Parkinson's disease: autoimmunity and neuroinflammation

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation

Impact of the Timing of Integrated Home Palliative Care Enrolment on Emergency Department Visits

Background: The association between timing of integrated home palliative care (IHPC) enrolment and emergency department (ED) visits is still under debate, and no studies investigated the effect of the timing of IPHC enrolment on ED visits, according to their level of emergency. This study aimed to investigate the impact of the timing of IHPC enrolment on different acuity ED visits. Methods: A retrospective, pre-/post-intervention study was conducted from 2013 to 2019 in Italy. Analyses were stratified by IHPC duration (short 90 days) and triage tags (white/green: low level of emergency visit; yellow/red: medium to-high level). The impact of the timing of IHPC enrolment was evaluated in two ways: incidence rate ratios (IRR) of ED visits were determined 1) before and after IHPC enrolment in each group and 2) post-IHPC among groups. Results: A cohort of 17983 patients was analysed. Patients enrolled early in the IHPC programme had a significantly lower incidence rate of ED visits than the pre-enrolment period (IRR=0.65). The incidence rates of white/green and yellow/red ED visits were significantly lower post-IHPC enrolment for patients enrolled early (IRR= 0.63 and 0.67, respectively). All results were statistically significant (p<0.001). Comparing the IHPC groups after enrolment versus the short group, medium and long IHPC groups had a significant reduction of ED visits (IRR=0.37, IRR=0.14 respectively), showing a relation between the timing of IHPC enrolment and the incidence of ED visits. A similar trend was observed after accounting for triage tags of ED visits. Conclusion: The timing of IHPC enrolment is related with a variation of the incidence of ED visits. Early IHPC enrolment is related to a high significant reduction of ED visits when compared to the 90-day pre-IHPC enrolment period and to late IHPC enrolment, accounting for both low-level and medium-to-high level emergency ED visits

Chronic diseases are strongly associated with sickness absences in a sample of Italian public employees

Abstrac

756 stable amelioration of hemophilia b in dogs by intravenous administration of lentiviral vectors expressing hyper functional factor ix

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the low prevalence of pre-existing immunity against HIV in humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing canine factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs with 6, 3.5 and 2.5 years of follow up. LV infusion was associated with transient signs of inflammatory response and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated two 10-kg hemophilia B dogs by peripheral vein administration of LVs expressing a codon-optimized and hyperfunctional canine FIX at a 5-fold higher dose than those previously administered. Intravenous LV administration was well tolerated with mild and self-limiting elevation of aminotransferases in one dog. In the dog that reached more than 1 year of follow up FIX activity ranged between 4-8% of normal. Treatment of two more dogs at a higher dose is underway. Overall, our studies position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

28. Intravenous Administration of Lentiviral Vectors Expressing Hyperactive Factor IX Converts Severe Into Mild Hemophilia B in a Canine Model

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the lack of pre-existing immunity against vector components in most humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing wild-type, codon-optimized (c.o.) or c.o. and hyperactive factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs (>9 years cumulative follow up). LV infusion was associated with transient signs of inflammation and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated an 11-kg, hemophilia B dog by peripheral vein administration of LVs expressing the c.o. and hyperactive canine FIX at a 5-fold higher dose than those previously administered. At the current follow-up (3 months after gene therapy) FIX activity is 6-9% of normal. Intravenous LV administration, coupled with a 1-day anti-inflammatory and anti-histamine pre-treatment, induced mild and selflimiting leukopenia and elevation of aminotransferases. Treatment of more hemophilia B dogs is underway to confirm and extend these results. Overall, our studies, which suggest comparable efficacy of LV by both portal and peripheral vein administration, position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

Promoting Laparoscopic Anterior Approach for a Very Low Presacral Primary Neuroendocrine Tumor Arising in a Tailgut Cyst

Tailgut cysts are rare congenital lesions that develop in the presacral space. As they can potentially conceal primary neuroendocrine tumors, surgical excision is suggested as the treatment of choice. However, specific management guidelines have yet to be developed. A posterior approach is usually preferred for cysts extending to the third sacral vertebral body. Conversely, a transabdominal approach is preferred for lesions extending upward to achieve an optimal view of the surgical field and avoid injuries

La chimica delle deposizioni atmosferiche e gli inquinanti atmosferici nelle aree del programma CONECOFOR nell\u27anno 2012

Atmospheric deposition was sampled in 13 forest sites in Italy, in the open field, under tree canopy and on stemflow, and analyzed for major ions, dissolved organic carbon and total nitrogen. Ozone concentration was also measured during spring and summer. The results were compared with time series dating back to 1997

Management of motor rehabilitation in individuals with muscular dystrophies. : 1st Consensus Conference report from UILDM – Italian Muscular Dystrophy Association (Rome, January 25-26, 2019)

Muscular dystrophy (MD) is a group of neuromuscular diseases characterized by progressive muscle weakness due to various mutations in several genes involved in muscle structure and function. The age at onset, evolution and severity of the different forms of MD can vary and there is often impairment of motor function and activities of daily living. Although there have been important scientific advances with regard to pharmacological therapies for many forms of MD, rehabilitation management remains central to ensuring the patient’s psychophysical well-being. Here we report the results of an Italian consensus conference promoted by UILDM (Unione Italiana Lotta alla Distrofia Muscolare, the Italian Muscular Dystrophy Association) in order to establish general indications and agreed protocols for motor rehabilitation of the different forms of MD

La chimica delle deposizioni atmosferiche e gli inquinanti atmosferici nelle aree del programma CONECOFOR nell\u27anno 2011

Atmospheric deposition was sampled in 22 forest sites in Italy, in the open field, under tree canopy and on stemflow, and analyzed for major ions, dissolved organic carbon and total nitrogen. Ozone concentration was also measured during spring and summer. The results were compared with time series dating back to 1997

Identifying people at risk for influenza with low vaccine uptake based on deprivation status: a systematic review

Background: Influenza vaccination is an important public health intervention for controlling disease burden, but coverage rates are still low also in risk groups. In order to identify non-vaccinating subgroups, deprivation and socio-economic indices, i.e. measures used to synthetically describe people\u2019s socio-economic status while taking into account several dimensions, may be used. We aimed to synthetize evidence from studies investigating association between deprivation/socio-economic indices and influenza vaccination coverage in population at risk\u2014 persons 65 years of age, individuals with comorbidities, pregnant women and health-care workers. Methods: We searched PubMed, ISI WoS, CINAHL and Scopus to identify observational studies published up to October 10th 2017 in English or Italian. Studies reporting quantitative estimates of the association between deprivation/socioeconomic indices and influenza vaccination coverage in populations at risk were included. Results: A total of 1474 articles were identified and 12 were eventually included in the final review. Studies were mostly cross-sectional, performed in European countries, from 2004 to 2017. Seven studies focussed on deprivation and five on socioeconomic indices. Studies on deprivation indices and vaccination coverage showed that people from the most deprived areas had lower coverage. Regarding socio-economic condition, results were contrasting, even though it may also be concluded that people from lower groups have lower vaccination coverage. Conclusions: Our work supports the possibility to identify people likely to have lower influenza vaccination coverage based on deprivation/socio-economic indices. Efforts should be performed in order to further strengthen robustness, transferability and suitability of these indices in addressing public health problems