute increases in food intake, the total amount of food eaten by controls and growth hormone secretagogues treated groups over the 12 experimental days was not significantly different. All groups pre-treated with cisplatin lost up to 5-10 % body weight in the first 4 days; they subsequently gained weight at a rate comparable with controls. Interestingly, rats which received JMV2894 demonstrated a faster gain in body weight than any other growth hormone secretagogues treated group and at the end of the protocol reached a weight similar to that of controls. JMV2894 did not stimulate perirenal and epididymal fat accumulation but reduced MuRF mRNA levels in skeletal muscles. In conclusion, our findings demonstrate that JMV2894 antagonizes cisplatin induced weight loss in rats and may prove useful in antagonizing cachexia associated with cancer and chemotherapy in humans.
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http://dx.doi.org/10.1007/s12020-016-1184-2DOI Listing
October 2017

Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease.

J Neurol 2017 Jan 19;264(1):40-48. Epub 2016 Oct 19.

Department of Neuroscience "Rita Levi Montalcini", University of Turin, via Cherasco 15, 10124, Turin, Italy.

To determine the clinical and demographic correlates of persistent, remitting, and new-onset impulse control behaviors (ICBs) before and after subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD). We compared the pre- and post-surgical prevalence of ICBs, classified as impulse control disorders (ICD), dopamine dysregulation syndrome (DDS), and punding in 150 consecutive PD STN-DBS-treated patients and determined the association with motor, cognitive, neuropsychological, and neuropsychiatric endpoints. At baseline (before STN-DBS), ICBs were associated with younger age (p = 0.045) and male gender (85 %; p = 0.001). Over an average follow-up of 4.3 ± 2.1 years of chronic STN-DBS there was an overall trend for reduction in ICBs (from 17.3 to 12.7 %; p = 0.095) with significant improvement in hypersexuality (12-8.0 %; p = 0.047), gambling (10.7-5.3 %; p = 0.033), and DDS (4.7-0 %; p < 0.001). ICB remitted in 18/26 patients (69 %) and persisted in 8/26 (31 %); the latter group was characterized by higher levodopa equivalent daily dose. Patients who developed a new-onset ICB during follow-up (n = 11/150) were characterized by younger age (p = 0.042), lower dyskinesia improvement (p ≤ 0.035), and a gender distribution with higher prevalence of women (p = 0.018). In addition, new-onset ICB was more common among patients with borderline, schizoid, and/or schizotypal traits of personality disorders; persistent ICB in those with obsessive-compulsive traits. PD-related ICBs exhibit a complex outcome after STN-DBS, with a tendency for overall reduction but with age, gender, dopaminergic therapy, and neuropsychiatric features exerting independent effects.
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http://dx.doi.org/10.1007/s00415-016-8314-xDOI Listing
January 2017

Advanced therapies in Parkinson's disease: Long-term retrospective study.

Parkinsonism Relat Disord 2016 08 17;29:104-8. Epub 2016 May 17.

Department of Neuroscience "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 10124 Torino, Italy.

Background: Levodopa/carbidopa intestinal gel infusion (LCIG) and subthalamic nucleus deep brain stimulation (STN-DBS) are approved therapies for advanced Parkinson's disease (PD) whose long-term comparability remains unclear.

Methods: We reviewed the 5-year data on activities of daily living (ADL) and motor complications (OFF time, dyskinesia duration, and dyskinesia severity), as measured by the Unified Parkinson Disease Rating Scale (UPDRS) section-II and section-IV (items 39, 32, and 33, respectively) in 60 PD patients exposed to STN-DBS (n = 20), LCIG (n = 20), and oral medical therapy (OMT) (n = 20) at similar baseline disability and cognitive state.

Results: STN-DBS and LCIG showed a similar magnitude of deterioration in ADL (+6.1 vs. +5.7 UPDRS-II; p = 0.709), but lesser than with OMT (+13.7 UPDRS-II; p = 0.005). OFF time also improved to the same extent in STN-DBS and LCIG (-62% vs. -54.5%; p = 0.830), while worsened with OMT (+78.6%; p < 0.001). STN-DBS and LCIG yielded greater improvement on dyskinesia compared to OMT (dyskinesia duration: -66.1% vs. -9.0% vs. +24.2% [p = 0.001]; dyskinesia severity: -68.8% vs. -18.0% vs. +16.2% [p = 0.002]), with relative superiority of STN-DBS over LCIG (p = 0.004 for duration; p = 0.014 for severity). The annualized rate of complication was lower in STN-DBS vs. LCIG (0.13 vs. 0.68; p < 0.001) but not different between STN-DBS and OMT (0.13 vs. 0.10; p = 0.795).

