Search

A variety of mathematical models of the cardiovascular system have been suggested over several years in order to describe the time-course of a series of physiological variables (i.e. heart rate, cardiac output, arterial pressure) relevant for the compensation mechanisms to perturbations, such as severe haemorrhage. The current study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. The present work proposes a first version of a differential-algebraic equations model, the model dynamical ODE model for haemorrhage (dODEg). The model consists of 10 differential and 14 algebraic equations, incorporating 61 model parameters. This model is capable of replicating the changes in heart rate, mean arterial pressure and cardiac output after the onset of bleeding observed in four experimental animal preparations and fits well to the experimental data. By predicting the time-course of the physiological response after haemorrhage, the dODEg model presented here may be of significant value for the quantitative assessment of conventional or novel therapeutic regimens. The model may be applied to the prediction of survivability and to the determination of the urgency of evacuation towards definitive surgical treatment in the operational setting.

Although mathematical modelling of pressure-flow dynamics in the cardiocirculatory system has a lengthy history, readily finding the appropriate model for the experimental situation at hand is often a challenge in and of itself. An ideal model would be relatively easy to use and reliable, besides being ethically acceptable. Furthermore, it would address the pathogenic features of the cardiovascular disease that one seeks to investigate. No universally valid model has been identified, even though a host of models have been developed. The object of this review is to describe several of the most relevant mathematical models of the cardiovascular system: the physiological features of circulatory dynamics are explained, and their mathematical formulations are compared. The focus is on the whole-body scale mathematical models that portray the subject’s responses to hypovolemic shock. The models contained in this review differ from one another, both in the mathematical methodology adopted and in the physiological or pathological aspects described. Each model, in fact, mimics different aspects of cardiocirculatory physiology and pathophysiology to varying degrees: some of these models are geared to better understand the mechanisms of vascular hemodynamics, whereas others focus more on disease states so as to develop therapeutic standards of care or to test novel approaches. We will elucidate key issues involved in the modeling of cardiovascular system and its control by reviewing seven of these models developed to address these specific purposes.

In this chapter, after having clarified which definition of emotion we followed, starting from Darwin and evolutionary psychology, we tried to examine the main mechanisms of emotional recognition from a behavioral and cerebral point of view: emotional contagion and cognitive empathy. The link between these skills and social cognition has been discussed. We tried to understand through the description of comparative studies on animals, studies on populations with cerebellar lesions in animals and humans, neurostimulation studies, and studies on neuropsychiatric pathologies with alterations to the cerebellar networks the possible involvement of the cerebellum in these mechanisms, also investigating its possible causal role. The evidence, even if mainly of a correlational type, is numerous and robust enough to be able to affirm the existence of significant involvement of the cerebellum in social cognition and in the recognition of negative emotions, especially fear.

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.MethodsA cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.ResultsA total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).DiscussionThe SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58%men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, withmen showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently,whereas patients with truncating variants presentedmore commonly cognitive decline (9.7%vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormalmotor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

La modellizzazione matematica è diventata ormai uno strumento essenziale nell’avanzamento delle conoscenze in qualsiasi campo della scienza, dall’econometria alla psicologia, dalla chimica all’epidemiologia, come vissuto di recente nella pandemia da SARS-coV-2. Anche quelle che erano una volta discipline “soft” come la biomedicina o l’ecologia possono ora usufruire di tecniche di rappresentazione ed esplicazione dei processi estremamente utili alla comprensione delle dinamiche in gioco. Questa evoluzione, dovuta in non piccola parte all’attuale disponibilità di abbondante potenza di calcolo elettronico a costi ridotti, non è però opera ed appannaggio soltanto della nostra generazione. Lo stesso Consiglio nazionale delle ricerche (CNR) fondato nel 1923 ha avuto come primo presidente il Prof. Vito Volterra, uno dei fondatori della biomatematica, il cui nome è storicamente legato alle equazioni di dinamica di popolazione da lui introdotte insieme a Lotka. Nel solco di tale tradizione oggi la biomatematica ha un ruolo primario nello studio delle dinamiche di inquinamento, diffusione di sostanze tossiche, bioaccumulo nelle specie di rilevanza alimentare, tossicocinetica, tossicodinamica ed epidemiologia delle malattie legate all’inquinamento. In tutte queste discipline viene affidato alla biomatematica il ruolo di svolgere o supportare interpretazioni quantitative dei dati e facilitare l’inquadramento delle esperienze specifiche degli specialisti di campo (esperti ambientali, biologi, epidemiologi e clinici), in una cornice protesa a collegare dati disparati in una logica di insieme coerente. Si tratta di un compito non facile, che richiede non solo lo sforzo di molti ricercatori con competenze complementari (biologi, medici, epidemiologi, analisti numerici, sistemisti, statistici), ma che deve anche fare i conti con le limitazioni dovute alla mancata disponibilità di dati talvolta cruciali, un fenomeno purtroppo frequente nelle indagini su sistemi complessi. Le pagine che seguono si propongono di illustrare, in modo comprensibile anche per non specialisti, alcuni di questi temi. Il capitolo comprende una panoramica su cosa sono i modelli statici e dinamici, ed in particolare quelli sviluppati in ambito “ambiente e salute”. Inoltre viene offerta al lettore una scheda riassuntiva del sistema formalizzato BioMatLab (MoSpec) dedicato all’implementazione dei modelli matematici in diversi linguaggi di programmazione, corredato da un link alla piattaforma online nella quale sono rese disponibili alla comunità scientifica alcuni modelli prodotti/implementati per lo studio delle dinamiche di interazione ambiente e salute sviluppate durante le attività del progetto CISAS (capitolo 14).

