Microbial risk factors of cardiovascular and cerebrovascular diseases: potential therapeutic options

Infection and inflammation may have a crucial role in the pathogenesis of atherosclerosis. This hypothesis is supported by an increasing number of reports on the interaction between chronic infection, inflammation, and atherogenesis. Assessment of serological and inflammatory markers of infection may be useful adjuncts in identifying those patients who are at a higher risk of developing vascular events, and in whom more aggressive treatments might be warranted

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders

Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disorder that targets upper and lower motor neurons and leads to fatal muscle paralysis. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for 15% of familial ALS cases, but several studies have indicated that SOD1 dysfunction may also play a pathogenic role in sporadic ALS. SOD1 induces numerous toxic effects through the pathological misfolding and aggregation of mutant SOD1 species, hence a reduction of the levels of toxic variants appears to be a promising therapeutic strategy for SOD1-related ALS. Several methods are used to modulate gene expression in vivo; these include RNA interference, antisense oligonucleotides (ASOs) and CRISPR/Cas9 technology. Areas covered: This paper examines the current approaches for gene silencing and the progress made in silencing SOD1 in vivo. It progresses to shed light on the key results and pitfalls of these studies and highlights the future challenges and new perspectives for this exciting research field. Expert opinion: Gene silencing strategies targeting SOD1 may represent effective approaches for familial and sporadic ALS-related neurodegeneration; however, the risk of off-target effects must be minimized, and effective and minimally invasive delivery strategies should be fine-tuned

Noncoding RNAs in Duchenne and Becker muscular dystrophies: role in pathogenesis and future prognostic and therapeutic perspectives

Noncoding RNAs (ncRNAs), such as miRNAs and long noncoding RNAs, are key regulators of gene expression at the post-transcriptional level and represent promising therapeutic targets and biomarkers for several human diseases, including Duchenne and Becker muscular dystrophies (DMD/BMD). A role for ncRNAs in the pathogenesis of muscular dystrophies has been suggested, even if it is still incompletely understood. Here, we discuss current progress leading towards the clinical utility of ncRNAs for DMD/BMD. Long and short noncoding RNAs are differentially expressed in DMD/BMD and have a mechanism of action via targeting mRNAs. A subset of muscle-enriched miRNAs, the so-called myomiRs (miR-1, miR-133, and miR-206), are increased in the serum of patients with DMD and in dystrophin-defective animal models. Interestingly, myomiRs might be used as biomarkers, given that their levels can be corrected after dystrophin restoration in dystrophic mice. Remarkably, further evidence demonstrates that ncRNAs also play a role in dystrophin expression; thus, their modulations might represent a potential therapeutic strategy with the aim of upregulating the dystrophin protein in combination with other oligonucleotides/gene therapy approaches

Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?

Spinal muscular atrophy (SMA) is a severe, inherited disease characterized by the progressive degeneration and death of motor neurons of the anterior horns of the spinal cord, which results in muscular atrophy and weakness of variable severity. Its early-onset form is invariably fatal in early childhood, while milder forms lead to permanent disability, physical deformities and respiratory complications. Recently, two novel revolutionary therapies, antisense oligonucleotides and gene therapy, have been approved, and might prove successful in making long-term survival of these patients likely. In this perspective, a deep understanding of the pathogenic mechanisms and of their impact on the interactions between motor neurons and other cell types within the central nervous system (CNS) is crucial. Studies using SMA animal and cellular models have taught us that the survival and functionality of motor neurons is highly dependent on a whole range of other cell types, namely glial cells, which are responsible for a variety of different functions, such as neuronal trophic support, synaptic remodeling, and immune surveillance. Thus, it emerges that SMA is likely a non-cell autonomous, multifactorial disease in which the interaction of different cell types and disease mechanisms leads to motor neurons failure and loss. This review will introduce the different glial cell types in the CNS and provide an overview of the role of glial cells in motor neuron degeneration in SMA. Furthermore, we will discuss the relevance of these findings so far and the potential impact on the success of available therapies and on the development of novel ones

The geometrical nature of optical resonances : from a sphere to fused dimer nanoparticles

We study the electromagnetic response of smooth gold nanoparticles with shapes varying from a single sphere to two ellipsoids joined smoothly at their vertices. We show that the plasmonic resonance visible in the extinction and absorption cross sections shifts to longer wavelengths and eventually disappears as the mid-plane waist of the composite particle becomes narrower. This process corresponds to an increase of the numbers of internal and scattering modes that are mainly confined to the surface and coupled to the incident field. These modes strongly affect the near field, and therefore are of great importance in surface spectroscopy, but are almost undetectable in the far field

A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project.

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms "multiple sclerosis" combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99-1.32, for preterm births RR = 0.93, 95% CI 0.72-1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47-1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin \u3bc-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease

thalamic damage predicts the evolution of primary progressive multiple sclerosis at 5 years

BACKGROUND AND PURPOSE: Reliable markers to monitor PPMS are still needed. We investigated whether conventional and DTI measures of thalamic damage are predictive of long-term disability accumulation in PPMS. MATERIALS AND METHODS: Brain conventional and DTI scans were obtained at baseline and after a mean follow-up of 15 months in 54 patients with PPMS and 8 healthy controls. Patients were reassessed clinically after 5 years. At baseline and follow-up, measures of lesion load, brain atrophy, and NTV were obtained. MD and FA histograms of the NAWM, the whole GM without the thalami, and the thalami were obtained. A multivariate analysis evaluated the predictors of long-term neurologic deterioration. RESULTS: At follow-up, 35 patients showed disability worsening. At baseline, compared with healthy controls, patients with PPMS had lower NTV ( P P = .002) and higher thalamic ( P = .002) and whole GM without the thalami ( P = .005) MD. During follow-up, the change of thalamic FA was higher in PPMS versus healthy controls ( P = .01). Baseline NTV and thalamic DTI quantities differed significantly between patients with PPMS with and without thalamic lesions. Baseline thalamic quantities were significantly correlated with the extent of brain T2 lesions and the severity of NAWM damage. The multivariate model included average NAWM MD (OR = 1.46, P = .005) and FA thalamic change (OR = 0.84, P = .02) as independent predictors of EDSS score deterioration (Nagelkerke R 2 = 0.55). CONCLUSIONS: Short-term accrual of thalamic damage and the severity of NAWM involvement predict the long-term accumulation of disability in PPMS