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Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative characterized by Philadelphia chromosome/translocation t(9;22) and proliferating granulocytes. Despite the clinical success of tyrosine kinase inhibitors (TKi) agents in the treatment of CML, most patients have minimal residual disease contained in the bone marrow microenvironment, within which stromal cells assume a pro-inflammatory phenotype that determines their transformation in cancer-associated fibroblasts (CAF) which, in turn can play a fundamental role in resistance to therapy. Insulin-like Growth Factor Binding Protein-6 (IGFBP-6) is expressed during tumor development, and is involved in immune-escape and inflammation as well, providing a potential additional target for CML therapy. Here, we aimed at investigating the role of IGFBP-6/SHH/TLR4 axis in TKi response. We used a CML cell line, LAMA84-s, and healthy bone marrow stromal cells, HS-5, in mono- or co-culture. The two cell lines were treated with Dasatinib and/or IGFBP-6, and the expression of inflammatory markers was tested by qRT-PCR; furthermore, expression of IGFBP-6, TLR4 and Gli1 were evaluated by Western blot analysis and immumocytochemistry. The results showed that both co-culture and Dasatinib exposure induce inflammation in stromal and cancer cells so that they modulate the expression of TLR4, and these effects were more marked following IGFBP-6 pre-treatment suggesting that this molecule may confer resistance through the inflammatory processes. This phenomenon was coupled with sonic hedgehog (SHH) signaling. Indeed, our data also demonstrate that HS-5 treatment with PMO (an inducer of SHH) induces significant modulation of TLR4 and overexpression of IGFPB-6 suggesting that the two pathways are interconnected with each other and with the TLR-4 pathway. Finally, we demonstrated that pretreatment with IGFBP-6 and/or PMO restored LAMA-84 cell viability after treatment with Dasatinib, suggesting that both IGFBP-6 and SHH are involved in the resistance mechanisms induced by the modulation of TLR-4, thus indicating that the two pathways may be considered as potential therapeutic targets.

Allorquando Le mosche del capitale vide la luce nella primavera del 1989 non suscitò, soprattutto nell’immediatezza della sua uscita, quel dibattito vitale e spregiudicato che l’autore avrebbe auspicato: né dunque una franca dialettica sulle questioni di politica industriale indotte con inusuale evidenza dal contenuto romanzesco, né una spassionata discussione sui caratteri di una proposta stilistica (quella appunto di quest’ultimo parto volponiano) che nel quadro della narrativa allora corre...

Background and aims: To explore the cognitive functioning of ET patients without dementia and delineate its imaging counterpart. Methods: We enrolled 99 subjects (49 non-demented ET patients and 50 education-matched healthy controls) that underwent neuropsychological and MRI evaluation. In order to identify the cognitive parameters that better reflect the profile of ET patients, we used a double statistical approach: (i) direct comparison between groups and (ii) machine learning approach with feature selection. Then, to evaluate the correlation between cognitive performances and the degree of brain atrophy in the ET group, we included the results derived from the uni- and multivariate analysis in whole-brain voxel-based morphometry (VBM) model. Results: In ET patients, the univariate analysis showed differences in cognitive tests evaluating executive functions (FAB, MCST-CA), verbal memory-delayed recall (RAVLT-DR), and working memory (Digit Span B). The relative scores were significantly worse compared to controls, although within the normal range (subclinical dysfunctions). The machine learning approach also provided similar findings: tests exploring the executive functions, verbal memory, and language (RAVLT-DR, FAB, COWAT, RAVLT-IR, TOKEN) showed the highest importance rank in classification's task. Regardless of the explored test, the MRI analysis revealed a correlation (p < 0.005 uncorrected, whole brain) between test scores and widespread areas including cerebellum, inferior and middle frontal cortices, cingulate cortices, and temporal cortex. Conclusion: This study improves the knowledge on cognitive impairment in ET, as our findings demonstrate a heterogeneous pattern of cognitive dysfunction involving memory, executive function, and language domains in the ET group. This clinical profile relates with the deep involvement of the cerebellum and its connections with large-scale brain structures, suggesting that changes spreading in wide-ranging brain pathways may contribute to the physiopathology of cognitive dysfunction in ET.

The full potential of digital technologies remains unrealised and their benefits unequally shared because of insufficient investment in enabling intangible assets and communication networks within and across countries. The COVID-19 shock poses new challenges and opportunities. Drawing on past and ongoing OECD work, the paper proposes a multipronged policy approach to durably accelerate the diffusion and uptake of digital technologies across all layers of society, and share their benefits more widely. The building blocks of the proposed LIFT approach include: Lifelong learning for all to ensure everybody has the opportunity to acquire and upgrade the skills needed to thrive in a digital world; Intangibles finance for the knowledge economy to allow more firms, especially small ones, to increase intangible investment and seize the opportunities offered by the digital transformation; Framework market conditions for the digital age to upgrade policies to the digital age, especially in the areas of taxation, competition law and enforcement, digital security, firms’ entry and exit, and e-government; Technology access via digital infrastructure to facilitate access to communication networks and accelerate the take up of digital technologies and their international diffusion.