Korrektur zu 10.1038/s41436-020-0899-x

It is known that, as the vast majority of the anthropogenically emitted mercury can be found in aquatic ecosystems, where several methylating bacteria are present, fish consumption represents the most critical intake source of the most toxic form of mercury, the methylmercury (MeHg). The aim of this work is to predict MeHg levels in the fish muscles which, being the edible portion, are part of the human diet. A physiologically based toxicokinetics model was developed to evaluate the kinetics of MeHg in red mullets. Fishes were described by means of a multi-compartment model including stomach, gut, blood, muscles and an additional compartment virtually encompassing all the remaining organs. Absorption, distribution and excretion were modelled considering different MeHg routes of administration and excretion: intake by ingestion of contaminated food, intake and elimination through inhalation-exhalation and excretion through feces. The model has been firstly validated on Terapon jarbua fish (using the weighted least squares method for parameter estimation) to be subsequently readapted to predict methylmercury concentrations in the muscle of red mullets (using an approximate Bayesian computation approach). This simple multicompartmental model could be considered part, a link in the chain, of a wider more complex project aiming at tracking the fate of MeHg from polluted seawater to the human end consumer. The present study could be useful to surveillance organizations in order to carry out a more comprehensive and informed risk assessment analysis and to take appropriate preventive measures by evaluating possible new MeHg concentration thresholds to minimize public health hazards.

