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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. 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%, 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

Current practice for seismic risk assessment typically considers that structural damage can only occur in a single seismic event. However, neglecting that earthquakes occur in clusters, both in space and in time, can lead to an underestimation of both seismic hazard and structural vulnerability. Indeed, past research has shown that neglecting aftershocks (seismic events following the mainshock in a sequence), can lead to non-negligible differences in the assessment of seismic hazard. From the point of view of structural vulnerability, the necessity of considering the effects of seismic sequences has also been highlighted by recent seismic events, such as the seismic sequences in Christchurch (2010-2011), in Emilia-Romagna (2012) and in central Italy (2016-2017), to name a few. These events showed that at least part of the seismic damage documented on the building heritage was due to the cumulative effect of multiple shocks clustered closely in time. Therefore, this thesis focuses on two components of seismic risk, i.e., the seismic hazard and structural vulnerability, and on how to treat them in order to account for sequence effects. In the context of seismic hazard, the thesis applies the Sequence-Based Probabilistic Seismic Hazard Analysis procedure to the United Kingdom. This part has been developed in collaboration with the firm Ove Arup and Partners London with the objectives of developing national hazard maps taking into account the effects of seismic sequences and investigating the effects of aftershocks in the assessment of seismic hazard. At the same time, regarding seismic vulnerability, the thesis addresses various issues in the estimation of state-dependent fragility curves, which are fragility models that allow for the possibility that a structure may have already been damaged by previous shocks. Initially, the assessment of state-dependent fragilities is addressed using back-to-back incremental dynamic analysis applied to individual structures belongin

Transarterial chemoembolization (TACE) in patients with hepatocellular cancer (HCC) on the waiting list for liver transplantation may be associated with an increased risk for hepatic artery complications. The present study aims to assess the risk for, primarily, intraoperative technical hepatic artery problems and, secondarily, postoperative hepatic artery complications encountered in patients who received TACE before liver transplantation. Available data from HCC liver transplantation recipients across six European centres from January 2007 to December 2018 were analysed in a 1 : 1 propensity score-matched cohort (TACE versus no TACE). Incidences of intraoperative hepatic artery interventions and postoperative hepatic artery complications were compared. Data on postoperative hepatic artery complications were available in all 876 patients (425 patients with TACE and 451 patients without TACE). Fifty-eight (6.6 per cent) patients experienced postoperative hepatic artery complications. In total 253 patients who had undergone TACE could be matched to controls. In the matched cohort TACE was not associated with a composite of hepatic artery complications (OR 1.73, 95 per cent c.i. 0.82 to 3.63, P = 0.149). Data on intraoperative hepatic artery interventions were available in 825 patients (422 patients with TACE and 403 without TACE). Intraoperative hepatic artery interventions were necessary in 69 (8.4 per cent) patients. In the matched cohort TACE was not associated with an increased incidence of intraoperative hepatic artery interventions (OR 0.94, 95 per cent c.i. 0.49 to 1.83, P = 0.870). In otherwise matched patients with HCC intended for liver transplantation, TACE treatment before transplantation was not associated with higher risk of technical vascular issues or hepatic artery complications.

The role of pathological findings after locoregional treatments as predictors of hepatocellular cancer recurrence after liver transplantation has been poorly addressed. The aim of the study was to identify the role of remnant vital tissue (RVT) of the target lesion in predicting hepatocellular cancer recurrence. Two hundred and seventy-six patients firstly undergoing locoregional treatment and then transplanted between January 2010 and December 2015 in four European Transplant Centres (i.e. Rome Tor Vergata, Birmingham, Brussels and Ancona) were enrolled in the study to investigate the role of pathological response at upfront locoregional treatment. At multivariable Cox regression analysis, RVT ≥2 cm was a strong independent risk factor for post-LT recurrence (HR = 5.6; P < 0.0001). Five-year disease-free survival rates were 60.8%, 80.9% and 95.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. When only Milan Criteria-IN patients were analysed, similar results were reported, with 5-year disease-free survival rates of 58.1%, 79.0% and 94.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. RVT is an important determinant of tumour recurrence after liver transplantation performed for hepatocellular cancer. Its discriminative power looks to be evident also in a Milan-IN setting, suggesting to more liberally use locoregional treatments also in these patients.

Vaccines recommendations are available for both healthcare professionals and the general public, but although the vaccination is the most effective method to prevent infectious diseases, the coverage is still behind the recommended rate. In Italy, according to a recent study, the anti-flu vaccination rate among healthcare worker range between 9% to 30%. The aim of our study was to identify knowledge, attitude and behaviours regarding influenza vaccination among community pharmacists in order to increase the coverage rate among healthcare professional. “PErCEIVE (Pharmacist pERCEption on Influenza VaccinE) in Umbria” was a cross sectional survey among community pharmacists in Umbria conducted between 16th November 2015 to 29th February 2016. The questionnaire was anonymous, on-line self-administered survey.Statistical analysis were performed using STATA/SE 12 software. The response rate was 28.91% (n= 72/249). Among the studied population 76.39% (n=55) had never performed influenza vaccine during the previous 5 years. Regarding source of information, only 15.28% of the subjects (n=11) consulted the scientific publications, vs 52.78% (n=38) who did not show any kind of interest upon the influenza vaccine. Our results show a low attitude to be vaccinated among pharmacists together with a low grade of awareness regarding the important role that pharmacists might play in order to reduce influenza burden, to promote health literacy among their patients and to decrease the risk of patients infection. Pharmacists might be crucial healthcare workers involved in health promotion, in vaccines’ uptake and practices progression.

