Publications by authors named "Ferdinando Cornelio"

28 Publications

  • Page 1 of 1

Mediterranean Diet and Cognitive Status in Free-Living Elderly: A Cross-Sectional Study in Northern Italy.

J Am Coll Nutr 2018 08 5;37(6):494-500. Epub 2018 Apr 5.

a International Center for the Assessment of Nutritional Status, Department of Food, Environmental, and Nutritional Sciences , University of Milan , Milan , Italy.

Objective: Few data are available on the Italian elderly population with regard to adherence to the Mediterranean diet (MD) and cognitive impairment. Our aim was to investigate adherence to the MD and its association with cognitive function in an Italian urban sample.

Methods: A cross-sectional study of 279 participants aged ≥ 65 years (80 men, 199 women) was carried out at a nutritional center. Adherence to the MD was evaluated using a 14-item questionnaire. Cognitive function was assessed with the Mini-Mental State Examination (MMSE).

Results: The clinical and nutritional assessments performed revealed 30.1% to have a dietary pattern in accordance with the MD; 13.6% had suspected or mild cognitive impairment (MMSE score ≤ 23). The MD pattern was associated with a lower risk of cognitive impairment (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.15-0.99; p = 0.045), as was the consumption of wine (OR = 0.37; 95% CI, 0.16-0.84; p = 0.018) and nuts (OR = 0.30; 95% CI, 0.13-0.69, p = 0.005). No association was found with other food groups.

Conclusion: A closer adherence to the MD was associated with a better cognitive status. Further cohort studies and randomized controlled trials are warranted.
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http://dx.doi.org/10.1080/07315724.2018.1442263DOI Listing
August 2018

Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy.

Biochim Biophys Acta 2015 Jul 17;1852(7):1451-64. Epub 2015 Apr 17.

Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy. Electronic address:

Excessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition.
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http://dx.doi.org/10.1016/j.bbadis.2015.04.013DOI Listing
July 2015

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.

Brain 2014 Jun 10;137(Pt 6):1643-55. Epub 2014 Apr 10.

1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.
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http://dx.doi.org/10.1093/brain/awu069DOI Listing
June 2014

Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.

Sleep Med 2014 May 12;15(5):582-5. Epub 2014 Feb 12.

DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. Electronic address:

Objective: We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.

Methods: Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed.

Results: History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities.

Conclusions: The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.
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http://dx.doi.org/10.1016/j.sleep.2013.09.028DOI Listing
May 2014

Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy.

Hum Mol Genet 2012 May 9;21(10):2205-10. Epub 2012 Feb 9.

Institute of Human Genetics, Technische Universität München, Munich 81675, Germany.

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.
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http://dx.doi.org/10.1093/hmg/dds035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465691PMC
May 2012

Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes.

J Neurol 2010 Jul 16;257(7):1119-23. Epub 2010 Feb 16.

Laboratory NBS Biotech, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.

Congenital myasthenic syndromes are rare genetic disorders compromising neuromuscular transmission. The defects are mainly mutations in the muscle acetylcholine receptor, or associated proteins rapsyn and Dok-7. We analyzed three unrelated Italian patients with typical clinical features of congenital myasthenic syndrome, who all benefitted from cholinesterase inhibitors. We found five mutations: a previously unreported homozygous alphaG378D mutation in the CHRNA1 gene, a previously unreported heterozygous epsilonY8X mutation associated with a known heterozygous epsilonM292del deletion in the CHRNE gene, and the common heterozygous N88K mutation associated with a previously unreported heterozygous IVS1 + 2T > G splice site mutation in the RAPSN gene. All three patients had two mutant alleles; parents or offspring with a single mutated allele were asymptomatic, thus all mutations exerted their effects recessively. The previously unreported mutations are likely to reduce the number of AChRs at the motor endplate, although the alphaG378D mutation might produce a mild fast channel syndrome. The alphaG378D mutation was recessive, but recessive CHRNA1 mutations have rarely been reported previously, so studies on the effect of this mutation at the cellular level would be of interest.
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http://dx.doi.org/10.1007/s00415-010-5472-0DOI Listing
July 2010

On the personal facets of quality of life in chronic neurological disorders.

Behav Neurol 2009 ;21(3):155-63

Laboratory of Neuropsychology, Department of Clinical Neurosciences, C. Besta Neurological Institute, Via Celoria 11, Milan, Italy.