Orientador: Alessandra Aparecida Viveiro Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin Resumo: Os diversos desafios enfrentados pelo Ensino de Ciências como, por exemplo, a necessidade de formar cidadãos cientificamente cultos, de contextualização dos conteúdos e a inserção das diferentes tecnologias no currículo, somam-se aos desafios educativos externos ao ensino, como a deterioração das condições de trabalho e a indisciplina, dificultando as práticas educativas em sala de aula. A literatura, compreendendo que tais desafios são ocasionados, principalmente, pelas diferentes concepções de educação, de Ciências e de ambiente, propõe como forma de superação um Ensino de Ciências que se desenvolva tendo como bases a interdisciplinaridade, a contextualização, as complexas relações entre ciência, tecnologia, sociedade e ambiente (CTSA), a perspectiva da História e Filosofia da Ciência e abordagens que envolvam atividades investigativas. Sabe-se que, apesar de tais indicações, o Ensino de Ciências atual ainda ocorre, predominantemente, de forma tradicional. Assim, partindo de tal constatação, a presente pesquisa tomou como premissa que em escolas não convencionais o Ensino de Ciências provavelmente ocorra de forma diferenciada. Essa hipótese levou a busca por formas diferenciadas de ensino, sendo que, por meio de publicações midiáticas e acadêmicas, chegou-se às chamadas "escolas alternativas". Tais escolas emergem em diferentes contextos e parecem seguir tendências pedagógicas com práticas que se distanciam daquelas desenvolvidas na maior parte das escolas. Como, então, se dá o Ensino de Ciências nessas escolas? Com o objetivo de identificar e descrever as características do Ensino de Ciências que ocorre em diferentes escolas alternativas, seguiu-se com uma pesquisa de abordagem qualitativa, do tipo estudo de caso múltiplo, no qual fizeram parte três escolas, identificadas depois como escola democrática, escola Waldorf e escola Freinet. A coleta de dados ocorreu por meio de documentos, entrevistas e observações diretas de aulas de Ciências. A análise do estudo contou com a descrição detalhada do Ensino de Ciências de cada uma das escolas selecionadas, seguindo a estratégia de análise "construção da explanação", descrita por Robert Yin. Os resultados obtidos apontam distintas formas de desenvolvimento do Ensino de Ciências em cada escola. Ao confluir os dados, entretanto, conclui-se que o Ensino de Ciências nessas escolas alternativas ainda ocorre de forma convencional, porém, com o desenvolvimento de algumas características que o aproximam do ensino preconizado pela literatura, o que permitiu que fossem elencadas práticas que podem orientar e inspirar outras escolas Abstract: The several challenges faced by science education, for example, the requirement of forming scientifically cult citizens, the contextualization of content and the insertion of different technologies into the curriculum, add to the educational challenges outside education, such as the conditions of work deteriorated and indiscipline, hindering the educational practices in the classroom. The literature, understanding that such challenges are caused, mainly, by different conceptions of education, science and the environment, proposes as a way of overcoming, a Science Education that develops through the following axes: interdisciplinarity, contextualization, science, technology and society (STS), History and Philosophy of Science and investigative activities. It is known that, despite such indications, the current Science Education still occurs predominantly in the traditional way. Thus, based on this observation, the present study assumed that, in non-conventional schools, Science Education probably occurs in a different way. This hypothesis led to the search for different forms of education, and through media and academic publications, we reached the so-called "alternative schools". Such schools emerge in different contexts and appear to follow pedagogical trends with practices that are far from those developed in most schools. How, then, does Science Education happen in those schools? With the purpose of describing Science Education in alternative schools and seeking contributions to the area, a qualitative research was carried out, a multiple case study, in which three schools were identified, later, as a democratic school, Waldorf School and Freinet School. Data collection occurred through documents, interviews and direct observations of science classes. The analysis of the study counted on the detailed description of the Science Education of each one of the selected schools, following the strategy of analysis "construction of the explanation", described by Robert Yin. The results show different ways of developing Science Education in each school. However, it is concluded that the teaching of science in alternative schools still occurs in a conventional way, but, with the development of some characteristics that bring it closer to the teaching recommended by the literature, which allowed the identification of practices and structures capable of orienting and / or inspiring other schools along the path of developing a Science Education closer to the one recommended Mestrado Ensino de Ciências e Matemática Mestra em Ensino de Ciências e Matemática

International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Hemorrhagic shock is the number one cause of death on the battlefield and in civilian trauma as well. Mathematical modeling has been applied in this context for decades; however, the formulation of a satisfactory model that is both practical and effective has yet to be achieved. This paper introduces an upgraded version of the 2007 Zenker model for hemorrhagic shock termed the ZenCur model that allows for a better description of the time course of relevant observations. Our study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. This model is capable of replicating the changes in mean arterial pressure, heart rate, and cardiac output after the onset of bleeding (as observed in four experimental laboratory animals) and achieves a reasonable compromise between an overly detailed depiction of relevant mechanisms, on the one hand, and model simplicity, on the other. The former would require considerable simulations and entail burdensome interpretations. From a clinical standpoint, the goals of the new model are to predict survival and optimize the timing of therapy, in both civilian and military scenarios.

Hemorrhagic shock is a form of hypovolemic shock determined by rapid and large loss of intravascular blood volume and represents the first cause of death in the world, whether on the battlefield or in civilian traumatology. For this, the ability to prevent hemorrhagic shock remains one of the greatest challenges in the medical and engineering fields. The use of mathematical models of the cardiocirculatory system has improved the capacity, on one hand, to predict the risk of hemorrhagic shock and, on the other, to determine efficient treatment strategies. In this paper, a comparison between two mathematical models that simulate several hemorrhagic scenarios is presented. The models considered are the Guyton and the Zenker model. In the vast panorama of existing cardiovascular mathematical models, we decided to compare these two models because they seem to be at the extremes as regards the complexity and the detail of information that they analyze. The Guyton model is a complex and highly structured model that represents a milestone in the study of the cardiovascular system; the Zenker model is a more recent one, developed in 2007, that is relatively simple and easy to implement. The comparison between the two models offers new prospects for the improvement of mathematical models of the cardiovascular system that may prove more effective in the study of hemorrhagic shock.

Objective Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. Methods We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. Results After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. Interpretation DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.