Vaccines recommendations are available for both healthcare professionals and the general public, but although the vaccination is the most effective method to prevent infectious diseases, the coverage is still behind the recommended rate. In Italy, according to a recent study, the anti-flu vaccination rate among healthcare worker range between 9% to 30%. The aim of our study was to identify knowledge, attitude and behaviours regarding influenza vaccination among community pharmacists in order to increase the coverage rate among healthcare professional. “PErCEIVE (Pharmacist pERCEption on Influenza VaccinE) in Umbria” was a cross sectional survey among community pharmacists in Umbria conducted between 16th November 2015 to 29th February 2016. The questionnaire was anonymous, on-line self-administered survey.Statistical analysis were performed using STATA/SE 12 software. The response rate was 28.91% (n= 72/249). Among the studied population 76.39% (n=55) had never performed influenza vaccine during the previous 5 years. Regarding source of information, only 15.28% of the subjects (n=11) consulted the scientific publications, vs 52.78% (n=38) who did not show any kind of interest upon the influenza vaccine. Our results show a low attitude to be vaccinated among pharmacists together with a low grade of awareness regarding the important role that pharmacists might play in order to reduce influenza burden, to promote health literacy among their patients and to decrease the risk of patients infection. Pharmacists might be crucial healthcare workers involved in health promotion, in vaccines’ uptake and practices progression.

In this work we showed that genotype-related patterns of hexosaminidase activity, isoenzyme composition, gene expression and ganglioside metabolism observed during embryonic and postnatal brain development are recapitulated during the progressive stages of neural precursor cell (NPC) differentiation to mature glia and neurons in vitro. Further, by comparing NPCs and their differentiated progeny established from Tay-Sachs (TS) and Sandhoff (SD) animal models with the wild-type counterparts, we studied the events linking the accumulation of undegraded substrates to hexosaminidase activity. We showed that similarly to what observed in brain tissues in TS NPCs and progeny, the stored GM2 was partially converted by sialidase to GA2, which can be then degraded in the lysosomes to its components. The latter can be used in a salvage pathway for the formation of GM3. Interestingly, results obtained from ganglioside feeding assays and from measurement of lysosomal sialidase activity suggest that a similar pathway might work also in the SD model. © 2009 International Society for Neurochemistry.

Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for a

Mesoangioblasts (MABs) are a subset of muscle-derived pericytes able to restore dystrophic phenotype in mice and dogs. However, their lifespan is limited and they undergo senescence after 25-30 population doublings. Recently, induced pluripotent stem cells (iPSCs) generated from reprogrammed fibroblasts have been demonstrated to have in vitro and in vivo myogenic potential when sorted for the SM/C-2.6 antigen. Furthermore, chimeric mice from mdx-iPSCs (DYS-HAC) cells showed tissue-specific expression of dystrophin. Nevertheless, myogenic differentiation protocols and the potential of iPSCs generated from different cell sources still present unanswered questions. Here we show that iPSCs generated from prospectively sorted MABs (MAB-iPSCs) are pluripotent as fibroblast-derived iPSCs (f-iPSCs). However, both teratoma formation and genetic cell manipulation assays identify a durable epigenetic memory in MAB-iPSCs, resulting in stronger myogenic commitment. Striated muscle tissue accounts for up to 70% of MAB-iPSC teratomas. Moreover, transfection with Pax3 and Pax7 induces a more robust myogenic differentiation in MAB-iPSCs than in f-iPSCs. A larger amount of CD56+ progenitors can be sorted from the MAB-iPSCs differentiating pool and, after transplantation into αsg-KO mice, can efficiently participate to skeletal muscle regeneration and restore αsg expression. Our data strongly suggest that iPSCs are a heterogeneous population and, when generated from myogenic adult stem cells, they exhibit a stronger commitment, paving the way for creating custom-made cell protocols for muscular dystrophies. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

View description: The purpose of this study is to investigate in what way the mother tongue language education integrates in a compulsory school activities and also which significance it has to the students who studies mother tongue language. My questions are following: How does the cooperation look like between mother tongue languages teacher, teacher and principal? How do students perceive the mother tongue language education? How does the mother tongue language education take place at the school? Method: This investigation is classified as a qualitative study and consists of theoretical points and empirical material such as interviews and observations. Based on hermeneutic view of tradition which means that I interpret all my material. Results: My results of this study is that the mother tongue language education does not integrate with the other school activities and the mother tongue language teachers does not cooperate with other teachers or principal at this school. The reason for this is mainly because the mother tongue language teachers work situation. I´ve also seen that language has to do with the creation of a personal identity. The students who studies mother tongue language education is generally happy with this type of education but agrees with that they only can use their mother tongue language outside school and at the mother tongue language education. Ann Ludvigsson writes in her thesis about how important it with the cooperation between teachers and how that can be good for the students development (Ludvigsson 2009:19-22).

