APOE epsilon2-4 and -491 polymorphisms are not associated with MS.
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Adult↗
Biomedical subjects
N Canal
Publications and source records attributed to N Canal.
Relevance of interleukin 1 receptor antagonist intron 2 polymorphism in Italian MS patients.
The A1/A1 genotype of the anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1Ra) polymorphism was more frequent in 339 Italian MS patients than in healthy controls (HCs) (odds ratio = 1.83). A more aggressive disease course was also associated with A1+ genotypes and might reflect the reduced ability of mononuclear cell cultures of A1+ HCs to produce IL-1Ra. We conclude that an IL-1Ra gene polymorphism is associated with occurrence of disease and clinical course variability in Italian MS patients.
Adult↗
Long-term follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests.
We evaluated the risk of developing clinically definite multiple sclerosis (CDMS) after an acute attack of isolated optic neuritis (ON) in 112 patients, in relation to demographic and paraclinical findings. Patients were examined by brain MRI, CSF analysis, and multiple evoked potentials (EPs); 10 were lost to follow-up, and the other 102 were enrolled in a prospective study (follow-up duration 6. 3 +/- 2.2 years). Of these, 37 (36.3%) developed CDMS after a mean interval of 2.3 +/- 1.6 years. The risk of developing CDMS was 13% after 2 years, 30% after 4, 37% after 6, and 42% after 8 and 10 years. Gender, age, and season of ON onset did not affect the risk. MS occurred in 37 of 71 patients (52.1%) with one MRI lesion or more; no patient with a normal MRI developed the disease. MS developed more frequently in patients with intrathecal IgG synthesis than in those without (43% vs. 28%), but the difference was not statistically significant. Multiple EPs showed a slight predictive value only including somatosensory EPs of the lower limb. Multiple sclerosis was mild in most cases (EDSS 2.2 +/- 1.9). The EDSS was less than 4 in 32 cases (86%), between 4 and 6 in 2 (5%), higher than 6.5 in 3 (8%).
Adult↗
Adhesion of mononuclear cells from multiple sclerosis patients to cerebral vessels in cryostat sections of normal human brain.
Leukocyte extravasation across the blood-brain barrier is a critical event in the pathogenesis of multiple sclerosis (MS). This complex multistep process includes the adhesion of leukocytes to the endothelial cells of the central nervous system microvasculature. To investigate this phenomenon in MS, we developed a modified version of the frozen-section assay. Peripheral blood mononuclear cells (PBM) from 26 MS patients, 26 healthy controls and 10 patients with other inflammatory non- neurological diseases (OIND) were co-incubated with cryostat sections of normal brain white matter, immunohistochemically labelled with anti-CD45 antibody and counterstained with Giemsa stain. CD45-positive PBM adherent to transected microvasculature were counted with an automated image analyzer. MS patients showed an increased number of vessel-bound PBM (48.8 +/- 36.4) with respect to healthy controls (27.4 +/- 20.7, P = 0.01) and OIND patients (22.6 +/- 7.8, P = 0.01). Significant differences were also obtained counting the number of vessel-bound PBM as a percent of total vascular cells between MS patients (12.7 +/- 7.2%) and healthy controls (6.9 +/- 5.4%, P = 0.002) or OIND patients (7.4 +/- 4.4%, P = 0.03). We confirm that PBM from MS patients show an increased potential of binding to cerebral vessels. The frozen-section assay provides a unique tool to study in situ the molecular interactions of leukocytes with brain vascular structures.
Adult↗
Laminin receptor alpha6beta4 integrin is highly expressed in ENU-induced glioma in rat.
Laminins and their receptors influence neoplastic growth and invasiveness. We recently reported the abnormal expression of a laminin receptor, alpha6beta4 integrin, in human astrocytomas. To further investigate the role of alpha6beta4 in gliomas, we produced an experimental model of glioma in rat by transplacental ethylnitrosourea (ENU) administration. This animal model allowed us to study the timing of alpha6beta4 expression during tumor development and the topography of expression in the tumor and the surrounding tissue. Immunohistochemistry, in situ hybridization, and immunoprecipitation studies demonstrated that alpha6beta4 heterodimer forms in experimental gliomas, and confirmed that alpha6beta4 is expressed diffusely in neoplastic cells and reactive astrocytes, but not in normal glia surrounding the tumors. Interestingly, alpha6beta4 was expressed from the early phases of tumor development, and more highly expressed by cells in the proliferative centers of the tumors. Both neoplastic cells and reactive astrocytes also expressed the glial growth factor (neuregulin) receptors, Erb-B2 and Erb-B3. Finally, alpha6beta4 expression was reduced in a subset of tumor blood vessels. Thus, this study suggests a potential role for alpha6beta4 in the pathogenesis of gliomas. Furthermore, this is the first description of altered integrin expression in experimental gliomas; transplacental ENU-induced gliomas in rat will provide a useful model to study the role of altered adhesion in the pathogenesis of human gliomas.