Online platform use has grown remarkably in the last decade. Despite this, our understanding of its implications for economic outcomes is scarce and often limited to case studies and advanced countries. Using a newly built harmonised international dataset of online platforms and their use across 43 countries, covering the 2013-18 period and seven areas of activity, we contribute to filling this gap. Specifically, we investigate whether and under which market conditions platform uptake leads to changes in incumbent firms’ productivity. We find that platform use increases labour productivity growth in firms operating in the same sector, and that this takes place through increases in value added growth as opposed to decreases in employment. What is more, productivity gains are greater for small firms and firms in the middle of the productivity distribution, suggesting that online platforms can play an important role in levelling the playing field between SMEs and large companies and in narrowing productivity gaps among firms. Finally, productivity gains are stronger in more dynamic platform markets. Our findings offer insights on factors and policies that can be leveraged to encourage platform development in ways that are beneficial for the economy.

Despite the rising importance and economy-wide effects of online platforms, the paucity of cross-country comparable data still hampers understanding of the structural and policy determinants of their diffusion. This study contributes to the understanding of multi-sided online platforms in three main ways. First, we build a harmonised international dataset of online platforms and their use across 43 OECD and G20 countries, covering the 2013-19 period and nine areas of activity. Second, we describe main trends in the use of platforms in the past years, and third, we investigate the structural and policy determinants of online platforms diffusion across countries and over time.

Introduction We investigated the imaging counterpart of two functional domains (ocular motor dysfunction and postural instability) in progressive supranuclear palsy (PSP) patients classified according to the new clinical diagnostic criteria. Methods Forty-eight patients with probable PSP-Richardson's syndrome (PSP-RS), 30 with probable PSP-parkinsonism (PSP-P), 37 with Parkinson's disease (PD), and 38 controls were enrolled. For each functional domain, PSP patients were stratified by two certainty levels: vertical supranuclear gaze palsy (O1) and slowness of vertical saccades (O2) for ocular motor dysfunction; early unprovoked falls and tendency to fall on the pull-test for postural instability. Voxel-based morphometry (VBM), whole-brain fractional anisotropy (FA) and MR planimetric measurements were analysed and compared across patient groups. Results O1 was present in 64%, and O2 in 36% of all PSP patients. All PSP-RS patients showed early unprovoked falls. TBSS whole-brain analysis revealed that superior cerebellar peduncles (SCPs) were the only structures with significantly lower FA values in PSP-RS compared with PSP-P patients. PSP/O1 patients had lower FA values in midbrain than PSP/O2 patients. By contrast, VBM revealed no differences in grey matter volume between PSP patient groups. MR Planimetric measurements confirmed atrophy of midbrain and SCPs, in line with DTI findings. Conclusions Our study demonstrates that SCPs were significantly more damaged in patients with PSP-RS in comparison with PSP-P patients, thus suggesting the role of SCPs in developing postural instability. Midbrain damage was less severe in O2 than in O1 patients, suggesting that the degree of vertical ocular dysfunction reflects the severity of midbrain atrophy.

The present pilot study was undertaken to investigate the impaired acquired color vision on Calabrian male sample showing this parameter as a biological marker in type 2 diabetes. All patients and controls underwent three pseudo-isochromatic clinical test batteries: Ishihara test, Farnsworth test, and City University test. The results show a specific loss of short-wavelength (blue sensitivity) and typical tritan responses in diabetic patients. Generally, in later stages of the disease, the red-green mechanisms are involved. By the impaired color vision study in diabetic patients, we can confirm the impaired retina-brain cortex pathway. We believe that the above not invasive test analysis can support the other instrumental and imaging analysis to study the impaired retina-brain cortex pathway. Moreover, we think that the present clinical method can be useful in terms of preventive medicine.

Background No prospective study of patients with Parkinson's disease (PD) has investigated the appearance of vertical gaze abnormalities, a feature suggestive of progressive supranuclear palsy (PSP). Objective To identify, within a cohort of patients with an initial diagnosis of PD, those who developed vertical gaze abnormalities during a 4-year follow-up, and to investigate the performance of new imaging biomarkers in predicting vertical gaze abnormalities. Methods A total of 110 patients initially classified as PD and 74 controls were enrolled. All patients underwent clinical assessment at baseline and every year up to the end of the follow-up. The pons/midbrain area ratio 2.0 and the Magnetic Resonance Parkinsonism Index 2.0 were calculated. Results After 4-year follow-up, 100 of 110 patients maintained the diagnosis of PD, whereas 10 PD patients (9.1%) developed vertical gaze abnormalities, suggesting an alternative diagnosis of PSP-parkinsonism. At baseline, the Magnetic Resonance Parkinsonism Index 2.0 was the most accurate biomarker in differentiating PD patients who developed vertical gaze abnormalities from those who maintained an initial diagnosis of PD. At the end of follow-up, both of these biomarkers accurately distinguished PSP-parkinsonism from PD. Conclusions Our results demonstrate that a number of patients with an initial diagnosis of PD developed vertical gaze abnormalities during a 4-year follow-up, and the diagnosis was changed from PD to PSP-parkinsonism. In PD patients, baseline Magnetic Resonance Parkinsonism Index 2.0 showed the best performance in predicting the clinical evolution toward a PSP-parkinsonism phenotype, enabling PSP-parkinsonism patients to be identified at the earliest stage of the disease for promising disease-modifying therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