Quality of life (QOL) is an important clinical endpoint, but it remarkably varies in patients with similar neurological conditions. This study explored the role of spirituality (i.e., the complex of personal transcendence, connectedness, purpose, and values) in determining QOL in chronic neurological disorders.~Seventy-two patients with epilepsy, brain tumours or ischemic or immune-mediate brain damage compiled inventories for QOL (WHOQOL 100), spirituality (Spiritual, Religious and Personal Beliefs, WHOSRPB), depression (Beck Depression Inventory, BDI), anxiety (State-Trait Anxiety Inventory, STAI), and cognitive self-efficacy (Multiple Ability Self-Report Questionnaire, MASQ) and underwent neuropsychological testing. With respect to 45 healthy controls, the patients reported worse QOL, with no difference between the four patient subgroups. Factor analyses of the WHOSRPB, STAI, and BDI scores and of the MASQ and neuropsychological test scores yielded four (Personal Meaning, Inner Energy, Awe and Openness, Mood) and three factors (Control Functions, Cognition, Memory), respectively. Mood, Cognition, Inner Energy, schooling, and subjective health status correlated with the WHOQOL scores, but at regression analysis only Mood and Inner Energy predicted QOL. This suggests that spirituality, as a personal dimension distinct from mood, contributes to determine QOL. A multidimensional assessment of QOL, including personal facets, may explain differences between patients with chronic neurological disorders.
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http://dx.doi.org/10.3233/BEN-2009-0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444279PMC
February 2010

Identification of international classification of functioning, disability and health relevant categories to describe functioning and disability of patients with myasthenia gravis.

Disabil Rehabil 2009 ;31(24):2041-6

Neurology, Public Health and Disability Unit-Neurological Institute C. Besta IRCCS Foundation, Milan, Italy.

Purpose: To describe functioning and health of patients with myasthenia gravis (MG) and to identify which are the most common problems patients encounter, by using the international classification of functioning, disability and health (ICF).

Method: Adult patients with MG were recruited at C. Besta Neurological Institute. The ICF checklist was administered in individual sessions. Categories were identified as relevant if they were reported as a problem by more than 30% of patients (within activities and participation, the threshold was counted on capacity qualifier).

Results: One hundred two patients were enrolled (mean age 47.2; inpatients were 29.4%, females 68.6%) and 54 ICF categories were selected: 14 body functions categories (26% out of total selected categories), 2 body structures (4%), 22 activities and participation categories (41%) and 16 environmental factors (29%). Environmental factors were essentially reported as facilitators.

Conclusions: Twelve ICF categories, not contained in ICF core-sets for neurological condition, related to mobility, household and labour activities were identified. The ICF categories identified in this study are an useful guideline for clinicians and researchers, for monitoring interventions and follow-up of clinical conditions on a broad set of functional areas, and for developing ICF-based assessment tools for patients with MG.
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http://dx.doi.org/10.3109/09638280902893634DOI Listing
January 2010

Concordance between severity of disease, disability and health-related quality of life in myasthenia gravis.

Neurol Sci 2010 Feb 9;31(1):41-5. Epub 2009 Oct 9.

Neurology, Public Health and Disability Unit, Scientific Directorate, Neurological Institute C. Besta, IRCCS Foundation, Via Celoria 11, 20133, Milan, Italy.

Aim of this study is to verify whether there is concordance between disease's severity, health-related quality of life (HRQoL) and disability in patients with myasthenia gravis (MG). 102 MG patients were clustered on the basis of HRQoL and disability scores into three groups: low disability and low HRQoL decrement (51 patients), intermediate disability and HRQoL decrement (28 patients), severe disability and high HRQoL decrement (23 patients). Cross tabulation with symmetric measures (Cramer's V and Contingency Coefficient) was used to verify the relationships between disease severity groups, based on the Myasthenia Gravis Foundation of America (MGFA) criteria, and obtained clusters. Results confirm a significant relationship between MG severity groups, HRQoL and disability profiles. In our opinion, HRQoL and disability instruments should be employed in clinical trials to match efficacy of treatments, measured on symptoms' reductions only, with their effects on patients' disability and HRQoL.
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http://dx.doi.org/10.1007/s10072-009-0167-yDOI Listing
February 2010

The relationship between health, disability and quality of life in myasthenia gravis: results from an Italian study.

J Neurol 2010 Jan 8;257(1):98-102. Epub 2009 Aug 8.