View description: The purpose of this study is to investigate in what way the mother tongue language education integrates in a compulsory school activities and also which significance it has to the students who studies mother tongue language. My questions are following: How does the cooperation look like between mother tongue languages teacher, teacher and principal? How do students perceive the mother tongue language education? How does the mother tongue language education take place at the school? Method: This investigation is classified as a qualitative study and consists of theoretical points and empirical material such as interviews and observations. Based on hermeneutic view of tradition which means that I interpret all my material. Results: My results of this study is that the mother tongue language education does not integrate with the other school activities and the mother tongue language teachers does not cooperate with other teachers or principal at this school. The reason for this is mainly because the mother tongue language teachers work situation. I´ve also seen that language has to do with the creation of a personal identity. The students who studies mother tongue language education is generally happy with this type of education but agrees with that they only can use their mother tongue language outside school and at the mother tongue language education. Ann Ludvigsson writes in her thesis about how important it with the cooperation between teachers and how that can be good for the students development (Ludvigsson 2009:19-22).

Item does not contain fulltext, OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy and dose response relationship of three doses of gadobenate dimeglumine for MRI of the breast and to compare the results with those obtained after a dose of 0.1 mmol/kg of body weight of gadopentetate dimeglumine. SUBJECTS AND METHODS. Gadobenate dimeglumine at 0.05, 0.1, or 0.2 mmol/kg of body weight or gadopentetate dimeglumine at 0.1 mmol/kg of body weight was administered by IV bolus injection to 189 patients with known or suspected breast cancer. Coronal three-dimensional T1-weighted gradient-echo images were acquired before and at 0, 2, 4, 6, and 8 min after the administration of the dose. Images were evaluated for lesion presence, location, size, morphology, enhancement pattern, conspicuity, and type. Lesion signal intensity-time curves were acquired, and lesion matching with on-site final diagnosis was performed. A determination of global lesion detection from unenhanced to contrast-enhanced and combined images was performed, and evaluations were made of the diagnostic accuracy for lesion detection and characterization. A full safety evaluation was conducted. RESULTS: Significant dose-related increases in global lesion detection were noted for patients who received gadobenate dimeglumine (p < 0.04, all evaluations). The sensitivity for detection was comparable for 0.1 and 0.2 mmol/kg of gadobenate dimeglumine, and specificity was highest with the 0.1 mmol/kg dose. Higher detection scores and higher sensitivity values for lesion characterization were found for 0.1 mmol/kg of gadobenate dimeglumine compared with 0.1 mmol/kg of gadopentetate dimeglumine, although more variable specificity values were obtained. No differences in safety were observed, and no serious adverse events were reported. CONCLUSION: Gadobenate dimeglumine is a capable diagnostic agent for MRI of the breast. Although preliminary, our results suggest that 0.1 mmol/kg of gadobenate dimeglumine may offer advantages ove

Item does not contain fulltext, OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy and dose response relationship of three doses of gadobenate dimeglumine for MRI of the breast and to compare the results with those obtained after a dose of 0.1 mmol/kg of body weight of gadopentetate dimeglumine. SUBJECTS AND METHODS. Gadobenate dimeglumine at 0.05, 0.1, or 0.2 mmol/kg of body weight or gadopentetate dimeglumine at 0.1 mmol/kg of body weight was administered by IV bolus injection to 189 patients with known or suspected breast cancer. Coronal three-dimensional T1-weighted gradient-echo images were acquired before and at 0, 2, 4, 6, and 8 min after the administration of the dose. Images were evaluated for lesion presence, location, size, morphology, enhancement pattern, conspicuity, and type. Lesion signal intensity-time curves were acquired, and lesion matching with on-site final diagnosis was performed. A determination of global lesion detection from unenhanced to contrast-enhanced and combined images was performed, and evaluations were made of the diagnostic accuracy for lesion detection and characterization. A full safety evaluation was conducted. RESULTS: Significant dose-related increases in global lesion detection were noted for patients who received gadobenate dimeglumine (p < 0.04, all evaluations). The sensitivity for detection was comparable for 0.1 and 0.2 mmol/kg of gadobenate dimeglumine, and specificity was highest with the 0.1 mmol/kg dose. Higher detection scores and higher sensitivity values for lesion characterization were found for 0.1 mmol/kg of gadobenate dimeglumine compared with 0.1 mmol/kg of gadopentetate dimeglumine, although more variable specificity values were obtained. No differences in safety were observed, and no serious adverse events were reported. CONCLUSION: Gadobenate dimeglumine is a capable diagnostic agent for MRI of the breast. Although preliminary, our results suggest that 0.1 mmol/kg of gadobenate dimeglumine may offer advantages ove