Effects of immersive virtual nature on nature connectedness: A systematic review and meta-analysis.

Objective: This study systematically summarizes the extant literature on the impacts of immersive virtual nature (IVN) on nature connectedness in the general population. Methods: Papers were considered eligible if peer-reviewed, in English language, comprising experimental or quasi-experimental trials, including at least one outcome relative to nature connectedness in the general population. Database search was conducted on Scopus, Web of Science, Google Scholar, Medline, and GreenFILE (22-28 November 2021). Risk of bias was established by the Cochrane RoB 2 tool. Data synthesis was conducted through meta-analysis according with the Cochrane Consumers and Communication Group guidelines. Results: Six eligible papers (9 studies; n = 730) were selected, in which IVN was compared to (i) non-immersive virtual nature, (ii) immersive virtual built environments, (iii) non-immersive virtual built environments, and (iv) actual nature. The risk of bias was predominantly "low" or of "some concerns." Meta-analyses showed a statistically significant overall effect for the first (g = 0.26; 95% CI = 0.06-0.45; I2 = 35%) and fourth group (g = -1.98; 95% CI = -3.21 to -0.75; I2 = 96%), the former in favor of IVN and the latter in favor of actual nature. Subgroup analyses were conducted for the first and second groups of studies to explore possible sources of heterogeneity. The small number of studies available limits the validity of the outcomes of the meta-analyses. Conclusion: The findings indicate that IVN may be an effective tool for the promotion of nature connectedness, although the evidence in this field is still limited and largely mixed. Recommendations for future research are discussed.

COVID-19 Clinical Features and Outcome in Italian Patients Treated with Biological Drugs Targeting Type 2 Inflammation.

This is a multicentric investigation involving two Italian centers that examined the clinical course of COVID-19 in patients receiving biological therapy targeting type 2 inflammation and those not receiving biologicals. Since the beginning of the COVID-19 pandemic, the management of respiratory and allergic disorders and the potential impact of biological therapy in the most severe forms has been a point of uncertainty. Our multicentric investigation aimed to compare the clinical course of COVID-19 and the impact of vaccination in an Italian cohort of patients with atopic disorders caused by a type 2 inflammation, such as eosinophilic asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). A questionnaire was given to patients coming to our outpatient clinic for the first evaluation or follow-up visit, asking for the clinical characteristics of the infection, the ongoing therapy during the infection, any relevant change, and the patient's vaccination status. We enrolled 132 atopic patients from two Italian centers; 62 patients were on biological therapy at the time of infection (omalizumab 31%, mepolizumab 26%, benralizumab 19%, and dupilumab 24%). The median age was 56 (IQR 22.8) for patients on biologicals and 48 (IQR 26.5) for those not on biologicals (p = 0.028). The two groups were comparable in terms of sex, body mass index (BMI), smoking history, and systemic oral corticosteroid use (OCS). There were no significant differences in non-biological therapy and comorbidity between the two groups. The patients not on biological therapy had a prevalence of 87% for asthma, 52% for CRSwNP, 10% for CSU, and 6% for AD. The patients on biologicals had a prevalence of 93% for asthma, 17% for CRSwNP, and 10% for CSU. In our work, we observed that mAbs targeting type 2 inflammation in patients with COVID-19 appeared to be safe, with no worsening of symptoms, prolongation of infection, or increase in hospitalizations. Between the two groups, there were no significant differences in the duration of swab positivity (p = 0.45) and duration of symptoms (p = 0.38). During COVID-19, patients on biologicals experienced a significant increase in common cold-like symptoms (p = 0.038), dyspnea (p = 0.016), and more, but not significant, asthma exacerbations, with no significant differences between the different biologicals. Regarding the vaccination status, we observed that there was an increased number of hospitalizations among unvaccinated patients in both groups, although the difference did not reach statistical significance. No patients on biologicals reported safety issues or adverse effects associated with the use of biological treatments during COVID-19. Our investigation showed that mAbs against type 2 inflammation given during Coronavirus Disease 2019 are safe and do not impact the clinical course or main outcomes. Therefore, we found no signals suggesting that anti-Th2 biological therapy should be discontinued during SARS-CoV-2 infection. Controlled studies and analysis, including data from registries and real-life studies, are required to draw firm conclusions regarding the safety or possible advantages that anti-type 2 mAbs could offer in particular clinical contexts, such as infections.