Neurology, Public Health and Disability Unit, Scientific Directorate, Neurological Institute C. Besta, IRCCS Foundation, Milan, Italy.

Myasthenia gravis (MG) produces long term disability and affects health-related quality of life (HRQoL). This paper reports the relationship between HRQoL and disability in a group of patients with MG. Adult patients with MG were consecutively enrolled at the Neurological Institute "Carlo Besta". The World Health Organization Disability Assessment Schedule II (WHO-DAS II) and the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36) were employed, and non-parametric analysis (Spearman's rank correlation and Mann-Whitney U test) performed. One hundred and two consecutive adult patients with MG (70 female; mean age 47.2, sd 15.7) were recruited. The majority of WHO-DAS II and SF-36 scales were significantly correlated; WHO-DAS II summary score correlated better with SF-36 Physical Composite Score (PCS), than with mental composite score (MCS). Significant differences are also reported between patients with different muscle involvement in PCS and WHO-DAS II scores, while no difference was observed in MCS. The impact of MG on disability and HRQoL increases consistently with the disease's severity. Our study highlights that measurements of HRQoL and disability in patients with MG are correlated and sensitive enough to capture different clinical profiles' features. They measure different clinical and psychosocial facets, therefore we recommend employing specific assessments both for quality of life and disability in public health and clinical research on myasthenia gravis.
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http://dx.doi.org/10.1007/s00415-009-5279-zDOI Listing
January 2010

Disability and functional profiles of patients with myasthenia gravis measured with ICF classification.

Int J Rehabil Res 2009 Jun;32(2):167-72

Neurological Institute C. Besta, IRCCS Foundation - Neurology, Public Health and Disability Unit, Scientific Directorate, Milan, Italy.

The objective of this study is to describe functional profiles of patients with myasthenia gravis (MG), and the relationships among symptoms, activities and environmental factors (EF), by using WHO's International Classification of Functioning Disability and Health (ICF). Patients were consecutively enrolled at the Besta Institute of Milan, Italy. The ICF checklist was administered and two count-based indices were developed: 'extension', containing ICF categories rated with qualifiers 1-4, and 'severity', containing ICF categories rated with qualifiers 3-4. Spearman's correlation was performed to identify the relationships among symptoms, activities and EF, and linear regressions to identify the best predictors of performance indices in the activities and participation (A and P) domains. One hundred and one patients joined this study. Different values are reported in capacity and performance, the latter being 17.1% less limited in 'extension' and 13% in 'severity' index. Higher correlation indices are observed between A and P and body functions (BFs), than between A and P and EF. Problems in A and P are better explained by BF impairments than by facilitators within EF. In conclusion, EF plays a relevant role in improving MG patients' functioning. Nevertheless, difficulties in A and P, such as lifting objects or doing housework, are explained more by impairments in BF (e.g. in muscle endurance) than by the effect of EF (e.g. drugs and the support of family members). Methodologies and tools are needed to couple symptoms assessment with an evaluation of difficulties in executing activities and the environment's role, to plan appropriate interventions to meet MG patients' needs, especially in the labour sector, as 20% of patients gave up working before the retirement age.
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http://dx.doi.org/10.1097/MRR.0b013e32831e4587DOI Listing
June 2009

Risk factors for tumor occurrence in patients with myasthenia gravis.

J Neurol 2009 Aug 29;256(8):1221-7. Epub 2009 Mar 29.

IRCCS Fondazione Istituto Neurologico C. Mondino, Pavia, Italy.

There is still uncertainty regarding risk factors for cancer occurrence in patients with myasthenia gravis (MG). The objective of this study is to determine the prevalence of extrathymic neoplasms in patients with MG and the factors associated with tumor occurrence. The archives of four tertiary MG centers were consulted and patients were interviewed on the main clinical features of the disease, the presence and type(s) of extrathymic neoplasms and other autoimmune disorders, and their symptomatic and immunosuppressant treatments (with detailed schedules). A retrospective cohort survey was undertaken comparing the demographic and clinical variables of patients with extrathymic neoplasms to those of the remaining MG population. 2,479 patients were traced and interviewed personally or through informants. The sample included 1,490 women and 989 men (mean age 54.7 years). Other autoimmune disorders were present in 216 cases (8.7%). Thymectomy was performed in 1,549 cases (62.5%), thymic hyperplasia and thymoma being the most common findings. Acetylcholinesterase-inhibitors were the most common treatment (93.5%), followed by steroids (64.3%), azathioprine (35.0%), plasma exchange (13.2%), immunoglobulins (7.5%), cyclosporine (5.3%), and cyclophosphamide (5.0%). 221 patients (8.9%) had one or more extrathymic tumors, 168 of which occurred after disease onset. Patients with and without extrathymic neoplasms were followed for 14.8 and 13.9 years, respectively. Variables shown by multivariate analysis to be associated with increased neoplastic risk included older age, thymoma and immunoglobulin use. Extrathymic tumors are a common finding in patients with MG and tend to be associated with age, thymoma, and immunoglobulin use.
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http://dx.doi.org/10.1007/s00415-009-5091-9DOI Listing
August 2009