Objectives: The aim of this study was to implement an algorithm that uses clinical, biological and genetic factors to guide levodopa dose prescriptions in Parkinson's disease (PD) patients. Methods: DNA was isolated from blood samples of 224 unrelated PD patients. The inclusion criteriawere the use of levodopa for at least 1 year and its favorable initial response. Two polymorphisms (rs10214163 and rs30196) of synaptic vesicle isoform C (SV2C) were genotyped with Taqman ® genotyping assays (Applied Biosystems, USA). A dopamine transporter (SLC6A3) VNTR (rs28363170) was genotyped by PCR-based methods. A multiple linear regression model included variables with P� 0.20 in univariate analyses between the outcome and/or the genetic factors. Results: The model explained 23% of levodopa dose variation [F ¼ 11.54; P

BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.

Background and purpose Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. Methods We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. Results We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (similar to 80% of patients), urinary urgency (similar to 30%) and pyramidal signs (similar to 70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. Conclusions The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study.Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3.We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded.Long-term DHA supplementation is an eligible treatment for SCA38.

Key Clinical Message Despite transient global amnesia is considered unusual in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and causal relation is still unclear, this report suggests to consider CADASIL in those patients with recurrent transient global amnesia, especially when MRI shows multifocal hyperintensities affecting the cerebral white matter or when it is followed by cognitive decline.

We hypothesized that the IL-1β-511 C>T polymorphism could be associated with the development of neurotoxicity and that it could be a possible biomarker to rate the risk of occurrence of neurotoxicity in cancer patients. Genomic DNA was extracted from 85 cancer patients: 49 received systemic chemotherapeutic treatment (CHT) and 36 patients did not receive it (No-CHT). All subjects were genotyped for the functionally active polymorphisms of IL-1β-511 C>T. We estimated neurotoxicity with the evaluation of neurological deficits. CHT patients showed erythrocytopenia, neurological deficit and a slight lowering of cognitive performance. The subgroup of patients carrying the CC genotype of the IL-1β-511 C>T gene showed lesser neurological deficits. In the context of cancer treatment, we suggested the potential value of IL-1β-511 C>T as genetic biomarkers to identify patients with higher risk to develop neurological deficits.

Common genetic risk factors are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Intermediate repeat expansions at the Ataxin-2 locus (ATXN2) are a risk factor for ALS and influence the phenotype. We assessed whether ATXN2 is a risk factor for FTD or modify clinical features in a data set of Italian patients. Three hundred sixty-eight unrelated FTD cases and 342 controls were enrolled. The frequency of intermediate CAG repeats in ATXN2 gene was not different comparing patients and controls. CAG repeats were interrupted by CAA in all patients carrying intermediate repeats. Interestingly, patients with an increased number of CAG repeats had an earlier onset of the disease than those without expansions (p = 0.011), and presented more frequently with parkinsonism (p = 0.010), and psychotic symptoms (p = 0.013) at disease onset. Our study does not support a major role of ATXN2 intermediate CAG expansions in predisposing to FTD but suggests that ATXN2 may act as a phenotype modifier.

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7, associated with a (CAG)

Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded.DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.

In this paper we report the effect of a combined transcranial direct current stimulation (tDCS) and speech language therapy on linguistic deficits following left brain damage in a stroke case. We show that simultaneous electrical excitatory stimulation to the left and inhibitory stimulation to the right parietal regions (dual-tDCS) affected writing and reading rehabilitation, enhancing speech therapy outcomes. The results of a comparison with healthy controls showed that application of dual-tDCS could improve, in particular, sub-lexical transcoding and, specifically, the reading of non-words with increasing length and complexity. Positive repercussions on patient's quality of functional communication were also ascertained. Significant changes were also found in other language and cognitive tasks not directly treated (comprehension and constructive apraxia).

INTRODUCTION The term "frontotemporal lobar degeneration" (FTLD) includes a large set of neurodegenerative diseases, which are heterogeneous in their genetic, pathologic and clinical aspects. This review will focus on the most recent contribution of neuroimaging tools on the diagnosis, characterization and pathogenesis of FTLD. EVIDENCE ACQUISITION Scopus, Ovid, PubMed and MEDLINE were searched for articles published from January 2012 up to December 2014. Searches were limited to articles published in English. Frontotemporal lobar degeneration as a key word was always in the search queries in combination with logic AND, and at least one other key word. EVIDENCE SYNTHESIS We found 91 papers of interest and reviewed their contents, finding in particular 4 major topics: the contribution of neuroimaging on the differential diagnosis; patients' functional characterization; new neuroimaging tools under development and pre-symptomatic genetic forms. CONCLUSIONS Neuroimaging techniques have shown to be useful supporting tools in diagnosis, even if not always determinant to reach a conclusive decision, and quite important to identify phenocopies. At the moment, there is not a neuroimaging biomarker that could track the progressive course of dementias and the effect of therapies, but it is possible that in the future Diffusion Tensor Imaging and molecular imaging could fill this void. Monitoring the evolution of the pathology in vivo for at least 5 years is essential, and this would only be possible in a large multicenter study; asymptomatic forms would require even longer observation periods.

