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1.  Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies 
Background
The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls.
Methods
Cerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other noninflammatory neurological disorders (NIND).
Results
Levels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed.
Conclusions
Our findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.
doi:10.1186/s12974-014-0188-1
PMCID: PMC4232674  PMID: 25391491
2.  Significant Low Prevalence of Antibodies Reacting with Simian Virus 40 Mimotopes in Serum Samples from Patients Affected by Inflammatory Neurologic Diseases, Including Multiple Sclerosis 
PLoS ONE  2014;9(11):e110923.
Many investigations were carried out on the association between viruses and multiple sclerosis (MS). Indeed, early studies reported the detections of neurotropic virus footprints in the CNS of patients with MS. In this study, sera from patients affected by MS, other inflammatory (OIND) and non-inflammatory neurologic diseases (NIND) were analyzed for antibodies against the polyomavirus, Simian Virus 40 (SV40). An indirect enzyme-linked immunosorbent assay (ELISA), with two synthetic peptides, which mimic SV40 antigens, was employed to detect specific antibodies in sera from patients affected by MS, OIND, NIND and healthy subjects (HS). Immunologic data indicate that in sera from MS patients antibodies against SV40 mimotopes are detectable with a low prevalence, 6%, whereas in HS of the same mean age, 40 yrs, the prevalence was 22%. The difference is statistically significant (P = 0.001). Significant is also the difference between MS vs. NIND patients (6% vs. 17%; P = 0.0254), whereas no significant difference was detected between MS vs OIND (6% vs 10%; P>0.05). The prevalence of SV40 antibodies in MS patients is 70% lower than that revealed in HS.
doi:10.1371/journal.pone.0110923
PMCID: PMC4218715  PMID: 25365364
3.  Comparison of Antibodies Hydrolyzing Myelin Basic Protein from the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis 
PLoS ONE  2014;9(9):e107807.
It was found that antibodies (Abs) against myelin basic protein (MBP) are the major components of the antibody response in multiple sclerosis (MS) patients. We have recently shown that IgGs from sera of MS patients are active in the hydrolysis of MBP. However, in literature there are no available data concerning possible MBP-hydrolyzing Abs in cerebrospinal fluid (CSF) of MS patients. We have shown that the average content of IgGs in their sera is about 195-fold higher than that in their CSF. Here we have compared, for the first time, the average content of lambda- and kappa-IgGs as well as IgGs of four different subclasses (IgG1-IgG4) in CSF and sera of MS patients. The average relative content of lambda-IgGs and kappa –IgGs in the case of CSFs (8.0 and 92.0%) and sera (12.3 and 87.7%) are comparable, while IgG1, IgG2, IgG3, and IgG4: CSF - 40.4, 49.0, 8.2, and 2.5% of total IgGs, respectively and the sera - 53.6, 36.0, 5.6, and 4.8%, decreased in different order. Electrophoretically and immunologically homogeneous IgGs were obtained by sequential affinity chromatography of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF efficiently hydrolyze MBP and that their average specific catalytic activity is unpredictably ∼54-fold higher than that of Abs from sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that anti-MBP abzymes of CSF may promote important neuropathologic mechanisms in this chronic inflammatory disorder and in MS pathogenesis development.
doi:10.1371/journal.pone.0107807
PMCID: PMC4180057  PMID: 25265393
4.  Comparison of DNA-Hydrolyzing Antibodies from the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis 
PLoS ONE  2014;9(4):e93001.
It was found that high-affinity anti-DNA antibodies were one of the major components of the intrathecal IgG response in multiple sclerosis (MS) patients [Williamson et al., PNAS, 2001]. Recently we have shown that IgGs from the sera of MS patients are active in the hydrolysis of DNA. Here we have shown, for the first time, that average concentration of total proteins (132-fold), total IgGs (194-fold) and anti-DNA antibodies (200-fold) in the sera is significantly higher than that in the cerebrospinal fluid (CSF) of fifteen MS patients. The relative activities of total protein from sera and CSFs varied remarkably from patient to patient. It was surprising that the specific DNase activity of the total protein of CSF reparations were 198-fold higher than the serum ones. Electrophoretically and immunologically homogeneous IgGs were obtained by sequential affinity chromatography of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF not only bind but efficiently hydrolyze DNA and that average specific DNase activity of homogeneous antibodies from CSF is unpredictably ∼49-fold higher than that from the sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that DNase IgGs of CSF may promote important neuropathologic mechanisms in this chronic inflammatory disorder and MS pathogenesis development.