et al., Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations., Research reported in this publication was supported in part by an ISMMS seed fund to E.G. and a Dean’s office grant to E.G. and I.M. We gratefully acknowledge use of the services and facilities of the Tisch Cancer Institute supported by the National Cancer Institute (NCI) Cancer Center Support grant (no. P30 CA196521), in particular the Hess sequencing core and the BiNGS shared facility. M.S. was supported by an NCI training grant (no. T32CA078207). J.S.Y.H. is supported by the Charles H. Revson Foundation. We acknowledge the technical contribution of D.A. Sánchez, J. Baranda, S. Baztan-Morales, M. Castillo de la Osa, A. Comins-Boo, C. del Álamo Mayo, S. Gil-Manso, B. Gonzalez, S. Hatem, J. Irure-Ventura, I. Miguens, S. Muñoz Martinez, M. Pereira, C. Rodrigues-Guerreiro, M. Rodriguez-Garcia, M.P. Rojo-Portolés and D. San Segundo. We also acknowledge Beckman Coulter for donating the equipment required for the determination of spike-specific IgG antibodies. W.M. was supported by grant no. NCI K00CA212474. This work was supported by ISMMS seed fund to J.O.; Instituto de Salud Carlos III, grant no. COV20-00668 to R.C.R.; Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 Research Call grant no. COV20/00181) cofinanced by European Development Regional Fund ‘A way to achieve Europe’ to E.P.-A.; Instituto de Salud Carlos III, Spain (grant no. COV20/00170); Government of Cantabria, Spain (grant no. 2020UIC22-PUB-0019) to M.L.H.; Instituto de Salud Carlos III (grant no. PI16CIII/00012) to P.P.; Fondo Social Europeo e Iniciativa de Empleo Juvenil YEI (grant no. PEJ2018-004557-A) to M.P.E. and grant no. REDInREN 016/009/009 ISCIII. This project has received funding from the European Union’s Horizon 2020 research and innovation program VACCELERATE under grant agreement no. 101037867 to J.O. S.G. is supported by grant nos. U24CA224319, U01DK124165 and P30 CA196521.

Recently, the LRP10 gene has been associated with Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). The aim of the present study was to evaluate the presence of mutations of the LRP10 gene in patients with PD or DLB from Southern Italy. Sequencing analysis revealed only 2 missense and 3 synonymous variants in patients and control subjects and a rare variant p.L622F in a PD case. These results suggest that LRP10 mutations are not a frequent cause of PD and DLB in Southern Italy.

This study investigates empirically how managerial practices have affected macroeconomic adjustment during the Great Recession after the 2008 economic crisis. We start by constructing a country*industry balanced panel data over the 2007-2015 period for eighteen industries in ten OECD countries, and complementing it by two indicators: an indicator of management quality at the country level based on the managerial practices categorical scores at firm level from Bloom et al. (2012); and an indicator at the industry level for the shocks stemming from the 2008 economic crisis. We then rely on the local projection method pioneered by Jorda (2005) to estimate the direct impacts of country management quality indicators and industry economic shocks as well as their joint impacts, on five variables of interest: value-added, employment, labor productivity, wage per employee and labor share during the Great Recession. We find that, in countries where management quality is higher, production and employment are more resilient during the Great Recession, with less production losses and employment damages, no effects on productivity, wage moderation and a slight increase in the labor shares. It appears, moreover, that this resilience is increasing with the size of industry shocks.

This paper assesses the possible dynamic effects of occupational entry regulations (OER) on productivity. It combines firm-level productivity data with a new cross-country policy indicator measuring the stringency of OER by the presence of administrative burdens, qualifications requirements, and mobility restrictions, for five professional and ten personal services. The evidence suggests that bold reforms easing OER, especially those concerning qualification requirements, could help increase the contribution of personal and professional services to aggregate productivity growth via two channels: the acceleration of their catch up to best global practices (within-firm channel), where firms in regulated sectors could gain up to 2.5 percentage points of productivity on average; and a higher contribution of labour reallocation to firms’ employment growth (between-firm channel), which could increase by up to 10 percent for the most productive firms.

COQ2 encodes para-hydroxybenzoate-polyprenyl transferase and, recently, mutations in this gene have been associated with the increase of the risk of multiple system atrophy (MSA) in Japanese cases. Subsequently, studies in Asian patients confirmed the role of COQ2 in the development of MSA, while other analysis failed to replicate these results in Caucasian population. We performed genetics screening of COQ2 in 100 MSA Italian patients. We did not find any pathogenic mutations; our results suggest that COQ2 is not a genetic risk factor for MSA in Italian population.

