Publications by authors named "Federica Esposito"

52 Publications

Mesenchymal Stromal Cells and Their Secretome: New Therapeutic Perspectives for Skeletal Muscle Regeneration.

Front Bioeng Biotechnol 2021 13;9:652970. Epub 2021 May 13.

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy.

Mesenchymal stromal cells (MSCs) are multipotent cells found in different tissues: bone marrow, peripheral blood, adipose tissues, skeletal muscle, perinatal tissues, and dental pulp. MSCs are able to self-renew and to differentiate into multiple lineages, and they have been extensively used for cell therapy mostly owing to their anti-fibrotic and immunoregulatory properties that have been suggested to be at the basis for their regenerative capability. MSCs exert their effects by releasing a variety of biologically active molecules such as growth factors, chemokines, and cytokines, either as soluble proteins or enclosed in extracellular vesicles (EVs). Analyses of MSC-derived secretome and in particular studies on EVs are attracting great attention from a medical point of view due to their ability to mimic all the therapeutic effects produced by the MSCs (i.e., endogenous tissue repair and regulation of the immune system). MSC-EVs could be advantageous compared with the parental cells because of their specific cargo containing mRNAs, miRNAs, and proteins that can be biologically transferred to recipient cells. MSC-EV storage, transfer, and production are easier; and their administration is also safer than MSC therapy. The skeletal muscle is a very adaptive tissue, but its regenerative potential is altered during acute and chronic conditions. Recent works demonstrate that both MSCs and their secretome are able to help myofiber regeneration enhancing myogenesis and, interestingly, can be manipulated as a novel strategy for therapeutic interventions in muscular diseases like muscular dystrophies or atrophy. In particular, MSC-EVs represent promising candidates for cell free-based muscle regeneration. In this review, we aim to give a complete picture of the therapeutic properties and advantages of MSCs and their products (MSC-derived EVs and secreted factors) relevant for skeletal muscle regeneration in main muscular diseases.
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http://dx.doi.org/10.3389/fbioe.2021.652970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172230PMC
May 2021

Assessment of the genetic contribution to brain magnetic resonance imaging lesion load and atrophy measures in multiple sclerosis patients.

Eur J Neurol 2021 Apr 17. Epub 2021 Apr 17.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background And Purpose: Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients.

Methods: Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis.

Results: Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p = 0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p = 0.004 and p = 0.008, respectively). As for SNPs, the rs7104613 mapping to SPON1 gene was associated with reduced deep grey matter volume (β = -0.731, p = 3.2*10 ) in PMS, whereas we found evidence of association between white matter volume and rs740948 mapping to SEMA3A gene (β = 22.04, p = 5.5*10 ) in RRMS.

Conclusions: Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.
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http://dx.doi.org/10.1111/ene.14872DOI Listing
April 2021

Dynamic Functional Connectivity in the Main Clinical Phenotypes of Multiple Sclerosis.

Brain Connect 2021 May 13. Epub 2021 May 13.

Neuroimaging Research Unit, Division of Neuroscience, IRCSS San Raffaele Scientific Institute, Milan, Italy.

Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances. RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks. dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC ( = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments ( = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances. MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage.
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http://dx.doi.org/10.1089/brain.2020.0920DOI Listing
May 2021

Involvement of Genetic Factors in Multiple Sclerosis.

Front Cell Neurosci 2020 1;14:612953. Epub 2020 Dec 1.

Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.3389/fncel.2020.612953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735985PMC
December 2020

Intracortical motor conduction is associated with hand dexterity in progressive multiple sclerosis.

Mult Scler 2020 Sep 25:1352458520960374. Epub 2020 Sep 25.

University Vita-Salute San Raffaele, Milan, Italy/Department of Neurorehabilitation, IRCCS Ospedale San Raffaele, Milan, Italy/Experimental Neurophysiology Unit, The Institute of Experimental Neurology (INSPE), IRCCS Ospedale San Raffaele, Milan, Italy.