Association of Circulating Antiretinal Antibodies With Clinical Outcomes in Retinitis Pigmentosa.

Purpose: To determine if circulating antiretinal antibodies (ARAs) differ between patients affected by retinitis pigmentosa (RP) and control participants and to assess whether ARAs are associated with clinical outcomes in patients with RP. Methods: Cross-sectional study involving a group of patients clinically diagnosed with RP and a control group of healthy participants. Serum autoantibodies against enolase, heat shock protein 70 (HSP70), and carbonic anhydrase II (CAII) were tested in all participants using Jess capillary Western blot. We compared ARA prevalence between the RP and control groups and investigated the association of serum ARA positivity with macular edema and vitreomacular disorders in patients affected by RP. Results: Thirty-six patients affected by RP and a control group of 39 healthy individuals were included. Overall, at least one ARA positivity was detected in 89% and 80% of participants in the RP and control groups, respectively. We observed a similar prevalence of anti-CAII and anti-enolase ARA between patients and controls (P = 0.87 and P = 0.35, respectively). Sera from patients with RP tested positive for anti-HSP70 ARAs more frequently than those from controls (53% vs. 36%), albeit without reaching statistical significance (P = 0.29). Among the 72 eyes with RP, 25% presented with macular edema (most often bilateral) and 33% with epiretinal membrane and/or lamellar macular hole. None of the three ARAs was associated with an increased risk of any macular complications in eyes affected by RP (all P > 0.05). Conclusions: The prevalence of circulating ARAs against enolase, HSP70, and CAII is similar between patients affected by RP and healthy individuals. Our results provide evidence against the association of ARAs with macular edema and vitreomacular interface disorders in RP.

Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology.

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llo mature and CD177hiCD101loCD62Llo and CD177loCD101loCD62Lhi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Llo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Llo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.

Safety of mRNA COVID-19 Vaccines in Patients with Inborn Errors of Immunity: an Italian Multicentric Study.

PURPOSE: Little is known about vaccine safety in inborn errors of immunity (IEI) patients during the current vaccination campaign for COVID-19. To better investigate the reactogenicity and adverse event profile after two, three, and four doses of mRNA vaccines, we conducted an observational, multicentric study on 342 PID patients from four Italian Referral Centres. METHODS: We conducted a survey on self-reported adverse reactions in IEI patients who received mRNA vaccine by administering a questionnaire after each dose. RESULTS: Over the whole study period, none of the patients needed hospitalization or had hypersensitivity reactions, including anaphylaxis and delayed injection site reaction. After two vaccination doses, 35.4% of patients showed only local reactogenicity-related symptoms (RrS), 44.4% reported both systemic and local RrS, and 5% reported only systemic RrS. In more than 60% of cases, local or systemic RrS were mild. After the first and second booster doses, patients showed fewer adverse events (AEs) than after the first vaccination course. Patients aged 50 years and older reported adverse events and RrS less frequently. Among AEs requiring treatment, one common variable immune deficiency patient affected by T cell large granular lymphocytic leukemia developed neutropenia and one patient had Bell's paralysis perhaps during herpes zoster reactivation. CONCLUSION: Although our follow-up period is relatively short, the safety data we reported are reassuring. This data would help to contrast the vaccine hesitancy often manifested by patients with IEI and to better inform their healthcare providers.

Neural precursor cells tune striatal connectivity through the release of IGFBPL1.

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity.

Effects of immersive virtual nature on nature connectedness: A systematic review protocol.

