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Translational approaches in neurorehabilitation: from Researcher’s bench to Patient’s bedside
No full textAim: To translate evidence-based methodologies of functional assessment and training from exercise and sports physiology to patients with neurological conditions.
Methods: Dynamometric, neurophysiological and clinico-functional assessments were comprehensively performed within a multi-layered agenda consisting of different trials (3 randomized controlled trials, 5 cross-sectional studies, 4 single-group proof-of concept interventional trials) conducted on both healthy subjects and individuals presenting neurological conditions with a special focus on multiple sclerosis. These studies were aimed at addressing muscle weakness and its related disabilities, with a specific focus on multiple sclerosis.
Results: Employing exercise and sports physiology techniques and methods with neurological patients, mostly multiple sclerosis, resulted into dynamometric and clinico-functional improvements which exceeded those commonly reported in clinical literature. In particular, the choice of strengthening exercise performed at maximal intensity proved well tolerated and effective in addressing muscle weakness due to neurological conditions. Moreover, assessment techniques borrowed from elite sports helped highlighting and characterizing the main differences between healthy and neurological individuals in terms of force production patterns and overall muscle capability.
Conclusion: Translational approaches like those explored in the present PhD project are to be considered as promising and innovative tools in the management of motor disabilities caused by pathological conditions of the nervous system
Whole exome sequencing in neurodevelopmental disorders: study of 10 families of Sardinian origin
No full textIntellectual disability (ID) represents a large and heterogeneous group of disorders with variable phenotypes and severity. The genetic aetiology of the 60% forms remains unexplained. Here we aimed to identify new genetic causes of autosomal recessive ID forms by using the Whole Exome Sequencing (WES) approach.
We selected 10 Sardinian families, with at least 2 patients affected by Multiple Congenital Anomalies and ID. The clinical description of each patient was reported using the terminology of Human Phenotype Ontology. We used the Illumina technology for WES.
We identified mutations in 2 out of the 10 families studied; a CKAP2L mutation in a family with Filippi Syndrome, and a CREBBP mutation in another family, leading to the Rubinstein-Taybi syndrome. Variants identified in 5 more families are under investigation to determine their implication in the phenotype. The search for candidate variants is ongoing for the remaining families.
The success rate of our WES is 20%, in line with that reported in literature (25-30%). WES may be the most cost-effective way to reach a diagnosis and guide appropriate management by significantly reducing the time and cost to diagnosis, but still remain significant challenges. Negative results where a diagnosis was not reached may be due to technical and scientific limitations or patient selection bias. To improve clinical and cost outcomes, diagnostic algorithms that include WES testing need to be created and implemented in the near future
Carriage rinofaringeo: distribuzione dei sierotipi di <i>Streptococcus pneumoniae</i> e di altri patogeni respiratori
No full textAim: Bacterial colonization is thought to be a prerequisite for an individual to become infected, but bacterial colonisation does not normally result in infection.
Streptococcus pneumonie infection is a major cause of childhood morbidity and mortality worldwide. The aim of this study is to understand the epidemiology of nasopharyngeal carriage of Streptococcus pneumoniae and other respiratory pathogens, in vaccinated children for implementing appropriate vaccination strategies.
Methods: 217 nasopharyngeal swabs were collected in a cohort population forvaccination, aged 3 to 13 years in northern Sardinia. Pneumococcal and other respiratory pathogens nasopharyngeal carriage prevalence and serogroups distribution were determined using validated molecular and cultural assays.
Results: Carriage rates was 22%, overall. The S. pneumoniae carriage prevalence was 60%(95% CI, 0,34-0,73),23%(95% CI, 0,13-0,27)and 16%(95% CI, 0,05-0,19)in nursery, in primary school and secondary school, respectively. Overall the most frequent S. pneumonia serotypes were 18(38%), 4(11%), 19F(4%), 3(17%), 5(15%) and 19A (4%). The only N. meningitidis serogroup in nursery and secondary school was B.
Conclusion: The S. pneumoniae carriage and other common respiratory bacteria prevalence were higher in nursery than in primary and secondary school. This study suggests that S. pneumoniae is present in the nasopharynx of the majority of children 3-5 years even if vaccinated. Overall N. meningitidis serogroup B was the most prevalent serogroup detected. The vaccine (Men C) selective pressure could be cause of this epidemiological picture. The study of the pneumococcal and other common respiratory bacteria survey, through analysis of prevalence of different serotypes is important to understand impact assessment of vaccine introduced in regional prevention plans
Is there a role for <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> in Parkinson's disease?