Background: Hand dexterity dysfunction is a key feature of disability in people with progressive multiple sclerosis (PMS). It underlies corticospinal tract (CST) and cerebellar integrity, as well as disruption of cortical networks, which are hardly assessed by standard techniques. Transcranial magnetic stimulation is a promising tool for evaluating the integrity of intracortical motor pathways.

Objective: To investigate neurophysiological correlates of motor hand impairment in PMS.

Methods: Antero-posterior (AP) stimulation of the primary motor cortex activates the CST indirectly through polysynaptic pathways, while a direct CST activation occurs with latero-medial (LM) directed current. Thirty PMS and 15 healthy controls underwent dominant hand motor evoked potentials (MEP) using AP and LM-directed stimulation, and a clinical assessment of dexterity (nine-hole peg test) and strength (MRC scale, grip and pinch).

Results: PMS with AP-LM latency difference 2.5 standard deviation above the mean of controls (33%) showed worse dexterity but no difference in upper limb strength. Accordingly, AP-LM latency shortening predicted dexterity (R = 0.538,  < 0.001), but not strength impairment. On the contrary, absolute MEP latencies only correlated with strength (grip: R = 0.381,  = 0.014; MRC: R = 0.184,  = 0.041).

Conclusion: AP-LM latency shortening may be used to assess the integrity polysynaptic intracortical networks implicated in dexterity impairment.
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http://dx.doi.org/10.1177/1352458520960374DOI Listing
September 2020

Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis.

Mult Scler 2020 Sep 25:1352458520961690. Epub 2020 Sep 25.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Fingolimod (FTY) is an effective second-line drug for relapsing-remitting multiple sclerosis, with ~50% patients showing no evidence of disease activity (NEDA) after 2 years. Nonetheless, the early identification of non-responders is extremely important, to promptly address them to more aggressive drugs.

Objectives: This cohort study evaluates FTY medium-term effectiveness, searching for early markers of treatment failure.

Patients And Methods: Three hundred eighty patients starting FTY were enrolled and classified according to NEDA and time to first relapse criteria at 4-year follow-up. Logistic and Cox regression analyses were applied to identify early predictors of non-response.

Results: At 4 years, 65.6% of patients were free from relapses and 35.4% had NEDA. Female gender was associated with a higher risk of non-response. Moreover, evidence of clinical and/or magnetic resonance imaging (MRI) activity during the first year of treatment was highly predictive of disease activity in the follow-up: the positive predictive value for non-response was 0.74 for the presence of ⩾1 relapse, 0.73 for the presence of ⩾1 active MRI lesion, and 0.83 for the presence of both clinical and MRI activity.

Conclusions: FTY effectiveness persists at medium-term follow-up; a close monitoring during the first year of treatment is warranted to early identify non-responders requiring treatment optimization.
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http://dx.doi.org/10.1177/1352458520961690DOI Listing
September 2020

MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes.

Mult Scler 2020 Sep 14:1352458520958356. Epub 2020 Sep 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood.

Objectives: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes.

Methods: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment.

Result: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)- = 0.19, -range = <0.001-0.04), z9HPT (right: OOB- = 0.14; left: OOB- = 0.24, -range = <0.001-0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB- = 0.16, -range = 0.02-0.04).

Conclusion: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.
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http://dx.doi.org/10.1177/1352458520958356DOI Listing
September 2020

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

J Neurol Neurosurg Psychiatry 2020 09 13;91(9):914-920. Epub 2020 Jul 13.

Department of Medical Sciences, Università degli Studi di Cagliari, Cagliari, Sardegna, Italy.

Introduction: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.

Materials And Methods: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.

Results: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months.

Discussion: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.
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http://dx.doi.org/10.1136/jnnp-2019-322480DOI Listing
September 2020

Impact of multiple sclerosis risk loci in postinfectious neurological syndromes.

Mult Scler Relat Disord 2020 Sep 24;44:102326. Epub 2020 Jun 24.

Fondazione Istituto Neurologico Nazionale IRCCS Mondino, via Mondino 2, 27100 Pavia, Italy.

