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BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.
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Idade de Início , Distúrbios Distônicos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Distúrbios Distônicos/fisiopatologia , Idoso , Fatores Sexuais , Sistema de Registros , Itália , Adulto Jovem , Distonia/fisiopatologia , Blefarospasmo/fisiopatologia , Progressão da DoençaRESUMO
INTRODUCTION: Up to one-third of ischemic strokes remained cryptogenic despite extensive investigations. Atrial fibrillation may be detected in a significant proportion of patients with embolic stroke of undetermined source, particularly after the introduction of implantable loop recorder in clinical practice. METHODS: We retrospectively included all the consecutive patients with embolic stroke of undetermined source referred to our units in the period November 2013 to December 2018 and in which an implantable loop recorder was positioned within 6 months from stroke event. Prevalence and predictors of atrial fibrillation were investigated. RESULTS: One hundred thirty-eight patients with embolic stroke of undetermined source fulfilling inclusion criteria were identified. The crude prevalence of atrial fibrillation at the end of observation period was of 45.7%. Incidence rates at 6, 12, 18, 24, and 36 months resulted, respectively, 31.8% (95% CI, 30.4-46.7), 38.0% (95% CI, 30.4-46.9), 42.6% (95% CI, 34.5-51.6), 46.6% (95% CI, 38.2-55.8), and 50.4% (95% CI, 41.6-59.9). On multivariate analysis, only excessive supraventricular electric activity and left atrial enlargement resulted to be significant predictors of atrial fibrillation (p = 0.037 and p < 0.0001, respectively). CONCLUSIONS: Atrial fibrillation may be detected in a relevant proportion (up to 50%) of patients with embolic stroke of undetermined source if a careful and extensive diagnostic work-up is employed. Excessive supraventricular electric activity and left atrial enlargement are significant predictors of the occurrence of atrial fibrillation in these patients.
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Fibrilação Atrial , AVC Embólico , Embolia Intracraniana , Acidente Vascular Cerebral , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Humanos , Embolia Intracraniana/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologiaRESUMO
Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.
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Distúrbios Distônicos , Torcicolo , Demografia , Humanos , Cervicalgia/epidemiologia , Torcicolo/complicações , Torcicolo/epidemiologiaRESUMO
OBJECTIVE: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHAGHSR neurons), its physiological implications and the neuronal circuit recruited by local ghrelin action. METHODS: We investigated the distribution of LHAGHSR neurons using different histologic strategies, including the use of a reporter mice expressing enhanced green fluorescent protein under the control of the GHSR promoter. Also, we investigated the physiological implications of local injections of ghrelin within the LHA, and the extent to which the orexigenic effect of intra-LHA-injected ghrelin involves the arcuate nucleus (ARH) and orexin neurons of the LHA (LHAorexin neurons) RESULTS: We found that: 1) LHAGHSR neurons are homogeneously distributed throughout the entire LHA; 2) intra-LHA injections of ghrelin transiently increase food intake and locomotor activity; 3) ghrelin's orexigenic effect in the LHA involves the indirect recruitment of LHAorexin neurons and the activation of ARH neurons; and 4) LHAGHSR neurons are not targeted by plasma ghrelin. CONCLUSIONS: We provide a compelling neuroanatomical and functional characterization of LHAGHSR neurons in male mice that indicates that LHAGHSR cells are part of a hypothalamic neuronal circuit that potently induces food intake.
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Núcleo Arqueado do Hipotálamo , Região Hipotalâmica Lateral , Camundongos , Masculino , Animais , Região Hipotalâmica Lateral/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Grelina/farmacologia , Grelina/metabolismo , Orexinas , Neurônios/metabolismo , Receptores de Grelina/metabolismo , Ingestão de AlimentosRESUMO
Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.
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Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.
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Neurônios , Óxido Nítrico , Receptores de Grelina , Animais , Grelina/metabolismo , Hipotálamo Posterior , Camundongos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Ratos , Receptores de Grelina/metabolismo , Transdução de SinaisRESUMO
The growth hormone secretagogue receptor (GHSR) has emerged as one of the most fascinating molecules from the perspective of neuroendocrine control. GHSR is mainly expressed in the pituitary and the brain, and plays key roles regulating not only growth hormone secretion but also food intake, adiposity, body weight, glucose homeostasis and other complex functions. Quite atypically, GHSR signaling displays a basal constitutive activity that can be up- or downregulated by two digestive system-derived hormones: the octanoylated-peptide ghrelin and the liver-expressed antimicrobial peptide 2 (LEAP2), which was recently recognized as an endogenous GHSR ligand. The existence of two ligands with contrary actions indicates that GHSR activity can be tightly regulated and that the receptor displays the capability to integrate such opposing inputs in order to provide a balanced intracellular signal. This article provides a summary of the current understanding of the biology of ghrelin, LEAP2 and GHSR and discusses the reconceptualization of the cellular and physiological implications of the ligand-regulated GHSR signaling, based on the latest findings.