Animals↗
Neuromyotonia, systemic lupus erythematosus and acetylcholine-receptor antibodies.
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Adult↗
Motor nerve biopsy studies in motor neuropathy and motor neuron disease.
The clinical presentation of motor neuropathy often resembles that of motor neuron disease, sometimes leading to an erroneous diagnosis. Moreover, the underlying pathological process in motor neuropathy has been rarely investigated and there are no systematic studies of the affected motor nerves. We describe a new motor nerve biopsy procedure, performed in 15 patients: 6 with motor neuropathy and 9 with motor neuron disease. The motor branch from the anterior division of the obturator nerve to the gracilis muscle in the thigh was biopsied. In both groups of patients the motor nerves exhibited depletion of myelinated nerve fibers. In motor neuropathy there was a significantly higher density of regenerative clusters of small myelinated fibers in comparison to motor nerves from patients with motor neuron disease. In addition, in 3 patients with motor neuropathy there was evidence for demyelination with thinly myelinated axons and small onion bulb formations. These pathological studies of motor nerve biopsies can help to differentiate motor neuropathy from motor neuron disease.
Adult↗
Axonal neuropathy associated with interferon-alpha treatment for hepatitis C: HLA-DR immunoreactivity in Schwann cells.
A 44-year-old man developed a peripheral neuropathy during treatment with interferon-alpha for chronic hepatitis C. The onset was insidious, beginning symmetrically in the hands with paresthesia. Neurophysiological investigation revealed a predominantly sensory axonal neuropathy. A sural nerve biopsy confirmed primary axonal damage. Immunofluorescence studies showed increased expression of HLA-DR molecules prevalently on Schwann cells of non-myelin-forming type.
Adult↗
Circulating fragments of myelin-associated alpha 6 beta 4 integrin in Guillain-Barré syndrome.
Guillain-Barré-Strohl syndrome (GBS) is an acute peripheral neuropathy causing reversible myelin damage. alpha 6 beta 4 is a laminin receptor of Schwann cells and myelin. Along with myelin breakdown, alpha 6 beta 4 immunoreactivity might be detected in patients' sera and provide a marker for monitoring GBS course. MAbs to beta 4 and alpha 6 were used in an ELISA test to detect protein in GBS serum samples as in normal individuals. In 66% GBS patients, alpha 6 beta 4 immunoreactivity was detected while controls were negative. The level of beta 4 was followed in different patients and found to fluctuate, always being positive in at least one sample. Treatment lowered immunoreactivity in two beta 4-positive GBS sera. Then, circulating alpha 6 beta 4 fragments represent a novel marker of extensive peripheral myelin damage and may be used to validate clinical diagnosis of GBS, evaluate its course and activity.
Acute Disease↗
Headache in a population-based elderly cohort. An ancillary study to the Italian Longitudinal Study of Aging (ILSA).
The aims of this ancillary study to the Italian Longitudinal Study of Aging were: (1) to provide reliable prevalence data on headache in an elderly population, (2) to classify the subtypes of headache according to International Headache Society criteria, and (3) to identify possible risk factors and associated pathologies in the elderly. A total of 312 subjects were examined, 148 women and 164 men, with a mean age of 73 years (SD 5.5). For 236 subjects (75.7%), 141 men (85.9%) and 95 women (64.2%), headache had never been a problem; 57 subjects (18.3%), 21 men (12.8%) and 36 women (24.3%), reported troublesome headache only in the past. Nineteen subjects (6%), 6 men (3.6%) and 13 women (8.8%), reported current headache: in this group tension-type headache was the most prevalent, accounting for 2.6%; secondary headaches ranked second, accounting for 2.2%; and only 1% had current migraine. Our data indicate female sex and younger age as risk factors for headache, and associate migraine and secondary headaches with hypertension, tension-type headaches and secondary headaches with diabetes, and tension-type headaches with myocardial ischemia.
Age Factors↗
Atypical hereditary neuropathy with liability to pressure palsies (HNPP): the value of direct DNA diagnosis.
We report two patients with suspected hereditary liability to pressure palsies. Neurophysiological studies showed a mixed axonal-demyelinating sensory-motor polyneuropathy with focal slowing of conduction velocities at the common sites of entrapment. Morphological studies on sural nerve biopsy from the proband showed active axonal regeneration without typical tomacula. Molecular analysis confirmed the presence of a deletion of chromosome 17p11.2 in both patients. Our observation confirms the heterogeneity of hereditary liability to pressure palsies and the relevance of DNA testing for the diagnosis of this hereditary neuropathy.
Adolescent↗
Autoimmunity and diabetic neuropathy.