Background: The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores.

Methods: Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS.

Results: PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0-1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p<0.0001). The difference was even larger for PINS with peripheral nervous system involvement (wGRS=20.6) vs BOMS.

Conclusion: The distinction between MS and PINS is not easy to make in clinical practice. However, our study shows that the new set of MS risk alleles does not confer increased susceptibility to PINS. These data support the importance to discriminate these cases from MS with pathophysiological and therapeutic implications.
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http://dx.doi.org/10.1016/j.msard.2020.102326DOI Listing
September 2020

α-synuclein overexpression in the retina leads to vision impairment and degeneration of dopaminergic amacrine cells.

Sci Rep 2020 06 15;10(1):9619. Epub 2020 Jun 15.

Telethon Institute of Genetics and Medicine, Telethon Foundation, Pozzuoli, Naples, Italy.

The presence of α-synuclein aggregates in the retina of Parkinson's disease patients has been associated with vision impairment. In this study we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic amacrine cells (DACs) in the retina. Adult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Before and after systemic injections of levodopa (L-DOPA), retinal responses and visual acuity-driven behavior were measured by electroretinography (ERG) and a water maze task, respectively. Amacrine cells and ganglion cells were counted at different time points after the injection. α-synuclein overexpression led to an early loss of DACs associated with a decrease of light-adapted ERG responses and visual acuity that could be rescued by systemic injections of L-DOPA. The data show that α-synuclein overexpression affects dopamine neurons in the retina. The approach provides a novel accessible method to model the underlying mechanisms implicated in the pathogenesis of synucleinopathies and for testing novel treatments.
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http://dx.doi.org/10.1038/s41598-020-66497-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295803PMC
June 2020

Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle.

EMBO Rep 2020 04 27;21(4):e49075. Epub 2020 Feb 27.

Stem Cell Fate Laboratory, CNR, Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy.

Macrophages are characterized by a high plasticity in response to changes in tissue microenvironment, which allows them to acquire different phenotypes and to exert essential functions in complex processes, such as tissue regeneration. Here, we report that the membrane protein Cripto plays a key role in shaping macrophage plasticity in skeletal muscle during regeneration and disease. Conditional deletion of Cripto in the myeloid lineage (Cripto ) perturbs MP plasticity in acutely injured muscle and in mouse models of Duchenne muscular dystrophy (mdx). Specifically, Cripto macrophages infiltrate the muscle, but fail to properly expand as anti-inflammatory CD206 macrophages, which is due, at least in part, to aberrant activation of TGFβ/Smad signaling. This reduction in macrophage plasticity disturbs vascular remodeling by increasing Endothelial-to-Mesenchymal Transition (EndMT), reduces muscle regenerative potential, and leads to an exacerbation of the dystrophic phenotype. Thus, in muscle-infiltrating macrophages, Cripto is required to promote the expansion of the CD206 anti-inflammatory macrophage type and to restrict the EndMT process, providing a direct functional link between this macrophage population and endothelial cells.
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http://dx.doi.org/10.15252/embr.201949075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132341PMC
April 2020

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Front Immunol 2019 13;10:1908. Epub 2019 Aug 13.

Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Rome, Italy.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.
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http://dx.doi.org/10.3389/fimmu.2019.01908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700292PMC
September 2020

A pharmacogenetic study implicates in the response to Interferon-β in multiple sclerosis.

Mult Scler 2020 08 21;26(9):1074-1082. Epub 2019 Jun 21.

Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSPE), IRCCS San Raffaele Scientific Institute, Milan, Italy/Department of Biomedical Sciences for Health, University of Milan, Milan, Italy/Department of Neurology, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients.

Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role.

Methods: Survival analysis was applied in three MS cohorts from different countries ( = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between expression, IFNβ and TTFR.

Results: Rs7298096 patients show a shorter TTFR than rs7298096-carriers (P = 3 × 10, hazard ratio = 1.41). Moreover, rs7298096 is associated with a higher expression in blood ( = 7.0 × 10), which was confirmed in vitro ( = 0.009). Finally, expression is downregulated by IFNβ treatment and related to TTFR.