Objective: Nature Connectedness, an individual's cognitive, affective, and behavioral connection with the natural world, has been linked to various health and well-being outcomes. As Nature Connectedness can be elicited and strengthened through direct contact with nature, in the past decade studies have investigated whether similar effects can be achieved through technologies that simulate highly immersive and realistic experiences of nature, such as Immersive Virtual Nature. This protocol describes the methodology for a systematic review that will summarize the existing evidence on the effects of Immersive Virtual Nature on Nature Connectedness in non-clinical populations. Methods: The review will be conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and MetaAnalyses. Terms such as "immersive virtual environment," "natural setting*," and "contact with nature" were searched in Scopus, WebOfScience, GoogleScholar, Medline, and GreenFILE (22-28 November 2021). Papers in English, describing experimental studies, with or without control/comparison, and testing the effects of Immersive Virtual Nature interventions on Nature Connectedness outcomes in non-clinical populations were included. The risk of bias will be assessed using Cochrane's Risk of Bias 2 for randomized studies, and the Risk Of Bias In Non-randomized Studies - of Interventions. The data synthesis will be performed through meta-analysis, assuming that the Cochrane Consumers and Communication Group guidelines are met. Conclusion: The findings will be relevant for understanding the potential and challenges of Immersive Virtual Nature as a tool to promote health and well-being in the general population, providing information on the consistency and limitations of the existing literature and recommendations for future research.

Heparin Protects Human Neural Progenitor Cells from Zika Virus-Induced Cell Death While Preserving Their Differentiation into Mature Neuroglial Cells.

Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. The key target cells of ZIKV infection, human neural progenitor cells (hNPCs), are highly permissive to infection that causes the inhibition of cell proliferation and induces cell death. We have previously shown that pharmaceutical-grade heparin inhibits virus-induced cell death with negligible effects on in vitro virus replication in ZIKV-infected hNPCs at the "high" multiplicity of infection (MOI) of 1. Here, we show that heparin inhibits formation of ZIKV-induced intracellular vacuoles, a signature of paraptosis, and inhibits necrosis and apoptosis of hNPCs grown as neurospheres (NS). To test whether heparin preserved the differentiation of ZIKV-infected hNPCs into neuroglial cells, hNPCs were infected at the MOI of 0.001. In this experimental condition, heparin inhibited ZIKV replication by ca. 2 log10, mostly interfering with virion attachment, while maintaining its protective effect against ZIKV-induced cytopathicity. Heparin preserved differentiation into neuroglial cells of hNPCs that were obtained from either human-induced pluripotent stem cells (hiPSC) or by fetal tissue. Quite surprisingly, multiple additions of heparin to hNPCs enabled prolonged virus replication while preventing virus-induced cytopathicity. Collectively, these results highlight the potential neuroprotective effect of heparin that could serve as a lead compound to develop novel agents for preventing the damage of ZIKV infection on the developing brain. IMPORTANCE ZIKV is a neurotropic virus that invades neural progenitor cells (NPCs), causing inhibition of their proliferation and maturation into neurons and glial cells. We have shown previously that heparin, an anticoagulant also used widely during pregnancy, prevents ZIKV-induced cell death with negligible inhibition of virus replication. Here, we demonstrate that heparin also exerts antiviral activity against ZIKV replication using a much lower infectious inoculum. Moreover, heparin interferes with different modalities of virus-induced cell death. Finally, heparin-induced prevention of virus-induced NPC death allows their differentiation into neuroglial cells despite the intracellular accumulation of virions. These results highlight the potential use of heparin, or pharmacological agents derived from it, in pregnant women to prevent the devastating effects of ZIKV infection on the developing brain of their fetuses.

Significant variations of dangerous exposures during COVID-19 pandemic in Italy: a possible association with the containment measures implemented to reduce the virus transmission.

