Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

Longitudinally Extensive Transverse Myelitis (LETM) and Myopericarditis in a 7-Month-Old Child with SARs-CoV-2 Infection.

INTRODUCTION: In the last few months, some pediatric cases with neurological and neuroradiological pictures related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported, often associated with multisystem inflammatory syndrome (MIS-C). The most frequently encountered pediatric neurological complications seem to be postinfectious immune-mediated acute disseminated encephalomyelitis (ADEM)-like changes of the brain, myelitis, neural enhancement, and splenial lesions. Concomitant neurological and cardiac involvement has been reported only in MIS-C, although specific clinical details are often not fully available. METHODS: In this case report, a very young child infected with SARs-CoV-2 and diagnosed as longitudinal extensive transverse myelitis with concomitant myo-pericarditis is presented. RESULTS: A previously healthy 7-month-old girl presented with abrupt onset of generalized weakness with inability to sit up. She had had mild respiratory symptoms 1 week earlier. Spinal magnetic resonance imaging (MRI) showed a T2-hyperintense intramedullary lesion extending from C4 to T2, compatible with acute longitudinally extensive transverse myelitis (LETM). Cerebrospinal fluid analysis was negative.Echocardiography and blood tests were suggestive for myo-pericarditis. Real time polymerase chain reaction for SARS-CoV-2 on nasopharyngeal swab sample tested positive. She was promptly treated with high dose of steroids and immunoglobulin with satisfactory clinical response. CONCLUSION: To the evolving literature of neurological complications of SARs-CoV-2 infection, we add the youngest patient described to date with isolated LETM and concomitant cardiac involvement. Our case suggests that clinicians should be aware of this association, although difficult to recognize in infants. Practitioners are encouraged to consider aggressive first-line immunotherapies with the final aim to prevent permanent disability.

Chronic immune sensory polyradiculopathy (CISP): First juvenile case description.

In its typical presentation, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) occurs more often in old males as a progressive/recurrent motor and sensory nerve dysfunction with tendon areflexia. However, CIDP has also atypical clinical presentations, including pure sensory neuropathies, among which chronic immune sensory polyradiculopathy (CISP) accounts for only 0.5% of all CIDP, with no juvenile cases reported as yet. A 17-year-old girl presented for a progressive sensory ataxia and hands clumsiness. Diffuse tendon areflexia and hypokinaesthesia were observed. Motor and sensory nerve conduction studies were normal. F-waves were normal in median nerves and elongated in tibial nerves. H-reflex and somatosensory evoked potentials (SSEP) were absent. CSF normal cellularity with hyperproteinorrachia was found. Paraneoplastic, metabolic, and paraproteinemic neuropathies were excluded. A diagnosis of CISP has been made based on the presence of pure sensory symptoms in a polyneuropathic distribution, normal peripheral nerve conduction studies, and two supportive criteria (SSEP and CSF). Our paper describes the first CISP case in the pediatric age. We confirm SSEP and CSF as useful complementary tests for this diagnosis also at this age and suggest that clinicians should consider CISP in the spectrum of sporadic sensory ataxias of the pediatric age. We also suggest that in the presence of normal F-wave and peripheral motor nerve conduction, an absent H-reflex can further substantiate SSEPs in the diagnosis of CISP. Intravenous immunoglobulins were rapidly effective and safe.

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10-3; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.

Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature.

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.

Natalizumab inhibits the expression of human endogenous retroviruses of the W family in multiple sclerosis patients: a longitudinal cohort study.

BACKGROUND: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome. OBJECTIVE: The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome. METHODS: Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays. RESULTS: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy. CONCLUSION: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.

Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.

BACKGROUND: Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses. METHODOLOGY/PRINCIPAL FINDINGS: In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines. CONCLUSIONS/SIGNIFICANCE: In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.

Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease.

BACKGROUND: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation. OBJECTIVE: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. METHODS: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. RESULTS: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. CONCLUSION: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.

Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report.

BACKGROUND: Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system and therapeutic inhibition of leukocyte migration with natalizumab, an anti-alpha4 integrin antibody, is highly effective in patients with MS. Recent studies performed in experimental animal models with relevance to human disease suggested a key role for blood-brain barrier damage and leukocyte trafficking mechanisms also in the pathogenesis of epilepsy. In addition, vascular alterations and increased leukocyte accumulation into the brain were recently documented in patients with refractory epilepsy independently on the disease etiology. CASE REPORT: Here we describe the clinical course of a 24-year-old patient with MS in whom abrupt tonic-clonic generalized seizures manifested at disease onset. Although MS had a more favorable course, treatment with glatiramer acetate and antiepileptic drugs for 7 years had no control on seizure generation and the patient developed severe refractory epilepsy. Interestingly, generalized seizures preceded new MS relapses suggesting that seizure activity may contribute to MS worsening creating a positive feedback loop between the two disease conditions. Notably, treatment with natalizumab for 12 months improved MS condition and led to a dramatic reduction of seizures. CONCLUSION: Our case report suggests that inhibition of leukocyte adhesion may represent a new potential therapeutic approach in epilepsy and complement the traditional therapy with anti-epileptic drugs.

Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis.

A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10), OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.

Novel reliable real-time PCR for differential detection of MSRVenv and syncytin-1 in RNA and DNA from patients with multiple sclerosis.

Two components of the HERV-W family of human endogenous retroviruses are activated during multiple sclerosis (MS) and proposed immunopathogenic co-factors: MSRV (MS-associated retrovirus), and ERVWE1 (whose env protein, syncytin-1, reaches the plasma membrane). MSRVenv and syncytin-1 are closely related, and difficult to distinguish each other. The sequences of extracellular MSRVenv and of syncytin-1 available in GenBank were compared with those found in MS patients and controls of the cohort under study. With respect to syncytin-1, MSRVenv sequences have a 12-nucleotide insertion in the trans-membrane moiety. Based on this insertion, discriminatory real-time PCR assays were developed, that can amplify selectively either MSRVenv or syncytin-1. The data of MS patients and controls indicated that MSRV and ERVWE1 are both expressed in the brain of MS patients, while only MSRV is present in the blood; MSRV was released in culture by PBMCs of MSRV-producer individuals. These cells expressed the complete MSRVenv gene in the absence of syncytin-1 expression, up to the final, fully glycosylated envelope protein product, since western blot staining with anti-HERV-Wenv antibody detected two bands of the same molecular weight (73 and 61kDa) of the fully glycosylated and partially glycosylated HERV-Wenv uncleaved proteins. Beyond MSRVenv DNA copy numbers were more abundant in MS patients than in healthy humans, while syncytin-1 were unchanged. These findings reinforce the link between MSRV and MS.

Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders.

Analyses of a 6-Mb region spanning the human leukocyte antigen (HLA) region from the HLA-DR to the HFE gene were performed in 37 families of Sardinian ancestry, all of whom had at least one autistic child, to identify genetic markers associated with autism spectrum disorders (ASD) development. In particular, four microsatellites (MIB, D6S265, MOGc, and D6S2239) and three single-nucleotide polymorphisms (SNPs; two in positions -308 and -238 in the promoter of the TNF-alpha and SNP rs2857766 [V142L] in exon 3 of the MOG gene) were analyzed. An intrafamilial case-control method (affected family-based controls) and transmission disequilibrium test analysis were used to evaluate the association of microsatellite and SNP markers with ASD-affected children. Results indicated positive associations with ASD for D6S265*220 (p < 0.01) and MOGc*131 (p < 0.05) and negative associations for MOGc*117 and MIB*346 alleles (p < 0.01) in ASD children. Polymorphism haplotype analysis indicated that D6S265 allele *220 and MOGc allele *131 were significantly more likely to be transmitted together, as a whole haplotype, to ASD children (p < 0.05). Conversely, the D6S265*224-MOGc*117-rs2857766(G) haplotype was significantly less frequently transmitted to ASD children (p < 0.01). The results present novel gene markers, reinforcing the hypothesis that genetic factors play a pivotal role in the pathogenesis of ASD.

NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is believed to be an autoimmune disease occurring in genetically predisposed individuals after an appropriate environmental exposure such as viral infections. Recent studies suggest a significant association between MS and the functional 5'-(GT)n polymorphism in the promoter region of the NRAMP1 gene. In the present study we aimed to evaluate the contribution of the allelic variation in the NRAMPI promoter to MS susceptibility and to study the role of viral infection in relation to specific NRAMP1 genotypes, in a Sardinian cohort. METHODS: Sixty MS patients and 66 healthy individuals were genotyped, and screened for the presence of Epstein-bar virus (EBV) and JC virus (JCV) sequences. RESULTS: Consistent with previous autoimmune disease studies, allele 3 at the functional 5'(GT)n promoter region repeat polymorphism, was significantly overrepresented among MS patients when compared to controls (p=0.02). The EBV and JCV sequences were detected in 8/60 (13.33%) and in 4/60 (6.66%) of MS patients respectively and in 5/66 (7.57%) and in 0/66 of controls. CONCLUSION: The allelic variation in the NRAMP1 promoter may contribute to MS susceptibility in the Sardinian population. The viral sequences were not confined to a specific NRAMP1 genotype.

Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out.

Different content of chitin-like polysaccharides in multiple sclerosis and Alzheimer's disease brains.