Conclusions: Rs7298096 could influence MS disease activity during IFNβ treatment by modulating expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.
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http://dx.doi.org/10.1177/1352458519851428DOI Listing
August 2020

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

PLoS Genet 2019 06 6;15(6):e1008180. Epub 2019 Jun 6.

Red Española de Esclerosis Múltiple REEM, Madrid, Spain.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
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http://dx.doi.org/10.1371/journal.pgen.1008180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553700PMC
June 2019

Caesarean section and infant formula feeding are associated with an earlier age of onset of multiple sclerosis.

Mult Scler Relat Disord 2019 Aug 21;33:75-77. Epub 2019 May 21.

Department of Neurology, San Raffaele Hospital, via Olgettina 48, 20132 Milan, Italy. Electronic address:

Mode of delivery and lactation are among the earliest factors influencing gut microbiota composition and potentially MS risk, but their contribution to MS susceptibility has been controversial. We investigated whether these factors could influence age at MS onset (AAO) on 2055 RRMS patients (mean age 28.4 years). Patients born by means of a caesarean section (10.9%) had an earlier AAO than those born through natural delivery (-5.2 years, p < 0.001). Patients fed with infant formula had an earlier AAO compared to patients breastfed, particularly considering those breastfed for at least 6 months (-4.2 years, p < 0.001). The association of vaginal delivery and natural breastfeeding with a later AAO of MS was particularly apparent in patients without a family history of MS, while disappeared in patients with familiarity for MS. The results suggest these modifiable environmental factors which act at the population level may have an influence on the onset of the disease.
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http://dx.doi.org/10.1016/j.msard.2019.05.010DOI Listing
August 2019

Imaging correlates of hand motor performance in multiple sclerosis: A multiparametric structural and functional MRI study.

Mult Scler 2020 02 18;26(2):233-244. Epub 2019 Jan 18.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/ Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Hand motor impairment has considerable effects on daily-life activities of patients with multiple sclerosis (pwMS). Understanding its anatomo-functional substrates is relevant to provide more specific therapeutic interventions.

Objectives: To investigate the association between hand motor performance and anatomo-functional magnetic resonance imaging (MRI) abnormalities in pwMS.

Methods: A total of 134 healthy controls (HC) and 366 pwMS underwent the Nine-Hole-Peg-Test (9HPT), structural and resting state (RS) functional MRI. Multivariate analyses identified the independent predictors of hand motor performance.

Results: PwMS versus HC showed widespread gray matter atrophy, microstructural white matter abnormalities, and decreased RS functional connectivity in motor and cognitive networks. Predictors of worse right-9HPT ( = 0.52) were decreased right superior cerebellar peduncle and right lemniscus fractional anisotropy (FA) ( ⩽ 0.02), left angular gyrus atrophy ( < 0.003), decreased RS connectivity in left superior frontal gyrus, and left posterior cerebellum ( < 0.001). Worse left 9HPT ( = 0.56) was predicted by decreased right corticospinal FA ( = 0.003), atrophy of left anterior cingulum and left cerebellum ( ⩽ 0.02), decreased RS connectivity of left lingual gyrus and right posterior cerebellum in cerebellar and executive networks ( ⩽ 0.02).

Conclusion: Structural and functional abnormalities of regions involved in motor functions contribute to explain motor disability in pwMS. The integration of clinical and advanced MRI measures contributes to improve our understanding of multiple sclerosis clinical manifestations.
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http://dx.doi.org/10.1177/1352458518822145DOI Listing
February 2020

Response to the commentary "The effect of C9orf72 intermediate repeat expansions in neurodegenerative and autoimmune diseases" by Biasiotto G and Zanella I..

Mult Scler Relat Disord 2019 01 14;27:79-80. Epub 2018 Oct 14.

Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, 20149 Milan, Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, 20122 Milan, Italy.