BACKGROUND: In response to the COVID-19 health emergency, mass media widely spread guidelines to stop the virus transmission, leading to an excessive and unaware use of detergents and disinfectants. In Italy and in other countries this tendency caused a significant increase of exposures to these products in 2020. Evaluating data collected by the Italian Pavia Poison Centre (PPC), this study intends to examine the relationship between the COVID-19 lockdown and the variations of exposures to specific product categories possibly associated to the containment measures implemented. Simultaneously, this work shows the effectiveness of the European Product Categorisation System (EuPCS) in surveillance activities of dangerous chemicals. METHODS: Exposure cases managed by the PPC during March-May 2020 (lockdown) and during the same months of 2017-2018-2019 were compared. Differences in categorical variables were tested with the Chi-square test. The level of significance was set at Alpha = .05. The study included all EuPCS groups but specifically focused on cleaners, detergents, biocides and cosmetics. RESULTS: During the lockdown, calls from private citizens showed a highly significant increase (+ 11.5%, p < .001) and occupational exposures decreased (- 11.7%, p = .011). Among Cleaners, exposures to Bleaches slightly increased while Drain cleaning products went through a significant reduction (- 13.9%, p = .035). A highly significant increase of exposures to Disinfectants was observed (+ 7.7%, p = .007), particularly to those for surfaces (+ 6.8%, p = .039). Regarding Cosmetics, both handwashing soaps and gel products significantly increased (respectively: + 25.0, p = .016 and + 9.7%, p = .028). Among children 1-5 years, the statistical significance is reached with exposures to Dishwashing detergents (+ 13.1%, p = .032), handwashing soaps (+ 28.6%, p = .014) and handwashing gel products (+ 16.8%, p = .010). Contrarily, Liquid Laundry Detergent Capsules decreased in a highly significant manner (- 25%; p = .001). The general severity of exposures showed a highly significant decrease (Moderate: - 10.1%, p = .0002). CONCLUSIONS: This study investigated the relationship between the COVID-19 lockdown and the variations of exposures to some product categories related to the containment measures. The results obtained support any action to be taken by Competent Authorities to implement measures for a safer use of cleaners/disinfectants. This paper shows the benefit in applying the EuPCS to categorize products according to their intended use, though an extension of this system to products not covered by CLP Regulation may be a further advantage.

Severity does not impact on exercise capacity in COVID-19 survivors.

BACKGROUND: current data on the impact of acute illness severity on exercise capacity and ventilatory efficiency of COVID-19 survivors, evaluated at cardiopulmonary exercise test (CPET), are limited. METHODS: in this post-hoc analysis of our previous observational, prospective, cohort study on mechanisms of exercise intolerance in COVID-19 survivors, we aimed at evaluating the impact of acute COVID-19 severity on exercise capacity, pulmonary function testing (PFT) and chest computed tomography (CT) outcomes. RESULTS: we enrolled 75 patients (18 with mild-to-moderate disease, 18 with severe disease, and 39 with critical disease). Mean (standard deviation - SD) follow-up time was 97 (26) days. Groups showed a similar PFT and CT residual involvement, featuring a mildly reduced exercise capacity with comparable mean (SD) values of peak oxygen consumption as percentage of predicted (83 (17) vs 82 (16) vs 84 (15), p = 0.895) among groups, as well as the median (interquartile range - IQR) alveolar-arterial gradient for O2 in mmHg at exercise peak (20 (15-28) vs 27 (18-31) vs 26 (21-21), p = 0.154), which was in the limit of normal. In addition, these patients featured a preserved mean ventilatory efficiency evaluated through the slope of the relation between ventilation and carbon dioxide output during exercise (27.1 (2.6) vs 29.8 (3.9) vs 28.3 (2.6), p = 0.028), without a clinically relevant difference. CONCLUSIONS: Disease severity does not impact on exercise capacity in COVID-19 survivors at 3 months after discharge, including a ventilatory response still in the limit of normal.

The complex and constantly evolving public health threat of new psychoactive substances in Italy: addressing the main functions of a national observatory of drugs.

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.

Prevalence of Stimulant, Hallucinogen, and Dissociative Substances Detected in Biological Samples of NPS-Intoxicated Patients in Italy.