Introduction There is growing evidence that a proportion of patients with Essential Tremor (ET) may develop a memory impairment over time. However, no studies have evaluated whether hippocampal damage really occur in ET. This study investigated the macro and micro-structural integrity of the hippocampus in ET subjects using a multimodal MRI approach. Methods Neuropsychological and MRI data were acquired from 110 participants (60 patients with ET and 50 age-, sex-, and education-matched healthy controls [HC]). Whole-brain T1-weighted and Diffusion Tensor Imaging (DTI) were performed to assess macro-and microstructural alterations. MRI parameters (volume; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi were obtained. In order to evaluate the relationship between MRI alterations and neurocognitive impairment, hippocampal parameters were also correlated with cognitive test scores. Results Compared to controls, ET patients showed a subclinical memory impairment with significantly lower memory scores, but within the normal ranges. Despite the subclinical damage, however, ET patients showed a significant increase in MD values in the bilateral hippocampi in comparison with HC. A significant correlation was also found between MD and memory scores in ET. Conclusion This study improves the knowledge on memory impairment in ET, as our results demonstrate for the first time the hippocampal microstructural damage related to subclinical memory impairment in ET patients. Further studies are needed before these findings can be considered predictive of a distinct ET subtype or suggestive of a co-occurent dementia.

This paper presents a range of policies to enhance adoption of digital technologies and firm productivity. It quantifies illustratively the effect of policy changes by combining the results of two recent OECD analyses on the drivers of adoption and their productivity benefits. Increasing access to high-speed internet, upgrading technical and managerial skills and implementing product and labour market reforms to facilitate the reallocation of resources in the economy are found to be the main factors supporting the efficient adoption of a selection of digital technologies. The most productive firms have benefitted relatively more from digitalisation in the past, contributing to a widening productivity gap with less productive firms. Policies should create the conditions for efficient adoption by less productive firms, which would help them to catch up, achieving a double dividend in terms of growth and inclusiveness. Enhancing skills has a key role to play in this area since less productive firms suffer relatively more from skill shortages.

Objective Several evidences demonstrated the role of white matter (WM) lesions in the pathogenesis of Vascular Parkinsonism (VP), a clinical entity characterized by parkinsonism, postural instability, marked gait difficulty and poor response to levodopa. However, the involvement of normal appearing white matter (NAWM) in VP still remains unknown. This study aimed to investigate the microstructural integrity of NAWM in VP compared to Parkinson's disease (PD) and controls using neuroimaging approach. Methods Magnetic resonance imaging data were acquired from 50 participants (15 VP, 20 PD and 15 controls). Diffusion tensor imaging (DTI) and Tract-based spatial statistics (TBSS) were performed to assess microstructural NAWM changes. In order to evaluate the relationship between specific fiber tract involvement and clinical picture, diffusion alterations were correlated with clinical features. Results Compared to PD patients and controls, significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in NAWM of corpus callosum, internal and external capsule, and corona radiata were present in VP. By contrast, DTI metrics were normal in NAWM-PD and controls. A significant correlation was found between FA and MD of anterior third of corpus callosum and clinical variables (postural instability, freezing-of-gait and symmetry of parkinsonism). Conclusions This study improves the knowledge on WM pathology in VP, as our results demonstrate that NAWM damage occurs in VP, but not in PD nor in controls. NAWM damage might relate to clinical picture and suggest that non-clearly-visible WM alterations may contribute to the physiopathology of this vascular disease.

According to embodied cognition, processing language with motor content involves a simulation of this content by the brain motor system. Patients with brain lesions involving the motor system are characterized by deficits in action verbs processing in the absence of dementia. We sought to assess whether action verbs interfere with the motor behavior of patients with Parkinson's disease (PD) having tremor dominant symptoms. PD tremor is considered to result from dysfunction of cortical-subcortical motor circuits driven by dopamine depletion. In addition, PD tremor is reduced during active movement execution. Therefore, likewise movement execution, the motor simulation of bodily actions predicted by the embodiment may show to be effective in modifying tremor by interfering with a dysfunctional motor system. Here, we asked to simply read and repeat words expressing a hand-related bodily action. Abstract verbs served as control. Changes in tremor kinematics were evaluated using a monoaxial accelerometer. Seventeen PD patients with rest tremor of the upper limbs were enrolled. Tremor amplitude was significantly smaller when reading action verbs as compared to abstract verbs. We provide empirical evidence supporting the embodied cognition theory by showing that circuits mediating tremor of PD patients are distinctively affected by processing action language.