Thymoma-associated myasthenia gravis: outcome, clinical and pathological correlations in 197 patients on a 20-year experience.

J Neuroimmunol 2008 Sep 22;201-202:237-44. Epub 2008 Aug 22.

Divisione Malattie Neuromuscolari e Neuroimmunologia, Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.

We studied 197 patients with thymoma-associated myasthenia gravis (T-MG) to identify variables that can influence the natural history of the disease and the therapeutical approaches. Multivariate analysis showed that neither clinical nor pathological variables were associated with a better chance to reach complete stable remission. The video-assisted thoracoscopic extended thymectomy (VATET) was not significantly correlated with a lower chance of achieving complete stable remission compared with the classical transsternal approach (T-3b) (p=0.1090). Thymoma recurrence was not correlated with surgery by VATET or T-3b. VATET was safe and reliable for removal of thymoma. The low chance of achieving remission (9.64%) in T-MG underlines the importance of an early diagnosis as well as the need for more aggressive therapeutic strategies.
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http://dx.doi.org/10.1016/j.jneuroim.2008.07.012DOI Listing
September 2008

Two cases of thymoma-associated myasthenia gravis without antibodies to the acetylcholine receptor.

Neuromuscul Disord 2008 Aug 25;18(8):678-80. Epub 2008 Jul 25.

Immunology and Muscular Pathology Unit, Neurological Institute Foundation Carlo Besta, Via Celoria 11, 20133 Milano, Italy.

Thymoma-associated myasthenia gravis is considered a more severe disease compared with non-thymomatous myasthenia gravis and is generally associated with antibodies to the acetylcholine receptor (AChR-Ab). Even though a single case of thymoma-associated myasthenia gravis with anti-muscle specific kinase (MuSK) antibodies has been reported, to our knowledge, seronegative thymoma-associated myasthenia gravis has not been described. We report on two cases of this disease without antibodies to AChR or MuSK as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings.
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http://dx.doi.org/10.1016/j.nmd.2008.06.368DOI Listing
August 2008

Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy.

J Neuroimmunol 2006 Jun 27;175(1-2):77-86. Epub 2006 Apr 27.

Department of Neuroimmunology and Neuromuscular Diseases, National Neurological Institute Carlo Besta, via Celoria 11, 20133 Milan, Italy.

Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease due to lack of the sarcolemmal protein dystrophin. Focal release of transforming growth factor-beta1 (TGF-beta1) is involved in fibrosis development. Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to those in DMD muscles occur in diaphragm of older mdx mice. To investigate the early development of fibrosis and TGF-beta1 involvement, we assessed diaphragms in 6-36-week-old mdx and C57/BL6 (control) mice for fibrosis, and used real-time PCR and ELISA to determine TGF-beta1 expression. Significantly greater fibrosis and TGF-beta1 expression were found in mdx from the 6th week. Mice treated with neutralizing antibody against TGF-beta1 had lower levels of TGF-beta1 protein, reduced fibrosis, unchanged muscles fiber degeneration/regeneration, but increased inflammatory cells (CD4+lymphocytes). These data demonstrate early and progressive fibrosis in mdx diaphragm accompanied by TGF-beta1 upregulation. Reduction of TGF-beta1 appears promising as a therapeutic approach to muscle fibrosis, but further studies are required to evaluate long term effects of TGF-beta1 immunomodulation on the immune system.
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http://dx.doi.org/10.1016/j.jneuroim.2006.03.005DOI Listing
June 2006

Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution.