A number of new psychoactive substances (NPS) have been released in the last decade, and the list of NPS continues to grow. This paper reports a retrospective evaluation of the toxicological analyses in 1,445 suspected intoxication cases by psychostimulant, hallucinogen, and dissociative NPS occurring in hospitals across Italy from 2011 to 2019. The objectives of the study were to contribute to the monitoring of the NPS diffusion based on analytically confirmed intoxications, and to evaluate the importance of the clinical toxicological laboratory in the diagnosis of NPS intoxication. For at least one NPS of the considered classes, 246 patients (17.0%) tested positive. Forty-four different NPS were detected and a consistent turnover was observed during the nine-year period, especially regarding cathinones. Among the positive cases, 47.2% tested positive for dissociative NPS, with particular regard to ketamine. Hallucinogens (30.9%) was the second most frequent NPS involved. Stimulants were found in 20% of the positive cases with a considerable presence of cathinones. Findings confirm the dynamism of the NPS phenomenon, underline the importance of awareness of this new public health threat among health care professionals, and highlight the need for analytical confirmation for the identification of the drugs in forensic contexts.

Exposure to Nail and False Eyelash Glue: A Case Series Study.

The use of artificial nail tips in professional manicure services and the application of false eyelashes are a growing trend among young women. Often, this "beauty routine" is performed at home without the supervision of an expert beautician, raising health problems due to either the spillage of these products or to accidental exposure to children. The aim of this study is to review the Pavia Poison Control Centre clinical records to identify the frequency, the most common route of exposure, and the possible risks associated to these events to support the decision-making process in emergency departments. The Pavia Poison Control Centre database was retrospectively searched for records reporting nail or false eyelash glue exposure from January 2007 to April 2020, and 42 patients were identified. Among the patients, 76% presented symptoms from mild to severe, while 24% were asymptomatic. The most common route of exposure was dermal, through cutaneous contact, as determined for 19 patients involved. Among these, seven patients presented with second-degree chemical burns, cutaneous erythema, and ocular symptoms. The most dangerous glue component was cyanoacrylate, leading to symptoms in 16 out of 22 patients, while three cases remained asymptomatic. Even if this exposure is relatively rare, nail and false eyelash glue can be seriously harmful, especially when exposure occurs via dermal or ocular routes. In the case of emergency, it is important to treat the patient as fast as possible to limit the damage caused by a burn. Moreover, even though these products are often perceived as harmless, safety precautions should be taken to prevent children from accidental contact.

A Mobile Application for Exercise Intervention in People Living with HIV.

PURPOSE: This study aimed to assess 16-wk improvements of physical fitness, metabolic, and psychological parameters in people living with HIV (PLWH) exercising with the support of a smartphone application, as compared with a control group exercising without application. METHODS: This was a randomized, open-label, pilot study enrolling PLWH in a 16-wk protocol consisting of moderate physical activity three times per week, which included an initial coach-supervised period of 4 wk, followed by 12 wk where participants trained independently. Participants were allocated to either an experimental group that trained using a smartphone application (APP) or a control group that practiced following a hard copy training program (No-APP). At baseline (BL) and after 16 wk (W16), patients were assessed for cardiorespiratory fitness, body composition, blood lipid profile, and POMS. RESULTS: Forty-eight PLWH were screened and 38 were eligible: 20 were allocated to the APP group and 18 to the No-APP group. Two APP and two No-APP participants were lost to follow-up. Intention-to-treat analysis showed a W16 improvement from BL of ≥15% V˙ O2peak in 13 (72%) of 18 in APP, but only in 3 (19%) of 16 in No-APP participants (P = 0.025). Significant W16 improvements were observed in APP, but not in No-APP participants, in V˙O2peak; fat mass and fat-free mass percent; total cholesterol, LDL cholesterol, and triglycerides; vigor; and total mood by POMS. Accordingly, significant percent change differences between the APP and the No-APP groups were observed in V˙O2peak; fat and fat-free mass percent; total cholesterol, LDL cholesterol, and triglycerides; and depression, vigor, anger, and total mood by POMS. CONCLUSIONS: Exercising using a smartphone application improved cardiorespiratory fitness, body composition, cholesterol profiles, and psychological outcomes in PLWH.