doi:10.1371/journal.pone.0093001
PMCID: PMC3988009  PMID: 24736683
5.  Technical, Anatomical, and Functional Study after Removal of a Symptomatic Cavernous Angioma Located in Deep Wernicke's Territories with Cortico-Subcortical Awake Mapping 
Introduction. The subcortical region underneath Wernicke's area (WA) is a critical crossing of the eloquent language pathways involved in all semantic, phonological, syntactic, and working memory elaboration. We report the resection of a CA located underneath the dominant WA discussing the functional and anatomical evidence provided by fMRI, dissections with Klingler's technique, and intraoperative mapping during awake surgery. Case Report. A 64-year-old right-handed female affected by daily complex focal seizures underwent f-MRI, showing language activations in the middle and inferior temporal gyri and an unusual free entry zone in the “classical” WA. The cortical intraoperative mapping partially confirmed the f-MRI results, and we approached the lesion directly through WA. Subcortical DES allowed the identification of the eloquent language pathways and the radical resection of the perilesional gliotic rim. The patient did not report deficits and she is seizures and drug free after 1-year surgery. Discussion. Cortical DES demonstrated the variability of the eloquent areas within the cortex of the dominant temporal lobe. The subcortical DES confirmed the crucial role in language elaboration and the anatomical course of the bundles underneath WA. Conclusions. Awake surgery with DES represents a reliable and dynamic technique also for safer and functional-customized resection of CAs.
doi:10.1155/2013/835029
PMCID: PMC3707287  PMID: 23864972
6.  Spontaneous and idiopathic chronic spinal epidural hematoma: two case reports and review of the literature 
European Spine Journal  2009;18(11):1555-1561.
Spinal epidural hematoma (SEH) represents the most frequent entity of acute or chronic spinal bleeding. Based upon pathogenesis, SEH can be classified as idiopathic, spontaneous, and secondary. The idiopathic forms are considered not to be attributed to any specific risk factors. Spontaneous SEH, accounting for 0.3–0.9% of all spinal epidural space occupying lesions, instead is associated with risk factors (such as substantial soft trauma or coagulation abnormalities). The chronic form, as our literature review revealed, is the rarest and its most frequent location is the lumbar spine. The pathophysiology of spontaneous and idiopathic SEH is still under debate: There are only a few reports in literature of chronically evolving SEH with progressively increasing pain and neurological impairment. Magnetic resonance imaging may be inconclusive for differential diagnosis. Here, we present two cases of lumbar chronic SEH with slow, progressive, and persistent lumbar radicular impairment. The first patient reported a minor trauma with slight back contusion and thus was classified as spontaneous SEH. In the second case not even a minor trauma was involved, so we considered it to be idiopathic SEH. In both cases preoperative blood and coagulation tests were normal and we did not find any other or co-factors in the patients’ clinical histories. MR imaging showed uncertain spinal canal obstructing lesions at L3 and L4 level in both cases. Surgical treatment allowed a correct diagnosis and resulted in full clinical and neuroradiological recovery after 1 year follow-up. Our aim is to discuss pathogenesis, clinical and radiological features, differential diagnosis and treatment options, on the background of relevant literature review.
doi:10.1007/s00586-009-1175-6
PMCID: PMC2899401  PMID: 19859747
Spontaneous; Idiopathic; Chronic; Hematoma; Epidural; Spinal
7.  Chlamydophila pneumoniae Infection and Its Role in Neurological Disorders 
Chlamydophila pneumoniae is an intracellular pathogen responsible for a number of different acute and chronic infections. The recent deepening of knowledge on the biology and the use of increasingly more sensitive and specific molecular techniques has allowed demonstration of C. pneumoniae in a large number of persons suffering from different diseases including cardiovascular (atherosclerosis and stroke) and central nervous system (CNS) disorders. Despite this, many important issues remain unanswered with regard to the role that C. pneumoniae may play in initiating atheroma or in the progression of the disease. A growing body of evidence concerns the involvement of this pathogen in chronic neurological disorders and particularly in Alzheimer's disease (AD) and Multiple Sclerosis (MS). Monocytes may traffic C. pneumoniae across the blood-brain-barrier, shed the organism in the CNS and induce neuroinflammation. The demonstration of C. pneumoniae by histopathological, molecular and culture techniques in the late-onset AD dementia has suggested a relationship between CNS infection with C. pneumoniae and the AD neuropathogenesis. In particular subsets of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. The role of Chlamydia in the pathogenesis of mental or neurobehavioral disorders including schizophrenia and autism is uncertain and fragmentary and will require further confirmation.