Am J Pathol 2005 Jul;167(1):129-39

Department of Neurology IV, Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Thymic abnormalities are present in approximately 80% of myasthenia gravis (MG) patients, and the thymus seems to be the main site of autosensitization to the acetylcholine receptor. In view of findings that the innate immune system can generate an autoimmune response, we studied the expression of Toll-like receptors (TLRs) 2 to 5, key components of innate immunity signaling pathways, in 37 thymuses from patients with autoimmune MG. TLR4 mRNA levels were significantly greater in thymitis (hyperplasia with diffuse B-cell infiltration) and involuted thymus than in germinal center hyperplasia and thymoma. By immunohistochemistry and confocal microscopy, cells positive for TLR4 protein were rarely detected in thymoma. However, in thymitis TLR4 protein was mostly found on epitheliomorphic (cytokeratin-positive) cells located in close association with clusters of acetylcholine receptor-positive myoid cells in thymic medulla and also at the borders between cortical and medullary areas. B cells were never TLR4-positive. TLR4 protein was also present in remnant tissue of involuted thymus. This is the first finding of a possible link between innate immunity and MG. We speculate that in a subgroup of MG patients, an exogenous or endogenous danger signal may activate the innate immune system and give rise to TLR4-mediated mechanisms contributing to autoimmunity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1603452PMC
http://dx.doi.org/10.1016/S0002-9440(10)62960-4DOI Listing
July 2005

Abnormal lysosomal and ubiquitin-proteasome pathways in 19p13.3 distal myopathy.

Ann Neurol 2004 Jul;56(1):133-8

Division of Neuromuscular Diseases, National Neurological Institute C. Besta, Milan, Italy.

We describe a second large Italian kindred with autosomal dominant vacuolar myopathy characterized by variable severity, adult-onset weakness of distal limb muscles, and no cardiac involvement. At least 19 individuals over four generations are affected. Histopathological and immunochemical features of the vacuoles, present in many fibers, indicate protein degradation abnormalities with dysregulation of the lysosomal pathway and activation of the ubiquitin-proteasomal pathway. Linkage analysis localized the defect to the 19p13.3 locus in a region with no known genes. We speculate that the primary defect may be an abnormality in the lysosomal degradation pathway or related components.
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http://dx.doi.org/10.1002/ana.20158DOI Listing
July 2004

Anti-MOG autoantibodies in Italian multiple sclerosis patients: specificity, sensitivity and clinical association.

Int Immunol 2004 Apr;16(4):559-65

Immunology and Muscular Pathology - Neurology IV, Istituto Nazionale Neurologico 'Carlo Besta', Milan, Italy.

There is considerable evidence that multiple sclerosis (MS) is an immune-mediated disease characterized by infiltration of inflammatory cells into the CNS and demyelination. Several myelin proteins may be encephalitogenic, including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein (MOG), the latter being expressed on the external layer of myelin sheaths and hence accessible to antibody attack. We investigated MOG autoreactivity in serum and cerebrospinal fluid (CSF) by ELISA, employing the recombinant extracellular domain of MOG as antigen. We tested serum samples from 262 MS patients (175 relapsing-remitting, 43 primary progressive and 44 secondary progressive), 131 patients with other neurological diseases (OND) and 307 healthy controls. No patients or controls were receiving immunomodulating treatments. We found anti-MOG antibodies in the serum of 13.7% MS patients, mainly in those with secondary progressive MS (25%), in 13.7% of OND patients and in 6.2% of controls. We found a direct correlation (R(2) = 0.6, P = 0.002) between disease severity and anti-MOG titer only in patients with primary and secondary progressive MS. Anti-MOG antibodies were present in the CSF of 11.4% MS patients and 18.9% OND patients. Intrathecal synthesis of anti-MOG antibodies was demonstrated in four (4.5%) of MS patients and no OND patients. Anti-MOG antibodies are not specific for MS; however, they may characterize a subset of MS patients and this may be revealed by serial assays in relation to changing disease phase.
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http://dx.doi.org/10.1093/intimm/dxh056DOI Listing
April 2004

Breakdown of tolerance to a self-peptide of acetylcholine receptor alpha-subunit induces experimental myasthenia gravis in rats.

J Immunol 2004 Feb;172(4):2697-703

Neurology IV, Neuromuscular Diseases and Autoimmunity, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.