Neural Stem Cells of the Subventricular Zone Contribute to Neuroprotection of the Corpus Callosum after Cuprizone-Induced Demyelination.

Myelin loss occurring in demyelinating diseases, including multiple sclerosis, is the leading cause of long-lasting neurological disability in adults. While endogenous remyelination, driven by resident oligodendrocyte precursor cells (OPCs), might partially compensate myelin loss in the early phases of demyelinating disorders, this spontaneous reparative potential fails at later stages. To investigate the cellular mechanisms sustaining endogenous remyelination in demyelinating disorders, we focused our attention on endogenous neural precursor cells (eNPCs) located within the subventricular zone (SVZ) since this latter area is considered one of the primary sources of new OPCs in the adult forebrain. First, we fate mapped SVZ-eNPCs in cuprizone-induced demyelination and found that SVZ endogenous neural stem/precursor cells are recruited during the remyelination phase to the corpus callosum (CC) and are capable of forming new oligodendrocytes. When we ablated SVZ-derived eNPCs during cuprizone-induced demyelination in female mice, the animals displayed reduced numbers of oligodendrocytes within the lesioned CC. Although this reduction in oligodendrocytes did not impact the ensuing remyelination, eNPC-ablated mice experienced increased axonal loss. Our results indicate that, in toxic models of demyelination, SVZ-derived eNPCs contribute to support axonal survival.SIGNIFICANCE STATEMENT One of the significant challenges in MS research is to understand the detrimental mechanisms leading to the failure of CNS tissue regeneration during disease progression. One possible explanation is the inability of recruited oligodendrocyte precursor cells (OPCs) to complete remyelination and to sustain axonal survival. The contribution of endogenous neural precursor cells (eNPCs) located in the subventricular zone (SVZ) to generate new OPCs in the lesion site has been debated. Using transgenic mice to fate map and to selectively kill SVZ-derived eNPCs in the cuprizone demyelination model, we observed migration of SVZ-eNPCs after injury and their contribution to oligodendrogenesis and axonal survival. We found that eNPCs are dispensable for remyelination but protect partially from increased axonal loss.

Topiramate protects apoE-deficient mice from kidney damage without affecting plasma lipids.

Topiramate is an anticonvulsant drug also prescribed for migraine prophylaxis that acts through several mechanisms of action. Several studies indicate that topiramate induces weight loss and a moderate reduction of plasma lipids and glucose. Based on these favourable metabolic effects, aim of this study was to evaluate if topiramate could modulate atherosclerosis development and protect target organs of dysmetabolic conditions. Thirty apoE-deficient mice were divided into three groups and fed for 12 weeks a high fat diet (Control) or the same diet containing topiramate at 0.125% and 0.250%. Body weight, water and food intake were monitored throughout the study. Plasma lipids and glucose levels were measured and a glucose tolerance test was performed. Atherosclerosis development was evaluated in the whole aorta and at the aortic sinus. Histological analysis of liver, kidney and adipose tissue was performed. Topiramate did not affect weight gain and food intake. Glucose tolerance and plasma lipids were not changed and, in turn, atherosclerosis development was not different among groups. Topiramate did not modify liver and adipose tissue histology. Conversely, in the kidneys, the treatment reduced the occurrence of glomerular lipidosis by decreasing foam cells accumulation and reducing the expression of inflammatory markers. Blood urea nitrogen levels were also reduced by treatment. Our results indicate that topiramate does not affect atherosclerosis development, but preserves kidney structure and function. The study suggests that topiramate could be investigated in drug repurposing studies for the treatment of glomerular lipidosis.

Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches. METHODS: We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs. RESULTS: We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells. CONCLUSION: Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery.

Neural precursor cell-secreted TGF-ß2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2-/- NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-ß2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-ß2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-ß2.