Chitin is an insoluble N-acetyl-glucosamine polymer coating fungi cell wall and several human parasites. It is hydrolysed by chitotriosidase (Chit); however, as chitin is absent in humans, the significance of human Chit activity is unknown. The level of plasma Chit activity positively correlates with Alzheimer's disease (AD) and multiple sclerosis (MS). A recent study revealed the presence of potentially detrimental chitin-like substances in AD brain by Calcofluor histochemistry, whilst its search in MS brains has never been described to date. Through a comparative immunohistochemical analysis we confirm the presence of abundant chitin-like deposition in AD brains but fail to demonstrate it in MS brains. Interestingly, co-localization of beta-amyloid, Calcofluor and the nuclear marker DAPI was observed. Therefore, Chit production in MS patients is induced by mechanisms other than those operating in AD. Microglia-derived Chit activity in MS may counterbalance the naturally occurring glucosamine aggregation, protecting the brain from the chitin-like substance deposition.

Multiple sclerosis and anti-Plasmodium falciparum innate immune response.

Several epidemiological investigations conducted in Sardinia, insular Italy, indicate that the strong selective pressure of malaria along the centuries may have concurred to the elevated genetic MS-risk in this region. To test such hypothesis in an experimental setting, we have compared the immune response to P. falciparum (the causative agent of malaria) in Sardinian MS patients relative to their ethnic healthy controls and control MS patients of different ethnicity. To this purpose, the P. falciparum-driven peripheral mononuclear cell proliferation, the production of pro-inflammatory cytokines of the innate immunity such as TNF-alpha, IL-6 and IL-12 and the ability to inhibit the parasite growth have been tested in relation to HLA-DR alleles and TNF promoter polymorphisms known of being associated to MS. We found that P. falciparum-induced proliferation, cytokine production and parasite killing are significantly augmented in Sardinian MS patients as compared to controls (p<0.01). Additionally, a correlation is found with genes associated to Sardinian MS, namely the TNF(-376A) promoter polymorphism and the class II HLA-DRB1*0405 allele. In conclusion, we have found evidences that some genetic traits formerly selected to confer a protective responses to P. falciparum now partially contribute to the elevated MS susceptibility amongst Sardinians.

Oligosaccharides in colostrum of Italian and Burkinabe women.

Human milk contains a large number of compounds to provide nutrition and defense for the newborn. Among these, oligosaccharides are present in concentrations up to 12 g/L, and their composition varies during lactation. Colostrum from 53 Burkinabe women were collected at the maternity department of St Camille Medical Centre in Ouagadougou (Burkina Faso, West Africa). Colostrum from 50 Italian women were collected at the maternity department of St Bambino Hospital in Catania (Catania, East Sicily, Italy). All mothers spontaneously delivered at term. Italian mothers received an injection of the ergot derivative ergotamine after delivery. Ergotamine, notoriously, delays breastfeeding initiation up to 2 to 3 days. Chromatographic separation of colostrum from both Burkinabe and Italian women showed a progressive appearance of oligosaccharides in the first 3 days. Burkinabe women showed high concentrations of 2-fucosyllactose and lower concentrations of lacto-N-fucopentaose I. By contrast, Italian women showed inverted behaviour. A comparable percentage of the secretor genotype for the Lewis blood group phenotype in both Burkinabe and Italian women was found. According to the different ethnicity, different milk oligosaccharide profiles were documented in the present study. 2-Fucosyllactose in milk should be biologically significant for Burkinabe infants because of the high levels found in their mothers' colostrum after the second day of lactation.

Chitotriosidase in patients with acute ischemic stroke.

BACKGROUND: Following an acute brain ischemia, local endothelia allow monocyte chemoattraction into the lesion site which contributes to brain damage through a group of neurotoxic factors. A relationship exists between the extent of brain damage and the plasma level of monocyte products, including chitotriosidase, though usually strictly related to preexisting infectious-inflammatory diseases. PURPOSE: Since chitotriosidase activity is also elevated in pathogen-free conditions, we tested whether chitotriosidase upregulation might be specifically related to stroke and unrelated to clinically relevant infectious diseases. METHODS: We studied the plasma level of chitotriosidase activity, TNF-alpha and IL-6 in 44 consecutive patients with acute brain ischemia without concomitant symptoms or signs of inflammatory-infectious diseases. Results were compared with stroke severity and outcome as detected by brain CT and NIH scale. Blood samples were collected, on average, 11 h after stroke onset. RESULTS: Chitotriosidase activity positively correlates with stroke severity, as measured by NIH scale (r = 0.69, p < 0.01), to the extent of brain damage as documented by CT (r = 0.75, p < or = 0.001) and the TNF-alpha level (r = 0.76, p < 0.001); it also inversely correlates with the IL-6 level (r = -0.43, p < or = 0.05). CONCLUSION: Our results indicate that chitotriosidase is a specific marker of macrophage activation occurring in stroke which directly correlates with stroke severity independently of preexisting inflammatory or infectious conditions.