Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the ...corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml interquartile range (IQR) 683-1113 to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
LMNA gene mutations have been associated with several diseases. Some of them are muscle disorders, including the autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD2 and ...EDMD3), limb-girdle muscular dystrophy 1B (LGMD1B) and congenital muscular dystrophy (MDCL). With few exceptions, most of the studies are focused on one of these phenotypes and data on large cohorts of myopathic patients are lacking. The aim of our study was to evaluate clinical, neurophysiologic, histological and molecular features of 77 myopathic patients mutated in LMNA gene and followed in different Italian neuromuscular centres. Patients with predominant or exclusively progeroid/lipodystrophic or cardiac phenotype were excluded. The cohort included 36 (46.8%) patients with LGMD1B phenotype, 30 (39%) with EDMD2 and 11 with MDCL (14.3%). Mean age at onset was 10.3 ± 12.3 years in patients with EDMD2, 29.5 ± 17.6 in LGMD1B and 0.4 ± 0.5 in MDCL. Independent walking was reached in all patients, with the exception of 4 (5.2%) MDCL, who never acquired the ability to stand up. Another 4 (5.2%) patients (3 LGMD1B and 1 EDMD2) lost ambulation, and 3 EDMD2 (3.9%), required monolateral support to walk. Cardiac involvement was found in 57 (74%) patients. Pacemaker or ICD were implanted in 42 (54.5%) patients (21 EDMD2, 18 LGMD1B and 3 MDCL), while heart transplant was performed in 5 (6.5%) patients (3 EDMD2 and 2 with LGMD1B). Six (7.8%) patients died due to cardiac problems (3 EDMD2 and 3 MDCL). Only 5 (6.5%) patients required non-invasive ventilation (4 EDMD2 and 1 CMD), confirming that respiratory problems are not a major issue in LMNA-associated myopathies. Ten novel mutations were detected. Despite EDMD2, LGMD1B and MDCL phenotypes are part of a continuum spectrum, their identification is clinically and prognostically relevant.
Vegetable production in open greenhouses is often associated with high inputs of synthetic pesticides. Introducing flowering plants into such greenhouses may promote the top-down pest suppression by ...natural enemies and reduce the reliance on pesticide use. However, it is not known how effective this practice is in organically and conventionally managed greenhouse crops. We assessed the influence of introducing flowering plants into open greenhouses with organically and conventionally managed tomato crops on the abundance of pests, natural enemies (NE), pollinators, and crop yield. We monitored tomato crops during two years in two greenhouses at four organic farms and four conventional farms that used integrated pest management (IPM). On each farm one greenhouse contained flower islands of basil (Ocimum bacilicum), marigold (Tagetes patula) and alyssum (Lobularia maritima), and the other greenhouse served as a control. Organic farms had yields comparable to conventional farms, a lower abundance of pests, less pest injury, and a higher abundance of NE. The cumulative pest:NE ratio was 9 for organic and 38 for conventional management. The effect of introducing flowering plants on arthropods depended significantly on the type of farm management. Conventionally managed tomato crops in greenhouses with seven flower islands per 100 m2 had 18% lower pest abundance compared to the control greenhouses without flowers, while flower islands did not significantly influence arthropod abundances in organically managed tomato crops. Tomato plants had a higher abundance of pests than the three introduced plant species in conventionally managed greenhouses, while marigold had a higher abundance of pests than tomato in organically managed greenhouses. Alyssum supported a relatively low pest abundance and high abundance of NE and pollinators. Our findings indicate that NE in IPM-conventionally managed greenhouses can benefit from resources provided by flowering plants, resulting in reduced pest abundance, while in organically managed greenhouses the conditions are already favourable for the suppression of pests and addition of floral resources does not further improve the effectiveness of NE. This finding highlights the potential of agroecological and organic management to reduce the reliance on synthetic pesticides without yield reduction.
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•Arthropod responses to flower islands in greenhouse tomato in organic and conventional systems were studied.•Organic systems had fewer pests and more natural enemies than conventional systems, and yields were comparable.•Arthropod responses to flower islands depended on the type of management system.•In conventional systems, greenhouses with flower islands had 18% lower pest abundance than greenhouses without flowers.•Adding flowers alone is not enough to suppress pests and a holistic approach is needed.
Cover crops with reduced tillage technology (CC-RT) can foster soil health and functioning, a crucial agroecological principle in any transition strategy to more sustainable agricultural systems. ...However, CC-RT commonly strongly relies on herbicides and synthetic fertilizers, and vegetable crop yields are variable and often low. We assessed the effects of two tillage systems (RT and conventional tillage) and the application of native effective microorganisms (NEM) on onion crop growth and development, yield, N-status, weed pressure, and soil physico-chemical and biological quality after a summer CC, without using herbicides or synthetic fertilizers. Using a participatory research strategy, we conducted a two-year experiment at an experimental station and a one-year trial on two commercial farms. Onion yields were generally low (between 10 and 16 Mg ha−1) and lower in 2019 than in 2020, and lower in RT than in CT in 2020. The relatively low yields in 2019 and RT were associated with poor crop growth and development and leaf-N concentrations below the critical threshold in the early stages of crop development. Soil bulk density was not limiting crop growth in any treatment. Soil mineral N was lower in 2019 than in 2020 and did not significantly differ between treatments. Soil biological activity was higher in RT than in CT. Although the CC residue soil cover in the early stages of the onion crop in RT was more than 50%, RT had a higher weed pressure than CT, which was reversed later in the growing season. The NEM application did not significantly affect most crop, weed, and soil variables. In conclusion, a reduced tillage system for onions without herbicides and synthetic fertilizers is within reach. However, further research is needed to manage weeds and soil N supply dynamics to make CC-RT feasible for no or low agrochemical input systems.