BACKGROUND: No prospective study of patients with Parkinson's disease (PD) has investigated the appearance of vertical gaze abnormalities, a feature suggestive of progressive supranuclear palsy (PSP). OBJECTIVE: To identify, within a cohort of patients with an initial diagnosis of PD, those who developed vertical gaze abnormalities during a 4-year follow-up, and to investigate the performance of new imaging biomarkers in predicting vertical gaze abnormalities. METHODS: A total of 110 patients initially classified as PD and 74 controls were enrolled. All patients underwent clinical assessment at baseline and every year up to the end of the follow-up. The pons/midbrain area ratio 2.0 and the Magnetic Resonance Parkinsonism Index 2.0 were calculated. RESULTS: After 4-year follow-up, 100 of 110 patients maintained the diagnosis of PD, whereas 10 PD patients (9.1%) developed vertical gaze abnormalities, suggesting an alternative diagnosis of PSP-parkinsonism. At baseline, the Magnetic Resonance Parkinsonism Index 2.0 was the most accurate biomarker in differentiating PD patients who developed vertical gaze abnormalities from those who maintained an initial diagnosis of PD. At the end of follow-up, both of these biomarkers accurately distinguished PSP-parkinsonism from PD. CONCLUSIONS: Our results demonstrate that a number of patients with an initial diagnosis of PD developed vertical gaze abnormalities during a 4-year follow-up, and the diagnosis was changed from PD to PSP-parkinsonism. In PD patients, baseline Magnetic Resonance Parkinsonism Index 2.0 showed the best performance in predicting the clinical evolution toward a PSP-parkinsonism phenotype, enabling PSP-parkinsonism patients to be identified at the earliest stage of the disease for promising disease-modifying therapies.

Objective Essential Tremor with resting tremor (rET) is a debated and poorly understood clinical phenotype. Converging evidences show that neurodegeneration of the cerebellum underlies the pathophysiology of ET, but it is not known if cerebellar changes also occurs in patients with rET. The aim of our study was to evaluate cerebellar microstructure in patients with ET with- (rET) and without resting tremor (ETwr) in comparison to healthy controls by MR Diffusion Tensor Imaging (DTI). Methods We studied 67 patients with ET (rET: 29 and ETwr: 38) and 39 age-matched healthy controls (HC). DTI was performed to measure fractional anisotropy (FA) and mean diffusivity (MD) of white and grey matter (WM, GM) in the entire cerebellum and in right and left cerebellar hemispheres. Results MD was significantly higher in the cerebellar GM of ET total group (10.39 ± 0.87) in comparison with HC (9.90 ± 0.71) (p = 0.0027). Interestingly, MD was significantly different when ETwr (10.48 ± 0.77) were compared with HC (p = 0.0017), whereas a trend toward significance were found between rET (10.29 ± 0.99) and HC (p = 0.067). No differences among groups were found in MD of cerebellar WM and in FA values neither in the WM nor in the GM. Conclusion Our results demonstrate the presence of microstructural changes in the cerebellum of patients with ET. It is noteworthy that rET showed intermediate values compared to HC and ETwr, suggesting that rET shares part of the pathophysiological mechanisms of ETwr, but cerebellar involvement seems do not fully account for rET. In addition to the cerebellar loops, other networks may play a role in rET pathophysiology.

It is unclear whether patients with different clinical phenotypes of Parkinson's disease (PD) differ in their risk of developing levodopa-induced dyskinesia. We evaluated the possible association between clinical phenotypes and risk of levodopa-induced dyskinesia in PD patients using a case-control design. The FRAGAMP study is a large Italian multicenter study. Patients affected by PD diagnosed according to the Gelb's criteria were enrolled and underwent a face-to-face interview. Clinical scales were used to evaluate motor and cognitive impairment. Presence of dyskinesia was assessed by the item 32 of the UPDRS section IV. On the basis of the most prominent motor symptoms at onset PD, patients were classified as tremor-dominant, akinetic-rigid, or mixed type. 485 PD patients (292 men; mean age 65.6 ± 9.8) were enrolled in the study of whom 128 (26.4 %) presented levodopa-induced dyskinesia. Of the 485 patients, 311 (64.1 %) were classified as tremor-dominant, 104 (21.4 %) as Akinetic-Rigid and 70 (14.4 %) as mixed type. Multivariate logistic regression analysis showed a significant negative association between tremor-dominant phenotype and levodopa-induced dyskinesia (adjusted OR 0.48; 95 % CI 0.23-1.00; p value 0.05). When analysis was stratified by age at onset a stronger negative association was found among the late onset (>50 years) PD patients (OR 0.28; 95 % CI 0.11-0.70; p value 0.007) while no association was found among patients with an early onset. Our findings support the hypothesis that the occurrence of resting tremor as an initial manifestation of PD may predict a lower probability of developing levodopa-induced dyskinesia.

DCTN1 encodes the largest subunit of dynactin complex essential in the retrograde axonal transport and cytoplasmic transport of vesicles; mutations in DCTN1 have been reported predominantly in individuals with Perry syndrome and, recently, in patients with progressive supranuclear palsy. Our genetic screening of DCTN1 in 79 patients with progressive supranuclear palsy, 100 patients with multiple system atrophy, and 28 patients with dementia with Lewy bodies from Italy revealed only synonymous and intronic variants, suggesting that DCTN1 mutations do not have a key role in the development of atypical parkinsonism in the Italian population.