No full textIn Parkinson's disease (PD) ZnT proteins play an important role. Zinc is a co-factor of numerous enzymes and stabilizes the tertiary structure of several proteins. Nothing is known about previous infections mediated by Mycobacterium avium subsp. paratuberculosis (MAP). We evaluated if a previous infection with MAP could induce the production of antibodies that cross-reacted with the Znt homologous antigenic peptides associated to Parkinson. The humoral response toward MAP3865c peptides, ZnT3 and ZnT10 was evaluated. The hypothesis of cross-reactivity needs to be confirmed; we have observed the presence of MAP in PD patients by PCR, positivity to MAP3865c peptides, therefore MAP infection but not cross-reaction with human homologous Znt proteins
Identification of <i>Chattonella</i> (Raphidophyceae) species in long-term phytoplankton samples from Santa Giusta Lagoon, Italy.
No full textChattonella species in a Mediterranean lagoon (Santa Giusta Lagoon, Sardinia, Italy) were identified by applying a molecular approach to fixed natural phytoplankton samples collected over the last two decades. Like the other raphidophytes, Chattonella cells are naked and lose their shape when fixed, making species identification difficult on the basis of their morphological characteristics. Employing species-specific primers (oBTG-005-F, oBTG-027-R, oBTG-028-R) for the amplification of the ITS-5.8S rDNA region, we established the occurrence of C. subsalsa in fixed natural phytoplankton samples collected in coincidence with fish death events. Additionally, we established the presence of the recently discovered C. cf. subsalsa Adriatic genotype by analysing cellular cultures obtained from the same lagoon in 2013. This is the second worldwide record of C. cf. subsalsa Adriatic genotype. Our results revealed that the species-specific primers oBTG-005-F and oBTG-028-R distinguished this new genotype only when present singularly. This study provides valuable data that increase knowledge of C. subsalsa genotypes and of the long-term occurrence of Chattonella blooms in a transitional ecosystem through the use of samples up to 20 years old
Modulation of dietary energy partitioning between milk production and body reserves in sheep and goats
No full textThe dissertation studied the mechanism behind energy partitioning between milk production and body reserves in dairy sheep and dairy goats supplemented with a high-starch (HS) diet during early lactation and with HS or low-starch (LS) diets in mid-lactation. First, the mechanism affecting the energy partitioning was reviewed. Then, the effect of HS and LS diets in mid-lactation on sheep and goats was tested simultaneously. In goats, the HS diet had a positive effect on milk production compared to LS. In sheep, HS increased body fatness, whereas LS favoured milk persistency. During the trial the hormonal and metabolic profile of sheep and goats from early to mid-lactation was studied. The two species had a different hormonal and metabolic profile: goats had higher growth hormone (GH) and lower insulin blood concentration than ewes, evidencing the better aptitude of the goat species to milk production rather than body fat deposition. No diet effect was observed. In addition, the digestibility of HS and LS diets in both species was
measured with in vivo digestibility trials. Dry matter digestibility and total digestible nutrients did not vary between sheep and goats and were higher for the HS than for the LS diet. In addition, the HS diet had higher non-fiber carbohydrates digestibility and lower neutral detergent fiber digestibility compared to LS. It appears that the productive differences observed were mainly due to the differences in hormonal profile between the species
Il Paesaggio storico della via Portuense a Roma: fonti e strumenti per la valorizzazione del patrimonio culturale in un contesto urbano in trasformazione
No full textThe territorial context of this research is a part of the south-western suburbs of Rome, which includes the suburban section of the ancient Via Portuensis within the fourth mile; the area roughly corresponds to the limits of the modern Portuense district.
The research is focused on the potential of a landscape study which uses a wide range of data from recent excavations, many of which are still unpublished, balancing research scopes with protection and valorization of cultural heritage. On the basis of the collection and systematization of scientific information, with regard to cartographic, archival, and archaeological sources, the research has been focused on the potential of enhancement and valorization of an urban area: so, a valorization plan has been set, and a virtual exhibition, accessible via web, has been designed. The virtual exhibition starts from the story of the territory, with a focus on some "key sites" on the ancient Via Portuense.