Conclusions: STN-DBS and LCIG showed comparable efficacy in ADL and OFF time, superior to OMT. STN-DBS yielded greater improvement in dyskinesia and lower long-term rate of complications than LCIG.
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http://dx.doi.org/10.1016/j.parkreldis.2016.05.015DOI Listing
August 2016

Suspended monolayer graphene under true uniaxial deformation.

Nanoscale 2015 Aug;7(30):13033-42

Institute of Chemical Engineering Sciences, Foundation of Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece.

2D crystals, such as graphene, exhibit the higher strength and stiffness of any other known man-made or natural material. So far, this assertion has been primarily based on modelling predictions and on bending experiments in combination with pertinent modelling. True uniaxial loading of suspended graphene is not easy to accomplish; however such an experiment is of paramount importance in order to assess the intrinsic properties of graphene without the influence of an underlying substrate. In this work we report on uniaxial tension of graphene up to moderate strains of ∼0.8%. This has been made possible by sandwiching the graphene flake between two polymethylmethacrylate (PMMA) layers and by suspending its central part by the removal of a section of PMMA with e-beam lithography. True uniaxial deformation is confirmed by the measured large phonon shifts with strain by Raman spectroscopy and the indication of lateral buckling (similar to what is observed for thin macroscopic membranes under tension). Finally, we also report on how the stress is transferred to the suspended specimen through the adhesive grips and determine the value of interfacial shear stress that is required for efficient axial loading in such a system.
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http://dx.doi.org/10.1039/c5nr03072bDOI Listing
August 2015

Earlier versus later subthalamic deep brain stimulation in Parkinson's disease.

Parkinsonism Relat Disord 2015 Aug 4;21(8):972-5. Epub 2015 Jun 4.

Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) has been recently compared to a possible "second therapeutic honeymoon" for Parkinson's disease, as it might prevent the development of severe motor complications and lessen the social adjustment associated to disease progression. This study aims to evaluate whether an early surgical treatment could result in better long-term outcomes, comparing the follow-up evolution of 203 parkinsonian patients, treated at different stages of the disease course.

Methods: The retrospective allocation to Early- or Late-Stimulated groups was performed in accordance to disease severity at the time of surgery and motor fluctuations duration. Then, the two groups clinical outcomes were compared after more than 8 years of follow-up by means of the Unified Parkinson's Disease Rating Scale, reporting the overall disability experienced by patients during the entire observational period.

Results: Subjects receiving an earlier STN-DBS showed a sustained improvement in the activities of daily living and motor complications, never reaching the severe levels of disability reported by Late-Stimulated patients at the time of surgical selection. After ≥8 years of follow-up the Early-Stimulated group still reported a 28.7% lower impairment in activities of daily living and 43.8% lower duration of waking day spent in OFF compared to their pre-surgical basal scores.

Conclusion: Although the limitation of a retrospective study design should be considered in the interpretation of data, our findings suggest that an earlier STN-DBS treatment might result in a more precocious stabilization of motor complications, with beneficial effects on the patient's social and professional life autonomy.
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http://dx.doi.org/10.1016/j.parkreldis.2015.06.001DOI Listing
August 2015

Alexithymia in patients with Parkinson's disease treated with DBS of the subthalamic nucleus: a case-control study.

Front Psychol 2014 13;5:1168. Epub 2014 Oct 13.

Department of Neuroscience, University of Turin Turin, Italy.

Objectives: To evaluate the effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) on alexithymia, a deficit in affective regulation, comparing patients with Parkinson's disease (PD) submitted to STN-DBS (DBS group) to PD patients not yet treated with STN-DBS (pre-DBS group) and to healthy participants (C group).

Methods: We recruited 27 consecutive STN-DBS PD patients, 38 consecutive pre-DBS patients and 27 healthy participants. Patients were assessed for alexithymia (Toronto Alexithymia Scale), depression, [beck depression inventory (BDI)], and cognitive functions (reasoning, memory, attentional, and executive tests).

Results: The DBS patients performed worse than the pre-DBS patients in the corsi's block-tapping test, in the phonemic fluency task and in the Frontal Assessment Battery. Around 30% of DBS (29.6%) and pre-DBS (31.6%) patients resulted alexithymic, compared with 14.8% in the C group. The results pointed out significantly higher alexithymia scores in both the DBS and pre-DBS groups compared with the C group, while no difference emerged between the DBS and pre-DBS groups. Pre-DBS group showed a significantly higher BDI score than the C group, while DBS group did not.

Conclusion: Although the results suggest that STN-DBS does not affect alexithymia, both the DBS and pre-DBS patients reported higher prevalence (about 30%) of alexithymia than did healthy subjects (14.8%).
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http://dx.doi.org/10.3389/fpsyg.2014.01168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195283PMC
October 2014