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http://dx.doi.org/10.1016/j.msard.2018.10.007DOI Listing
January 2019

No C9orf72 repeat expansion in patients with primary progressive multiple sclerosis.

Mult Scler Relat Disord 2018 Oct 1;25:192-195. Epub 2018 Aug 1.

Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Milan 20145, Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milan 20122, Italy. Electronic address:

Pathological repeat expansion (RE) of the C9orf72 hexanucleotide sequence is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia disease continuum, although other heterogeneous clinical phenotypes have been documented. The occurrence of multiple sclerosis (MS) in some C9orf72 carriers with a more severe ALS disease course has suggested a possible modifying role for MS. However, C9orf72 RE seems not to play a role in MS pathogenesis. In this study, we screened C9orf72 in 189 Italian patients with primary progressive MS (PPMS), a rare clinical form characterized by less inflammation over neurodegenerative features. We failed to detect C9orf72 RE, but a significant representation of intermediate alleles (≥ 20 units) was observed in our PPMS cohort (2.1%) compared to healthy controls (0%, p < 0.05). In the normal range, allele distribution showed a trimodal pattern (2,5,8-repeat units) in PPMS and healthy controls with no significant difference. Our findings further demonstrate that C9orf72 RE is not genetically associated to MS spectrum, but suggest that intermediate alleles may represent risk factors as already reported for Parkinson disease.
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http://dx.doi.org/10.1016/j.msard.2018.07.047DOI Listing
October 2018

Functional and structural plasticity following action observation training in multiple sclerosis.

Mult Scler 2019 10 7;25(11):1472-1487. Epub 2018 Aug 7.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Hand motor deficits contribute to multiple sclerosis (MS)-related disability. Action observation training (AOT) is promising to improve upper limb function in neurologic patients.

Objectives: In this preliminary study, we investigated AOT effects on dominant-hand motor performance in MS patients with upper limb motor impairment and performed an explorative analysis of their anatomical and functional magnetic resonance imaging (MRI) substrates.

Methods: In total, 46 healthy controls (HC) and 41 MS patients with dominant-hand motor impairment were randomized to AOT (HC-AOT = 23; MS-AOT = 20; watching daily-life action videos and execution) or control-training (HC-Control = 23; MS-Control = 21; watching landscapes videos and execution). Behavioral, structural, and functional (at rest and during object manipulation) MRI scans were acquired before and after a 2-week training.

Results: After training, MS groups improved in right upper limb functions, mainly in AOT group ( from 0.02 to 0.0001). All groups showed regional increased and decreased gray matter volume, with specific AOT effects in fronto-temporal areas in MS-AOT ( < 0.001), without white matter (WM) integrity modifications. Increased and reduced recruitments of the action observation matching system and its connections in MS-AOT were found ( < 0.001). Motor improvements were correlated with volumetric and functional MRI modifications ( from -0.78 to 0.77,  < 0.001).

Conclusion: The 10-day AOT promotes clinical improvements in MS patients through structural and functional modifications of the action observation matching system.
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http://dx.doi.org/10.1177/1352458518792771DOI Listing
October 2019

Assessing the role of innovative therapeutic paradigm on multiple sclerosis treatment response.

Acta Neurol Scand 2018 Nov 22;138(5):447-453. Epub 2018 Jul 22.

Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.

Objective: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course.

Materials And Methods: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011.

Results: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis.

Conclusions: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies.
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http://dx.doi.org/10.1111/ane.12999DOI Listing
November 2018

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.

Ann Neurol 2018 07 3;84(1):51-63. Epub 2018 Jul 3.

UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA.

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.

Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.

Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.

Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.
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http://dx.doi.org/10.1002/ana.25263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119489PMC
July 2018

Break-out session highlights.

Neurodegener Dis Manag 2017 Nov;7(6s):45-49

Department of Neurology, University Hospital, Friedrich-Alexander University, Erlangen-Nuremberg, Germany.