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Receptores de Grelina/metabolismo , Animais , Humanos , Transdução de SinaisRESUMO
The growth hormone secretagogue receptor (GHSR) is a G-protein-coupled receptor (GPCR) highly expressed in the brain, and also in some peripheral tissues. GHSR activity is evoked by the stomach-derived peptide hormone ghrelin and abrogated by the intestine-derived liver-expressed antimicrobial peptide 2 (LEAP2). In vitro, GHSR displays ligand-independent actions, including a high constitutive activity and an allosteric modulation of other GPCRs. Beyond its neuroendocrine and metabolic effects, cumulative evidence shows that GHSR regulates the activity of the mesocorticolimbic pathway and modulates complex reward-related behaviors towards different stimuli. Here, we review current evidence indicating that ligand-dependent and ligand-independent actions of GHSR enhance reward-related behaviors towards appetitive stimuli and drugs of abuse. We discuss putative neuronal networks and molecular mechanisms that GHSR would engage to modulate such reward-related behaviors. Finally, we briefly discuss imaging studies showing that ghrelin would also regulate reward processing in humans. Overall, we conclude that GHSR is a key regulator of the mesocorticolimbic pathway that influences its activity and, consequently, modulates reward-related behaviors via ligand-dependent and ligand-independent actions.
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Grelina , Receptores de Grelina , Humanos , Ligantes , Recompensa , Transdução de SinaisRESUMO
BACKGROUND: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized. MATERIALS AND METHODS: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part. RESULTS: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site. DISCUSSION AND CONCLUSION: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.
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Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/fisiopatologia , Sistema de Registros , Extremidade Superior/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Pescoço/fisiopatologia , Estudos Retrospectivos , Crânio/fisiopatologia , Torcicolo/epidemiologia , Torcicolo/fisiopatologiaRESUMO
Growth hormone secretagogue receptor (GHSR), the receptor for ghrelin, is expressed in key brain nuclei that regulate food intake. The dopamine (DA) pathways have long been recognized to play key roles mediating GHSR effects on feeding behaviors. Here, we aimed to determine the role of GHSR in DA neurons controlling appetitive and consummatory behaviors towards high fat (HF) diet. For this purpose, we crossed reactivable GHSR-deficient mice with DA transporter (DAT)-Cre mice, which express Cre recombinase under the DAT promoter that is active exclusively in DA neurons, to generate mice with GHSR expression limited to DA neurons (DAT-GHSR mice). We found that DAT-GHSR mice show an increase of c-Fos levels in brain areas containing DA neurons after ghrelin treatment, in a similar fashion as seen in wild-type mice; however, they did not increase food intake or locomotor activity in response to systemically- or centrally-administered ghrelin. In addition, we found that satiated DAT-GHSR mice displayed both anticipatory activity to scheduled HF diet exposure and HF intake in a binge-like eating protocol similar to those in wild-type mice, whereas GHSR-deficient mice displayed impaired responses. We conclude that GHSR expression in DA neurons is sufficient to both mediate increased anticipatory activity to a scheduled HF diet exposure and fully orchestrate binge-like HF intake, but it is insufficient to restore the acute orexigenic or locomotor effects of ghrelin treatment. Thus, GHSR in DA neurons affects appetitive and consummatory behaviors towards HF diet that take place in the absence of caloric needs.