Insufficient diffusion of new technologies has been quoted as one possible reason for weak productivity performance over the past two decades (Andrews et al., 2016). This paper uses a novel data set of digital technology usage covering 25 industries in 25 European countries over the 2010-16 period to explore the drivers of digital adoption across two broad sets of digital technologies by firms, cloud computing and back or front office integration. The focus is on structural and policy factors affecting firms’ capabilities and incentives to adopt -- including the availability of enabling infrastructures (such as high-speed broadband internet), managerial quality and workers skills, and product, labour and financial market settings. We identify the effects of structural and policy factors based on the difference-in-difference approach pioneered by Rajan and Zingales (1998) and show that a number of these factors are statistically and economically significant for technology adoption. Specifically, we find strong support for the hypothesis that low managerial quality, lack of ICT skills and poor matching of workers to jobs curb digital technology adoption and hence the rate of diffusion. Similarly our evidence suggests that policies affecting market incentives are important for adoption, especially those relevant for market access, competition and efficient reallocation of labour and capital. Finally, we show that there are important complementarities between the two sets of factors, with market incentives reinforcing the positive effects of enhancements in firm capabilities on adoption of digital technologies

Insufficient diffusion of new technologies has been quoted as one possible reason for weak productivity performance over the past two decades (Andrews et al., 2016). This paper uses a novel data set of digital technology usage covering 25 industries in 25 European countries over the 2010-16 period to explore the drivers of digital adoption across two broad sets of digital technologies by firms, cloud computing and back or front office integration. The focus is on structural and policy factors affecting firms’ capabilities and incentives to adopt -- including the availability of enabling infrastructures (such as high-speed broadband internet), managerial quality and workers skills, and product, labour and financial market settings. We identify the effects of structural and policy factors based on the difference-in-difference approach pioneered by Rajan and Zingales (1998) and show that a number of these factors are statistically and economically significant for technology adoption. Specifically, we find strong support for the hypothesis that low managerial quality, lack of ICT skills and poor matching of workers to jobs curb digital technology adoption and hence the rate of diffusion. Similarly our evidence suggests that policies affecting market incentives are important for adoption, especially those relevant for market access, competition and efficient reallocation of labour and capital. Finally, we show that there are important complementarities between the two sets of factors, with market incentives reinforcing the positive effects of enhancements in firm capabilities on adoption of digital technologies

Introduction The aim of our study was to investigate the effect of apomorphine and placebo on resting tremor in tremor-dominant Parkinson's disease (tPD) patients. Methods Fifteen tPD patients were enrolled. Each patient underwent two treatments on two consecutive days: on day one the patients received a subcutaneous injection of placebo, while on day two they received apomorphine. On each day, the patients underwent three electrophysiological recording sessions: T0, T1, and T2: before, 30 min, and 60 min after the treatment respectively. Electrophysiological changes in tremor amplitude were evaluated using a triaxial accelerometer. Results Placebo was effective in improving resting tremor in all tPD patients (p = 0.009) at T1, but not at T2. Eight out of 15 tPD patients (53.3%) responded to placebo with an at least 70% reduction in tremor amplitude compared to the basal condition (responders). By contrast, seven out of 15 tPD patients (46.7%) did not show any variation in tremor amplitude after placebo administration (non-responders). Apomorphine induced a marked reduction in tremor amplitude at 30 min and 60 min in all investigated tPD patients. Of note, the decrease in tremor amplitude in placebo responders was similar to that achieved with dopaminergic stimulation induced by apomorphine. Conclusions Our study demonstrates that placebo was very effective in reducing resting tremor in about half of patients with tPD. The decrease in tremor amplitude in placebo responders was similar to that induced by apomorphine. The cerebral mechanisms underlying the placebo effect on resting tremor need further investigations.

Introduction Differentiating clinically progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) may be challenging, especially in the absence of vertical supranuclear gaze palsy (VSGP). The Magnetic Resonance Parkinsonism Index (MRPI) has been reported to accurately distinguish between PSP and PD, yet few data exist on the usefulness of this biomarker for the differentiation of PSP-P from PD. Methods Thirty-four patients with PSP-P, 46 with PSP-Richardson's syndrome (PSP-RS), 53 with PD, and 53 controls were enrolled. New consensus criteria for the clinical diagnosis of PSP were used as the reference standard. The MRPI, and a new index termed MRPI 2.0 including the measurement of the third ventricle width (MRPI multiplied by third ventricle width/frontal horns width ratio), were calculated on T1-weighted MR images. Results The MRPI differentiated patients with PSP-P from those with PD with sensitivity and specificity of 73.5% and 98.1%, respectively, while the MRPI 2.0 showed higher sensitivity (100%) and similar specificity (94.3%) in differentiating between these two groups. Both biomarkers showed excellent performance in differentiating PSP-P patients with VSGP from those with PD, but the MRPI 2.0 was much more accurate (95.8%) than MRPI in differentiating PSP-P patients with slowness of vertical saccades from PD patients. Conclusion The MRPI 2.0 accurately differentiated PSP-P patients from those with PD. This new index was more powerful than MRPI in differentiating PSP patients in the early stage of the disease with slowness of vertical saccades from patients with PD, thus helping clinicians to consolidate the diagnosis based on clinical features, in vivo.