A popular feature of the Multiple Sclerosis Experts Summit is interactive break-out sessions to discuss various aspects of multiple sclerosis (MS), including MS spasticity and general management of MS patients. The format encourages participation and active discussion, thus providing attendees with the opportunity to exchange their experiences of the day-to-day management of MS in clinical practice. Following feedback provided by each session leader, key messages are summarized and presented in a plenary session by the Summit chair. Topics covered in this year's country break-out sessions included: triggering factors for MS; decision-making in MS and the importance of patients' risk perception; assessment and management of MS spasticity.
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http://dx.doi.org/10.2217/nmt-2017-0042DOI Listing
November 2017

NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients.

Mult Scler 2018 10 9;24(11):1507-1510. Epub 2017 Nov 9.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat) and Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients.
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http://dx.doi.org/10.1177/1352458517739137DOI Listing
October 2018

Clinical deterioration due to co-occurrence of multiple sclerosis and glioblastoma: report of two cases.

Neurol Sci 2017 Feb 11;38(2):361-364. Epub 2016 Nov 11.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy.

Clinical worsening during the course of multiple sclerosis (MS) might be secondary to not only an incomplete recovery after relapses, to progressive accumulation of deficits, but also to other etiologies, different from MS. This report discusses the cases of two MS patients showing a gradual and progressive deterioration of locomotor and cognitive functions which were due to the co-occurrence of MS and glioblastoma. Additional investigations (especially magnetic resonance imaging) are strongly recommended to exclude concomitant pathologies in MS patients suffering from new neurological symptoms over weeks to months, without remission, or an unexpected rapid and progressive accumulation of disability.
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http://dx.doi.org/10.1007/s10072-016-2763-yDOI Listing
February 2017

Efficacy and safety of nabiximols (Sativex(®)) on multiple sclerosis spasticity in a real-life Italian monocentric study.

Neurol Sci 2016 Feb 16;37(2):235-42. Epub 2015 Oct 16.

Department of Neurology, San Raffaele Scientific Institute, Via Olgettina 48, 20132, Milan, Italy.

Multiple sclerosis (MS) patients frequently suffer from limb spasticity and pain despite antispastic treatments. To investigate nabiximols efficacy and safety in a real-world monocentric Italian cohort, the following data were collected at baseline, week 4, 14 and 48: Ambulation Index (AI), 10-min walking test (10MWT), combined Modified Ashworth scale (cMAS), scores at numerical rating scale for spasticity (sNRS) and pain (pNRS). Responder status was defined as a ≥20 % reduction in sNRS after 4 weeks of treatment. 144 MS patients (123 progressive and 21 relapsing-remitting) complaining of moderate-to-severe spasticity (mean sNRS: 7.5) were included: 138 (95.8 %) completed the first month of therapy and were classified as follows-23.2 % were non-responders, 5.1 % were responders but discontinued treatment due to side effects, 71.7 % were responders with a mean 32 % reduction in sNRS (p < 0.001). In responders sNRS further decreased between 4 and 14 weeks (p = 0.03). Similarly, pNRS improvement was seen during the first month and between 4 and 14 weeks (p < 0.001 and p = 0.004, respectively). Moreover, at 4 weeks responders showed a significant (p < 0.05) improvement in cMAS, AI and 10MWT, which was maintained at 14 weeks. At 1-year follow-up, a benefit was still evident on spasticity and painful symptoms with a low drop-out rate. Confusion/ideomotor slowing, fatigue and dizziness were the most frequent side effects; no major adverse events were reported. Shorter disease duration at treatment start was associated with better response. This real-world study confirms nabiximols efficacy and safety in the treatment of MS-related spasticity and pain, which is maintained up to 48 weeks.
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http://dx.doi.org/10.1007/s10072-015-2392-xDOI Listing
February 2016

The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF.

Reprod Sci 2016 Apr 6;23(4):515-23. Epub 2015 Oct 6.

Department of Woman and Child Health, University of Padua, Padua, Italy.

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9-22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-β-estradiol (E(2)) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E(2) at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with "isolated" increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation.
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http://dx.doi.org/10.1177/1933719115608000DOI Listing
April 2016

The burden of multiple sclerosis variants in continental Italians and Sardinians.