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Comportamento Consumatório/fisiologia , Dieta Hiperlipídica , Comportamento Alimentar/fisiologia , Receptores de Grelina/fisiologia , Animais , Regulação do Apetite/genética , Comportamento Animal/fisiologia , Neurônios Dopaminérgicos/metabolismo , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Preferências Alimentares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Grelina/genética , Receptores de Grelina/metabolismoRESUMO
BACKGROUND: Acute peripheral trauma is a controversial risk factor for idiopathic dystonia. MATERIALS AND METHODS: We retrospectively analyzed data from the Italian Dystonia Registry regarding the occurrence of acute peripheral trauma severe enough to require medical attention in 1382 patients with adult-onset idiopathic dystonia and 200 patients with acquired adult-onset dystonia. RESULTS: Patients with idiopathic and acquired dystonia showed a similar burden of peripheral trauma in terms of the number of patients who experienced trauma (115/1382 vs. 12/200, pâ¯=â¯0.3) and the overall number of injuries (145 for the 1382 idiopathic patients and 14 for the 200 patients with secondary dystonia, pâ¯=â¯0.2). Most traumas occurred before the onset of idiopathic or secondary dystonia but only a minority of such injuries (14 in the idiopathic group, 2 in the acquired group, pâ¯=â¯0.6) affected the same body part as that affected by dystonia. In the idiopathic group, the elapsed time between trauma and dystonia onset was 8.1⯱â¯9.2 years; only six of the 145 traumas (4.1%) experienced by 5/1382 idiopathic patients (0.36%) occurred one year or less before dystonia onset; in the acquired dystonia group, the two patients experienced prior trauma to the dystonic body part 5 and 6 years before dystonia development. DISCUSSION AND CONCLUSION: Our data suggest that the contribution of peripheral acute trauma to idiopathic dystonia is negligible, if anything, and likely involves only a small subset of patients.
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Distúrbios Distônicos/etiologia , Traumatismos dos Nervos Periféricos/complicações , Sistema de Registros , Doença Aguda , Idoso , Distúrbios Distônicos/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Traumatismos dos Nervos Periféricos/epidemiologia , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Introduction: Cervical dystonia (CD) is one of the most common forms of adult-onset isolated dystonia. Recently, CD has been classified according to the site of onset and spread, in different clinical subgroups, that may represent different clinical entities or pathophysiologic subtypes. In order to support this hypothesis, in this study we have evaluated whether different subgroups of CD, that clinically differ for site of onset and spread, also imply different sensorimotor features. Methods: Clinical and demographic data from 842 patients with CD from the Italian Dystonia Registry were examined. Motor features (head tremor and tremor elsewhere) and sensory features (sensory trick and neck pain) were investigated. We analyzed possible associations between motor and sensory features in CD subgroups [focal neck onset, no spread (FNO-NS); focal neck onset, segmental spread (FNO-SS); focal onset elsewhere with segmental spread to neck (FOE-SS); segmental neck involvement without spread (SNI)]. Results: In FNO-NS, FOE-SS, and SNI subgroups, head tremor was associated with the presence of tremor elsewhere. Sensory trick was associated with pain in patients with FNO-NS and with head tremor in patients with FNO-SS. Conclusion: The frequent association between head tremor and tremor elsewhere may suggest a common pathophysiological mechanism. Two mechanisms may be hypothesized for sensory trick: a gating mechanism attempting to reduce pain and a sensorimotor mechanism attempting to control tremor.
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BACKGROUND: Ground waters are an important resource of water supply for human health and activities. Groundwater uses and applications are often related to its composition, which is increasingly influenced by human activities.In fact the water quality of groundwater is affected by many factors including precipitation, surface runoff, groundwater flow, and the characteristics of the catchment area. During the years 2004-2007 the Agricultural and Food Authority of Apulia Region has implemented the project "Expansion of regional agro-meteorological network" in order to assess, monitor and manage of regional groundwater quality. The total wells monitored during this activity amounted to 473, and the water samples analyzed were 1021. This resulted in a huge and complex data matrix comprised of a large number of physical-chemical parameters, which are often difficult to interpret and draw meaningful conclusions. The application of different multivariate statistical techniques such as Cluster Analysis (CA), Principal Component Analysis (PCA), Absolute Principal Component Scores (APCS) for interpretation of the complex databases offers a better understanding of water quality in the study region. RESULTS: Form results obtained by Principal Component and Cluster Analysis applied to data set of Foggia province it's evident that some sampling sites investigated show dissimilarities, mostly due to the location of the site, the land use and management techniques and groundwater overuse. By APCS method it's been possible to identify three pollutant sources: Agricultural pollution 1 due to fertilizer applications, Agricultural pollution 2 due to microelements for agriculture and groundwater overuse and a third source that can be identified as soil run off and rock tracer mining. CONCLUSIONS: Multivariate statistical methods represent a valid tool to understand complex nature of groundwater quality issues, determine priorities in the use of ground waters as irrigation water and suggest interactions between land use and irrigation water quality.