Experimental autoimmune myasthenia gravis (EAMG), a model for human myasthenia (MG), is routinely induced in susceptible rat strains by a single immunization with Torpedo acetylcholine receptor (TAChR). TAChR immunization induces anti-AChR Abs that cross-react with self AChR, activate the complement cascade, and promote degradation of the postsynaptic membrane of the neuromuscular junction. In parallel, TAChR-specific T cells are induced, and their specific immunodominant epitope has been mapped to the sequence 97-116 of the AChR alpha subunit. A proliferative T cell response against the corresponding rat sequence (R97-116) was also found in TAChR-immunized rats. To test whether the rat (self) sequence can be pathogenic, we immunized Lewis rats with R97-116 or T97-116 peptides and evaluated clinical, neurophysiological, and immunological parameters. Clinical signs of the disease were noted only in R97-116-immunized animals and were confirmed by electrophysiological signs of impaired neuromuscular transmission. All animals produced Abs against the immunizing peptide, but anti-rat AChR Abs were observed only in animals immunized with the rat peptide. These findings suggested that EAMG in rats can be induced by a single peptide of the self AChR, that this sequence is recognized by T cells and Abs, and that breakdown of tolerance to a self epitope might be an initiating event in the pathogenesis of rat EAMG and MG.
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http://dx.doi.org/10.4049/jimmunol.172.4.2697DOI Listing
February 2004

Myasthenia gravis (MG): epidemiological data and prognostic factors.

Ann N Y Acad Sci 2003 Sep;998:413-23

Immunology and Muscular Pathology Unit, National Neurological Institute Carlo Besta, 20133 Milan, Italy.

Data from 756 myasthenic patients were analyzed for diagnostic criteria, clinical aspects, and therapeutic approaches. The patients were followed up at our institution from 1981 to 2001. Clinical evaluation was performed according to the myasthenia gravis score adopted at our clinic. Clinical features of each patient (comprising demographic, clinical, neurophysiological, immunological, radiological, and surgical data, as well as serial myasthenia gravis scores) were filed in a relational database containing more than 7000 records. Clinical efficacy and variables influencing outcome were assessed by life-table methods and Cox proportional hazards regression analysis. Complete stable remission, as defined by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, was the end point for good prognosis. Four hundred and ninety-nine patients (66%) were female and 257 (34%) were male. Mean follow-up was 55.1 +/- 48.1 months. Onset of symptoms peaked in the third decade in females, whereas the male distribution was bimodal with peaks in the third and sixth decades. Modality of myasthenia gravis presentation was as follows: ocular, 39.3%; generalized, 28.5%; bulbar, 31.3%; and respiratory, 0.8%. Thymectomy was carried out on 63.7% of our patients by different approaches: (1) transcervical; (2) transsternal; (3) video-thoracoscopic mini-invasive surgery. The last approach has been preferentially used in more recent years and accounted for 62.4% of the thymectomized myasthenia gravis population. Univariate analysis and Kaplan-Meier analysis showed that variables such as sex (female), age at onset (below 40 years), thymectomy, and histological diagnosis of thymic hyperplasia were significantly associated with complete stable remission, whereas on multivariate analysis only age at onset below 40 years and thymectomy were confirmed.
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http://dx.doi.org/10.1196/annals.1254.054DOI Listing
September 2003

Effect on T cell recognition and immunogenicity of alanine-substituted peptides corresponding to 97-116 sequence of the rat AChR alpha-subunit.

Ann N Y Acad Sci 2003 Sep;998:395-8

Immunology and Muscular Pathology Unit, National Neurological Institute Carlo Besta, 20133 Milan, Italy.

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http://dx.doi.org/10.1196/annals.1254.049DOI Listing
September 2003

Analysis of SjTREC levels in thymus from MG patients and normal children.

Ann N Y Acad Sci 2003 Sep;998:270-4

Immunology and Muscular Pathology Unit, Istituto Nazionale Neurologico Carlo Besta, 20133 Milan, Italy.

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http://dx.doi.org/10.1196/annals.1254.029DOI Listing
September 2003

Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study.

J Neuroimmunol 2003 Sep;142(1-2):130-6

Department of Neuromuscular Diseases, Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy.

Muscle inflammation is characteristic of inflammatory myopathies but also occurs in muscular dystrophy with lack of the sarcolemmal protein dysferlin. We quantified inflammatory cells and major histocompatibility complex (MHC) expression in muscle from 10 patients with dysferlinopathy. Infiltrating cells were always present although numbers varied considerably; macrophages were more common than T cells, T cytotoxicity was absent, and MHC class I was overexpressed on muscle fibers. These findings differ from polymyositis (PM) but are closely similar to those in SJL/J mice (which lack dysferlin) and emphasize the relationship between absence of dysferlin and immune system abnormalities in muscle.
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http://dx.doi.org/10.1016/s0165-5728(03)00255-8DOI Listing
September 2003

Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up.