Background Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the most common neurodegenerative form of parkinsonism. Recently, a pathogenic mutation (p.N855S) in DNAJC13 was linked to autosomal dominant Lewy body PD in a Dutch–German–Russian Mennonite multi-incident kindred, and was found in five additional patients. In this study, we performed a comprehensive screening of the DNAJC13 gene in familial PD and sporadic PD to assess the frequency of known and novel rare nonsynonymous variants. Methods We screened 563 sporadic and 168 familial PD patients and a control series (n = 1000) for the coding region of DNAJC13. Results Our sequencing analysis identified two carriers of the c.2708G > A (p.R903K) variant in exon 24 of DNAJC13. One of these carriers is a familial PD. Conclusion The p. R903K variant was not found in 1000 healthy controls and it is localized in a functional domain of the DNAJC13 protein. Further studies are necessary to evaluate the role of DNAJC13 variants in PD.

This paper identifies and analyses some key challenges that OECD and partner economies may face over the coming 50 years if underlying global trends relating to growth, trade, inequality and environmental pressures prevail. For example, global growth is likely to slow and become increasingly dependent on knowledge and technology, while the economic costs of environmental damages will mount. The rising economic importance of knowledge will tend to raise returns to skills, likely leading to further increases in earning inequalities within countries. While increases in pre-tax earnings do not automatically transform into rising income inequality, the ability of governments to cushion this impact may be limited, as rising trade integration and consequent rising mobility of tax bases combined with substantial fiscal pressures may hamper such efforts. The paper discusses to what extent national structural policies can address these and other interlinked challenges, but also points to the growing need for international coordination and cooperation to deal with these issues over the coming 50 years.

Alzheimer’s disease (AD) and Parkinson’s disease with dementia (PDD) are characterized by a different mnesic failure, particularly in memory cued recall. Although hippocampal involvement has been shown in both these diseases, it remains unknown whether a selective damage of specific subfields within the hippocampus may be responsible for the peculiar mnesic profile observed in AD and PDD. To explore this topic, we combined a multimodal 3 T-MRI hippocampal evaluation (whole-brain T1-weighted and diffusion tensor imaging) with a hippocampal-targeted neuropsychological assessment (Free and Cued Selective Reminding Test [FCSRT]) in 22 AD subjects, 18 PDD and 17 healthy controls. Macro- and microstructural features (volume; shape; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi (whole and subfields) were obtained. Correlations between MRI-derived parameters and neuropsychological evaluations were performed. In the comparison between AD and PDD, the multimodal analysis allowed us to identify that subiculum, CA1 and CA4-DG were differently involved in these diseases and correlated with immediate and delayed total recall items of FCSRT. Moreover, compared to controls, AD showed a reduction in almost all subfields, with a MD increase in the same regions, whereas PDD displayed a volume loss, less severe than AD, more evident in the CA2-3 and presubiculum subfields. Our study provides new evidence that hippocampal subregions had different vulnerability to damage related to AD and PDD. The combination of the in vivo analysis of hippocampal subfields with the FCSRT paradigm provided important insights into whether changes within specific hippocampal subfields are related to the different mnesic profile in AD and PDD patients.

To assess the type and degree of both red–green and blue–yellow color vision deficiencies of Calabrian males affected by multiple sclerosis. Eighty Calabrian male patients were enrolled (age range 18–70 years; mean age 40.6 ± 12.4 years) showing a disease duration mean of 10.6 ± 8.2 years (range = 0.5–46 years) coming from the Institute of Neurology, Magna Graecia University, Catanzaro. Optic neuritis present in the medical histories of the 21 patients does not influence color vision. Excluding seven colorblind subjects and one affected by a bilateral maculopathy, the analyzed sample group was 72. Seventy controls were matched for age and sex. An ophthalmologist examined all patients and controls in order to rule out diabetic retinopathy, cataracts, senile maculopathy, or ocular fundus’ anomalies. The Ishihara test identified the colorblind patients. The City University Test screened for people with abnormal color vision by grading the severity of color vision deficiency. The second part of the City University Test as well as the Farnsworth Test confirmed both the color vision deficiency type and degree. Fifty-one percentage (37/72) of the patients showing a color vision deficiency were subdivided into two subgroups: subgroup one showed red–green deficiency (57%, 21/37); subgroup two showed a coupled red–green and blue–yellow deficiency (43%, 16/37). Furthermore, we found two distinct curves showing a groove within the first 10 years of the disease. Both monocular and binocular analyses allowed us to identify the patients showing the monocular color vision deficiency, but they were well compensated by binocular vision. We think that the majority of the patients with the red–green deficiency will develop the coupled red–green and blue–yellow deficiency in the latter years of multiple sclerosis.