The collected data, translated into digital format, were published on SITAR webgis portal that guarantees their dissemination
Prognostic value of the fibrosis-4 index in human immunodeficiency virus type-1 infected patients initiating antiretroviral therapy with or without hepatitis C virus
No full textObjective: To evaluate the Fibrosis (FIB)-4 index as a predictor of major liver-related events (LRE) and liver-related death (LRD) in human immunodeficiency virus (HIV) type-1 patients initiating combination antiretroviral therapy (cART).
Design: Retrospective analysis of a prospective cohort study.
Setting: Italian HIV care centers participating to the ICONA Foundation cohort.
Participants: Treatment-naive patients enrolled in ICONA were selected who: initiated cART, had hepatitis C virus (HCV) serology results, were HBsAg negative, had an available FIB-4 index at cART start and during follow up.
Methods: Cox regression models were used to determine the association of FIB4 with the risk of major LRE (gastrointestinal bleeding, ascites, hepatic encephalopathy, hepato-renal syndrome or hepatocellular carcinoma) or LRD.
Results: Three-thousand four-hundred seventy-five patients were enrolled: 73.3% were males, 27.2% HCV seropositive. At baseline (time of cART initiation) their median age was 39 years, had a median CD4+ T cell count of 260 cells/uL, and median HIV RNA 4.9 log copies/mL, 65.9% had a FIB-4 <1.45, 26.4% 1.45–3.25 and 7.7% >3.25. Over a follow up of 18,662 person-years, 41 events were observed: 25 major LRE and 16 LRD (incidence rate, IR, 2.2 per 1,000 PYFU [95% confidence interval, CI 1.6–3.0]). IR was higher in HCV seropositives as compared to negatives (5.9 vs 0.5 per 1,000 PYFU). Higher baseline FIB-4 category as compared to <1.45 (FIB-4 1.45–3.25: HR 3.55, 95% CI 1.09–11.58; FIB-4 >3.25: HR 4.25, 1.21–14.92) and time-updated FIB-4 (FIB-4 1.45–3.25: HR 3.40, 1.02–11.40; FIB-4 >3.25: HR 21.24, 6.75–66.84) were independently predictive of major LRE/LRD, after adjusting for HIV- and HCV-related variables, alcohol consumption and type of cART.
Conclusions: The FIB-4 index at cART initiation, and its modification over time are risk factors for major LRE or LRD, independently of infection with HCV and could be used to monitor patients on cART
Microenvironmental modulation of decorin and lumican in temozolomide-resistant glioblastoma and neuroblastoma cancer stem-like cells
No full textThe presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential
Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2 (Translational Sciences)
No full textObjective: Gestational diabetes mellitus (GDM) produces fetal hyperglycemia with increased lifelong risks for the exposed offspring of cardiovascular and other diseases. Epigenetic mechanisms induce long-term gene expression changes in response to in utero environmental perturbations. Moreover, microRNAs (miRs) control the function of endothelial cells (ECs) under physiological and pathological conditions and can target the epigenetic machinery. We investigated the functional and expressional effect of GDM on human fetal ECs of the umbilical cord vein (HUVECs). We focused on miR-101 and 1 of its targets, enhancer of zester homolog-2 (EZH2), which trimethylates the lysine 27 of histone 3, thus repressing gene transcription. EZH2 exists as isoforms α and β.
Approach and Results: HUVECs were prepared from GDM or healthy pregnancies and tested in apoptosis, migration, and Matrigel assays. GDM-HUVECs demonstrated decreased functional capacities, increased miR-101 expression, and reduced EZH2- β and trimethylation of histone H3 on lysine 27 levels. MiR-101 inhibition increased EZH2 expression and improved GDM-HUVEC function. Healthy HUVECs were exposed to high or normal D-glucose concentration for 48 hours and then tested for miR-101 and EZH2 expression. Similar to GDM, high glucose increased miR-101 expression. Chromatin immunoprecipitation using an antibody for EZH2 followed by polymerase chain reaction analyses for miR-101 gene promoter regions showed that both GDM and high glucose concentration reduced EZH2 binding to the miR-101 locus in HUVECs. Moreover, EZH2-β overexpression inhibited miR-101 promoter activity in HUVECs.
Conclusions: GDM impairs HUVEC function via miR-101 upregulation. EZH2 is both a transcriptional inhibitor and a target gene of miR-101 in HUVECs, and it contributes to some of the miR-101-induced defects of GDM-HUVECs