Item does not contain fulltext Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing. 25 p.

Introduction SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified. Objective The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38. Methods We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation. Results Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease. Conclusions SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions., Highlights • SCA38, due to ELOVL5 gene mutation, is a rare form of inherited ataxia. • Characteristic clinical features include pes cavus and hyposmia. • Limb ataxia, dysarthria, dysphagia, and ophtalmoparesis were observed during disease course. • SCA38 is slowly progressive; loss of activities of daily living were observed only after 20 years. • Imaging documented cerebellar atrophy with sparing of cerebral cortex.

We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively "pure" olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction--particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability.

Background Idiopathic basal ganglia calcifications (IBGC), also known as Fahr’s disease, are neurological diseases characterized by symmetric calcium deposits in basal ganglia and other brain regions. Clinically, IBGC patients show high phenotypic heterogeneity, both in the clinical manifestations and neuroradiological findings. Recently, PDGFRB, PDGFB, XPR1 and SLC20A2 have been identified as causative genes for IBGC [1]. The aim of this study was to report on two Italian patients with idiopathic basal ganglia calcifications associated with novel mutations in the SLC20A2 gene who both presented with episodic migraine.

Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto-correlated error around the expected drift.

MRI demonstrated extensive cortical involvement in a patient with pathologically proven Creutzfeldt-Jacob disease. The whole brain was atrophic; some of the supratentorial cortex, putamen and caudate nucleus gave high signal on T2-weighted images; the changes were more extensive on diffusion-weighted images (DWI). Comparison of the history, and the sites of atrophy and signal change suggested that the latter predominates in regions with long-lasting damage and prevalent gliosis, while high signal on DWI indicate current neuronal loss. This case widens the range of MRI findings in patients with Creutzfeldt-Jacob disease, and suggests that some information about the progression of the disease can be extracted from single MRI study.

Although multiple sclerosis (MS) has been classically regarded as a primarily white matter disorder, recent histopathologic studies have shown that the gray matter may be also heavily affected. Subpial demyelination appears as large bands of myelin loss extending from the surface of the cortex into its deeper layers.1 In vivo this change can only be visualized by ultra-high-fields MRI.2 We describe a patient presenting a neurologic disease that rapidly led to spastic paraplegia and death. Plaques of demyelination were absent in the white matter of the brain, but the neuropathologic diagnosis was MS, based on severe and widespread loss of myelin in the spinal cord. Extensive subpial demyelination involved the …

Primary intracerebral haemorrhages (PICH) are defined as haemorrhages within the brain parenchyma in the absence of readily identifiable causes. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary vascular disease and its mainly clinical manifestations are early-onset infarcts. Spontaneous lobar haematomas are a rare occurrence. We report a very unusual presentation of CADASIL in a 65 year-old man carrying a new NOTCH3 mutation. The clinical onset of the disease was related to an intracerebral haematoma following colon surgery and causing a delirium. In brief, our report suggests that CADASIL must be considered in patient with PICH.

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

Several studies have evaluated the association between APOE gene polymorphisms and the risk for amyotrophic lateral sclerosis (ALS), with inconclusive results. The aim of our study was to further define the risk associated with carriage of the APOE alleles and development and clinical characteristics of ALS. We performed a comprehensive meta-analysis of all existing studies investigating the association between the APOE gene and ALS published up to September 2013, comprising a total of 4249 ALS patients and 10,397 controls. Pooled odds ratios (OR) were estimated using the random effect (RE) model. Results showed that the carriage of different APOE alleles had no effect on disease risk. In particular, the ϵ4 allele was not associated with a significantly increased disease risk (ϵ4 carriers vs. non-ϵ4 carriers: RE OR 1.18; 95% CI 0.91-1.53). In conclusion, our study suggests that the APOE gene does not have a significant effect in ALS aetiopathogenesis.