J Neurol Sci 2003 Aug;212(1-2):31-6

Immunology and Muscular Pathology Unit, Department of Neuromuscular Diseases, Istituto Nazionale Neurologico Carlo Besta Via Celoria 11, 20133 Milan, Italy.

The aims of this study were to assess the efficacy of video-assisted thoracoscopic extended thymectomy (VATET) as a treatment for myasthenia gravis (MG) and to identify prognostic factors for thymectomy success. Clinical efficacy and variables influencing outcome were assessed by life-table and Cox proportional hazards regression analysis. Complete stable remission (CSR), as defined by the MGFA Medical Task Force, was the end point for efficacy. VATET was performed in 159 MG patients and T-3b in 47 MG patients. At 6 years of follow-up, CSR, assessed by life-table analysis, was 50.6% in non-thymomatous VATET patients and 48.7% in non-thymomatous T-3b surgery. By univariate analysis, the presence of thymic hyperplasia (P=0.0002) and treatment only with anticholinesterases (P<0.0001) were positively associated with the probability of CSR. By multivariate analysis, the chance of complete remission was significantly increased by the use of anticholinesterases (odds ratio [OR] 2.45; 95% confidence interval [CI] 1.44-4.17; P=0.001) and the presence of thymic hyperplasia (OR 1.96; 95% CI 1.05-3.68; P=0.036). VATET seems to be effective in inducing CSR in MG with an efficiency similar to that of the T-3b transsternal (TS) approach; it is easy to perform in experienced hands and is associated with low morbidity and negligible esthetic sequelae.
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http://dx.doi.org/10.1016/s0022-510x(03)00087-xDOI Listing
August 2003

Fibrogenic cytokines and extent of fibrosis in muscle of dogs with X-linked golden retriever muscular dystrophy.

Neuromuscul Disord 2002 Nov;12(9):828-35

Myopathology and Immunology Unit, Istituto Nazionale Neurologico 'Carlo Besta', Via Celoria 11, 20133, Milan, Italy.

Fibrosis in Duchenne muscular dystrophy patients' muscle seems to be mediated by fibrogenic cytokines, particularly transforming growth factor-beta1. Golden retriever muscular dystrophy is a model of Duchenne dystrophy characterised by severe myopathy and muscle fibrosis. We evaluated mRNA levels and protein distribution of transforming growth factor-beta1, connective tissue growth factor and collagens in muscle of golden retriever muscular dystrophy dogs at different ages. Fibrosis occurs early in golden retriever muscular dystrophy dogs and transforming growth factor-beta1 levels tend to be high up to 60 days of age (P=0.019 at 30 days), suggesting that transforming growth factor-beta1 is involved in the early stages of fibrosis. We also found greater expression of connective tissue growth factor in golden retriever muscular dystrophy than control muscle (P=0.0065 at 30 days), suggesting involvement of this molecule in fibrosis progression. Our findings sustain the hypothesis that cytokines are actively involved in fibrosis in golden retriever muscular dystrophy, as it seems to be in humans, and confirm the utility of this model for investigating new therapeutic approaches for Duchenne dystrophy.
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http://dx.doi.org/10.1016/s0960-8966(02)00071-8DOI Listing
November 2002

IL-1 genes in myasthenia gravis: IL-1A -889 polymorphism associated with sex and age of disease onset.

J Neuroimmunol 2002 Jan;122(1-2):94-9

Neuromuscular Disease Department, National Neurological Institute, C. Besta, Milan, Italy.

Myasthenia gravis (MG) is a multifactorial autoimmune disease of the neuromuscular junction. We investigated the relation between four polymorphisms of the interleukin (IL)-1 gene cluster on 2q12-22, and MG susceptibility and clinical features in a large cohort of individuals. No polymorphism was associated with MG susceptibility. However, the IL-1A -889 CC genotype was associated with early disease onset (p=0.0044) in the whole MG group and the subgroup of CC males developed MG about 18 years earlier than males carrying other IL-1A -889 genotypes (p=0.022). This finding suggests that IL-1A is a disease modifier in MG, or is in linkage disequilibrium with an unknown locus on chromosome 2.
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http://dx.doi.org/10.1016/s0165-5728(01)00449-0DOI Listing
January 2002