Mult Scler 2015 Oct;21(11):1385-95

Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.

Background: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored.

Objective: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians.

Methods: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves.

Results: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles.

Conclusions: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
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http://dx.doi.org/10.1177/1352458515596599DOI Listing
October 2015

Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction.

Neurol Neuroimmunol Neuroinflamm 2015 Aug 9;2(4):e129. Epub 2015 Jul 9.

Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.

Objective: To investigate the role of known multiple sclerosis (MS)-associated genetic variants in MS familial aggregation, clinical expression, and accuracy of disease prediction in sporadic and familial cases.

Methods: A total of 1,443 consecutive patients were screened for MS and familial autoimmune history in a hospital-based Italian cohort. Among them, 461 sporadic and 93 familial probands were genotyped for 107 MS-associated polymorphisms. Their effect sizes were combined to calculate the weighted genetic risk score (wGRS).

Results: Family history of MS was reported by 17.2% of probands, and 33.8% reported a familial autoimmune disorder, with autoimmune thyroiditis and psoriasis being the most frequent. No difference in wGRS was observed between sporadic and familial MS cases. In contrast, a lower wGRS was observed in probands with greater familial aggregation (>1 first-degree relative or >2 relatives with MS) (p = 0.03). Also, female probands of familial cases with greater familial aggregation had a lower wGRS than sporadic cases (p = 0.0009) and male probands of familial cases (p = 0.04). An inverse correlation between wGRS and age at onset was observed (p = 0.05). The predictive performance of the genetic model including all known MS variants was modest but greater in sporadic vs familial cases (area under the curve = 0.63 and 0.57).

Conclusions: Additional variants outside the known MS-associated loci, rare variants, and/or environmental factors may explain disease occurrence within families; in females, hormonal and epigenetic factors probably have a predominant role in explaining familial aggregation. The inclusion of these additional factors in future versions of aggregated genetic measures could improve their predictive ability.
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http://dx.doi.org/10.1212/NXI.0000000000000129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503410PMC
August 2015

Serum Stem Cell Factor Assay in Elderly Poor Responder Patients Undergoing IVF: A New Biomarker to Customize Follicle Aspiration Cycle by Cycle.

Reprod Sci 2016 Jan 7;23(1):61-8. Epub 2015 Jul 7.

Department of Woman and Child Health-University of Padua, Padua, Italy.

In humans, stem cell factor (SCF), produced during follicular phase, may reflect a successful stimulation and oocyte maturation and so it may be a predictor of in vitro fertilization (IVF) outcome. An observational cohort study was conducted on 37 poor responders scheduled for fresh nondonor IVF/intracytoplasmic sperm injection treatment with standard controlled ovarian stimulation (COS) using recombinant follicle-stimulating hormone (rFSH; S-COS group). A total of 35 women received a second treatment using both rFSH and recombinant luteinizing hormone (rLH; LH-COS group). From 144 samples collected at pickup day, serum concentration of SCF (s-SCF) and follicular levels of SCF (f-SCF) were measured by enzyme-linked immunosorbent assay (ELISA) kit. No differences were observed between the 2 protocols in terms of both f-SCF and s-SCF levels. The comparison between f-SCF and s-SCF levels showed a strong linear correlation. The comparison between s-SCF levels and clinical outcomes showed a statistically significant correlation between both the number of metaphase II (MII) oocytes retrieved and the embryos obtained after fertilization. Cases with at least 3 MII oocytes showed s-SCF values >800 pg/mL, 2 MII oocytes >600 pg/mL, and 1 MII oocytes >400 pg/mL. In 100% of cases with s-SCF <400 pg/mL, no MII oocytes were recovered. All 5 pregnancies occurred in patients with s-SCF values >1000 pg/mL. The introduction of s-SCF assay in the management of poor-responder patients may contribute to solving the dilemma of whether to cancel or proceed with the stimulation cycle.
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http://dx.doi.org/10.1177/1933719115594020DOI Listing
January 2016