•A cover crop–reduced tillage system for onion production without herbicides and synthetic fertilizers was studied.•Reduced tillage provided >80% soil cover, increased biological activity and did not constrain soil bulk density.•Onion yields were 50% lower than the regional average and lower in reduced than in conventional tillage.•Onion leaf N concentrations in reduced tillage were lower than in conventional tillage and weed pressure was higher.•Weed suppression and N availability in reduced tillage in no or low agrochemical input systems are still challenging.
In order to clarify the role of angiogenic factors in polyneuropathy of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome, we measured the serum ...concentrations of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in 11 patients and correlated these with VEGF and EPO peripheral nerve expression and the degree of endoneurial vessel involvement. We found that POEMS syndrome was associated with high levels of serum VEGF and, conversely, low levels of serum EPO. Similarly, in POEMS nerves VEGF was highly expressed in blood vessels and some non-myelin-forming Schwann cells. In contrast, the expression of VEGF receptor 2 was down-regulated compared with that in normal nerves. Both EPO and EPO receptor were localized to the nerve vasculature and were expressed to similar extents in normal and POEMS nerves. The inverse correlation between VEGF and EPO serum levels was maintained during the clinical course; however, both levels returned to normal when there was a response to therapy. High serum VEGF, low serum EPO and high peripheral nerve VEGF were all associated with more severe endoneurial vessel involvement and nerve damage. Light microscopy showed an increased thickness of the basal lamina and a narrowing of the lumina of endoneurial vessels in POEMS samples, while proliferation of endothelial cells and opening of tight junctions were observed by electron microscopy. The present data support the role of angiogenic factors as diagnostic and prognostic markers of POEMS syndrome. They also suggest that VEGF and EPO are involved in the pathogenesis of polyneuropathy. In conclusion, establishing the role of angiogenic factors in polyneuropathy may lead to a better understanding of the effects of VEGF and EPO on microangiopathy and Schwann cell function.
The aim is to provide an up-to-date overview of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome with special regard to the available therapy ...options.
In the past 20 years this rare plasmaproliferative disorder has been extensively characterized from a clinical point of view with complete description of the typical features as well as of other organ involvement not considered in the acronym as nephropathy or pachimeningitis. In this syndrome, the serum levels of vascular endothelial growth factor (VEGF) are abnormally elevated and now this is considered one of the major criteria for making the diagnosis. VEGF has also a prognostic value, as it decreases in response to therapy and definitely has a pathogenetic role in the multisystem involvement of POEMS. Recently great advance occurred in the treatment of POEMS syndrome with new immunomodulatory drugs such as lenalidomide, autologous peripheral blood stem cell transplantation or bevacizumab, an anti-VEGF monoclonal antibody.
Although many aspects of POEMS syndrome remain unclear, a valid biomarker of disease, VEGF, is available for diagnosis as well as a wide range of therapeutic options.
Converging evidence points to a pivotal role of vascular endothelial growth factor (VEGF) in neuronal protection and a lack of its activity in neurodegenerative disorders. To investigate this ...possible association, we screened the VEGF gene promoter for various well‐known single‐nucleotide polymorphisms in a series of 249 consecutively recruited Italian patients with sporadic Alzheimer's disease (AD). Genetic analysis indicated different distributions of two single‐nucleotide polymorphisms in the AD population compared with healthy control subjects. In particular, the frequencies of −2578A/A and −1198C/T genotypes were significantly greater in AD patients than in control subjects (23.7 vs 14.7% and 2.8 vs 0%, respectively). The −2578A/A genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype. The risk was significantly increased with respect to various VEGF genotype combinations. In contrast, no difference in serum VEGF levels was detected comparing 96 patients and 49 control subjects. These findings suggest that polymorphisms within the promoter region of the VEGF gene confer greater risk for AD, probably by reducing its neuroprotective effect, and confirm the biological role of VEGF in neurodegenerative processes. Ann Neurol 2005;57:373–380
The neuropilins, NP-1 and NP-2, are coreceptors for Sema3A and Sema3F, respectively, both of which are repulsive axonal guidance molecules. NP-1 and NP-2 are also coreceptors for vascular endothelial ...growth factor (VEGF). The neuropilins and their ligands are known to play prominent roles in axonal pathfinding, fasciculation, and blood vessel formation during peripheral nervous system (PNS) development. We confirmed a prior report (Exp. Neurol. 172 (2001) 398) that VEGF mRNA levels rise during Wallerian degeneration in the PNS and herein demonstrate that NP-1, NP-2, Sema3A, and Sema3F mRNA levels increase in peripheral nerves distal to a transection or crush injury. In a sciatic nerve crush model, in which axonal regeneration is robust, the highest levels of Sema3F mRNA below the injury site are in the epi- and perineurium. Our results suggest the possibility that the neuropilins and their semaphorin ligands serve to guide, rather than to impede, regenerating axons in the adult PNS.
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