doi:10.1155/2010/273573
PMCID: PMC2825657  PMID: 20182626
8.  The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology 
Brain  2008;131(7):1912-1925.
Small fibre neuropathy (SFN), a condition dominated by neuropathic pain, is frequently encountered in clinical practise either as prevalent manifestation of more diffuse neuropathy or distinct nosologic entity. Aetiology of SFN includes pre-diabetes status and immune-mediated diseases, though it remains frequently unknown. Due to their physiologic characteristics, small nerve fibres cannot be investigated by routine electrophysiological tests, making the diagnosis particularly difficult. Quantitative sensory testing (QST) to assess the psychophysical thresholds for cold and warm sensations and skin biopsy with quantification of somatic intraepidermal nerve fibres (IENF) have been used to determine the damage to small nerve fibres. Nevertheless, the diagnostic criteria for SFN have not been defined yet and a ‘gold standard’ for clinical practise and research is not available. We screened 486 patients referred to our institutions and collected 124 patients with sensory neuropathy. Among them, we identified 67 patients with pure SFN using a new diagnostic ‘gold standard’, based on the presence of at least two abnormal results at clinical, QST and skin biopsy examination. The diagnosis of SFN was achieved by abnormal clinical and skin biopsy findings in 43.3% of patients, abnormal skin biopsy and QST findings in 37.3% of patients, abnormal clinical and QST findings in 11.9% of patients, whereas 7.5% patients had abnormal results at all the examinations. Skin biopsy showed a diagnostic efficiency of 88.4%, clinical examination of 54.6% and QST of 46.9%. Receiver operating characteristic curve analysis confirmed the significantly higher performance of skin biopsy comparing with QST. However, we found a significant inverse correlation between IENF density and both cold and warm thresholds at the leg. Clinical examination revealed pinprick and thermal hypoesthesia in about 50% patients, and signs of peripheral vascular autonomic dysfunction in about 70% of patients. Spontaneous pain dominated the clinical picture in most SFN patients. Neuropathic pain intensity was more severe in patients with SFN than in patients with large or mixed fibre neuropathy, but there was no significant correlation with IENF density. The aetiology of SFN was initially unknown in 41.8% of patients and at 2-year follow-up a potential cause could be determined in 25% of them. Over the same period, 13% of SFN patients showed the involvement of large nerve fibres, whereas in 45.6% of them the clinical picture did not change. Spontaneous remission of neuropathic pain occurred in 10.9% of SFN patients, while it worsened in 30.4% of them.
doi:10.1093/brain/awn093
PMCID: PMC2442424  PMID: 18524793
neuropathy; pain; skin biopsy; quantitative sensory testing; neurophysiology
9.  Multiple Sclerosis and HERV-W/MSRV: A Multicentric Study 
We designed a large multicentric study to analyse the presence of MSRV particles in blood and CSF of a large cohort of patients and controls from different European areas. 149 MS patients and 153 neurological and healthy controls were selected from Sardinia, Spain, Northern-Italy and Sweden. To avoid biological and inter-assay variability MSRV was detected within a single laboratory through nested and real-time PCR assays specific for pol and env genes. MSRV detection in blood and CSF of MS patients and controls in populations of different ethnicity gave significant differences (p<0.05 compared to neurological controls and <0.001 compared to healthy controls). The presence and viral load of MSRV are significantly associated with MS as compared to neurological and healthy controls in all ethnic groups.
PMCID: PMC3614662  PMID: 23675056
human endogenous retrovirus; HERV-W; MSRV; multiple sclerosis

Results 1-9 (9)