Background: Using Diffusion Tensor Imaging (DTI), we tested the hypothesis that cerebellar abnormalities in fractional anisotropy (FA) may be involved in cognitive dysfunctions in Relapsing-Remitting (RR)-Multiple Sclerosis (MS). Objective: The aim of our study was to investigate the microstructural integrity in MS of regions that connect in both feedforward and feedback pathways to cortical areas, i.e., Superior Cerebellar Peduncles (SCP), Middle Cerebellar Peduncles (MCP), Dentate nuclei (DN) and Thalamus (Th). Patients and methods: We studied 46 patients with RR-MS (21 with cerebellar signs and 25 without) and 23 normal subjects. All subjects underwent cognitive testing. Results: In patients with a cerebellar phenotype, cognitive performance in all considered domains was from moderately to strongly related (p

We evaluated the possible association between head trauma and Parkinson's disease (PD). The FRAGAMP (Fattori di Rischio Ambientali e Genetici Associati alla Malattia di Parkinson) study is a large Italian multicenter case-control study carried out to evaluate the possible role of environmental and genetic factors in PD. Cases and controls were enrolled from six movement disorders centers located in the Central-Southern Italy. A standardized questionnaire was administered to record demographic, epidemiological, and clinical data. Positive history of head trauma was considered only if the head trauma preceded the onset of PD. All cases and controls underwent a standard neurological examination. Adjusted ORs and 95% CI were estimated using multivariate analysis (logistic regression). Four hundred ninety-two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. A positive history for head trauma was reported by 106 (21.5%) PD patients and by 62 (13.5%) healthy controls. Multivariate analysis (OR adjusted by age, sex, family history, coffee smoking, and alcohol consumption) showed a significant positive association between PD and head trauma with an adjusted OR of 1.50 (95%CI 1.04-2.17; p value 0.03). In agreement with literature data, our study supports the positive association between head trauma and PD.

Objective: To identify a biomarker for predicting the appearance of vertical supranuclear gaze palsy (VSGP) in patients affected by progressive supranuclear palsy–parkinsonism (PSP-P). Methods: Twenty-four patients with PSP-P were enrolled in the current study. Patients were clinically followed up every 6 months until the appearance of VSGP or the end of the follow-up (4 years). Participants underwent MRI at baseline and at the end of follow-up. Magnetic resonance parkinsonism index (MRPI), an imaging measure useful for diagnosing PSP, was calculated. Results: Twenty-one patients with PSP-P completed follow-up, and 3 patients dropped out. Eleven of 21 patients with PSP-P developed VSGP after a mean follow-up period of 28.5 months (range 6–48 months), while the remaining 10 patients with PSP-P did not develop VSGP during the 4-year follow-up period. At baseline, patients with PSP-P who later developed VSGP had MRPI values significantly higher than those of patients not developing VSGP without overlapping values between the 2 groups. MRPI showed a higher accuracy (100%) in predicting VSGP than vertical ocular slowness (accuracy 33.3%) or postural instability with or without vertical ocular slowness (accuracy 71.4% and 42.9%, respectively). Conclusions: Our study demonstrates that MRPI accurately predicted, on an individual basis, the appearance of VSGP in patients with PSP-P, thus confirming clinical diagnosis in vivo.

BACKGROUND AND PURPOSE: The superior cerebellar peduncle is damaged in progressive supranuclear palsy. However, alterations differ between progressive supranuclear palsy with Richardson syndrome and progressive supranuclear palsy-parkinsonism. In this study, we propose an automated tool for superior cerebellar peduncle integrity assessment and test its performance in patients with progressive supranuclear palsy with Richardson syndrome, progressive supranuclear palsy-parkinsonism, Parkinson disease, and healthy controls. MATERIALS AND METHODS: Structural and diffusion MRI was performed in 21 patients with progressive supranuclear palsy with Richardson syndrome, 9 with progressive supranuclear palsy-parkinsonism, 20 with Parkinson disease, and 30 healthy subjects. In a fully automated pipeline, the left and right superior cerebellar peduncles were first identified on MR imaging by using a tractography-based atlas of white matter tracts; subsequently, volume, mean diffusivity, and fractional anisotropy were extracted from superior cerebellar peduncles. These measures were compared across groups, and their discriminative power in differentiating patients was evaluated in a linear discriminant analysis. RESULTS: Compared with those with Parkinson disease and controls, patients with progressive supranuclear palsy with Richardson syndrome showed alterations of all superior cerebellar peduncle metrics (decreased volume and fractional anisotropy, increased mean diffusivity). Patients with progressive supranuclear palsy-parkinsonism had smaller volumes than those with Parkinson disease and controls and lower fractional anisotropy than those with Parkinson disease. Patients with progressive supranuclear palsy with Richardson syndrome had significantly altered fractional anisotropy and mean diffusivity in the left superior cerebellar peduncle compared with those with progressive supranuclear palsy-parkinsonism. Discriminant analysis with the sole use of significant variables separated progressive supranuclear palsy-parkinsonism from progressive supranuclear palsy with Richardson syndrome with 70% accuracy and progressive supranuclear palsy-parkinsonism from Parkinson disease with 74% accuracy. CONCLUSIONS: We demonstrate the feasibility of an automated approach for extracting multimodal MR imaging metrics from the superior cerebellar peduncle in healthy subjects and patients with parkinsonian. We provide evidence that structural and diffusion measures of the superior cerebellar peduncle might be valuable for computer-aided diagnosis of progressive supranuclear palsy subtypes and for differentiating patients with progressive supranuclear palsy-parkinsonism from with those with Parkinson disease.