Autoimmunity has been implicated in the pathogenesis of diabetic neuropathy. A number of putative target antigens have been investigated in the attempt to find a relationship between the presence of autoantibodies and the presence of neuropathy. Attention has been given to antibodies against nerve growth factor, adrenal medulla, sympathetic and parasympathetic structures, glutamic acid decarboxylase and phospholipids. Data in the literature do not support a clear-cut difference in frequency of positivity or titres between patients with or without diabetic neuropathy. Moreover, it is not clear whether autoantibodies to the above-mentioned antigens, whenever present, play a role in causing nerve damage or if they simply reflect the presence of nerve damage. Longitudinal studies are needed to clarify some conflicting data in the literature.
Adrenal Medulla↗
Beta 4 integrin and other Schwann cell markers in axonal neuropathy.
Schwann cell gene expression is dynamically regulated after peripheral nerve injury and during regeneration. We hypothesized that the changes in protein expression described after rat peripheral nerve injury could be used to identify single Schwann cell-axon units in human axonal neuropathy. Therefore, we performed immuno-fluorescence staining on sections of injured rat sciatic nerves compared with sections of neuropathic human sural nerves. We chose the markers beta 4 integrin, P0 glycoprotein, and glial fibrillary acidic protein (GFAP) to characterize Schwann cells, and neurofilament-heavy (NF-H) to recognize axons. Normal rat or human myelin-forming units demonstrated a sharp ring of beta 4 staining at their outer surface, P0 staining in the myelin sheath, and NF-H staining in the axon. Acutely denervated rat units transited from broken rings of beta 4 and P0 staining, to diffuse beta 4 and absent P0 and NF-H staining. Chronically denervated rat Schwann cells re-expressed beta 4 more highly, but in a diffuse, non-polarized pattern. In contrast, regenerating units re-expressed beta 4, P0, and NF-H; beta 4 staining was polarized to the outer surface of Schwann cells. Finally, GFAP staining increased progressively after injury and decreased during regeneration in the distal nerve stump. In neuropathic human sural nerves, we identified units exhibiting each of these beta 4, P0, and NF-H staining patterns; the proportion of each pattern correlated best with the extent and chronicity of axonal injury. Thus, synchronous injury of rat sciatic nerve predicts patterns of Schwann cell marker expression in human axonal neuropathy. In addition, the unique changes in the polarity of beta 4 integrin expression, in combination with changes in P0 and NF-H expression, may distinguish normal from denervated or reinnervated myelin-forming Schwann cells in human sural nerve biopsies.
Adult↗
Functional basis of memory impairment in multiple sclerosis: a[18F]FDG PET study.
Structural neuroimaging has been used to correlate lesional patterns with the cognitive profile of patients with multiple sclerosis (MS), especially for "frontal" dysfunction. However, a clear-cut anatomical explanation has yet to be found for the long-term memory deficit which is a hallmark of MS cognitive impairment. We have used PET to measure regional cerebral glucose metabolism (rCMRglc) in a group of 15 MS patients with involvement of verbal and/or spatial long-term memory. These patients were compared with 10 normal controls and 13 MS patients unimpaired on all neuropsychological tests. Relative to the controls, MS patients with memory deficits showed a significant bilateral reduction of rCMRglc in the hippocampus, cingulate gyrus, thalamus, associative occipital cortex, and cerebellum. Direct comparisons between patients with memory deficits and the group of unimpaired MS patients showed a metabolic reduction in the left thalamus and in both hippocampi. Seven of the memory-impaired patients also had neuropsychological signs of frontal dysfunction. These patients were compared with patients who had isolated memory deficit. Here we observed a further metabolic reduction in a number of brain regions including bilateral prefrontal cortex, inferior parietal cortex, and basal ganglia. Our findings indicate that hypometabolism of thalamic and deep cortical gray structures of the temporal lobe is associated with episodic memory dysfunction in MS. On the other hand, pathological performance on tests designed to assess frontal functions was associated with widespread reduction of glucose metabolism.
Adult↗
Erythrocytic calpain-calpastatin system in Alzheimer's disease.
Calpains, calcium activated neutral proteases (CANP), and calpastatin (CAST), their specific inhibitor, are involved in the proteolysis of amyloid precursor protein (APP), which is thought to be abnormal in Alzheimer's disease (AD). We studied the CANP/CAST system in erythrocytes of 14 clinically probable AD patients, 11 young and 14 old controls. CANP and CAST activities in the control subjects significantly correlated with increasing age; old controls showed a significant increase in CANP and CAST activities compared to young controls. Values of CANP and CAST activities in AD patients were similar to those of young controls. The physiological gage-related increase in proteolysis seems to be lost in AD patients, and this could play a role in the pathogenesis of the disease. However, due to the overlap of results between patients and controls, we could not reliably differentiate the healthy from the disease state on the basis of erythrocytic CANP/CAST activity.
Aged↗
Relationship between pharmacodynamic activity and cognitive effects of eptastigmine in patients with Alzheimer's disease. Eptastigmine Study Group.
OBJECTIVE: To assess the safety, tolerability, pharmacodynamics, and preliminary efficacy of eptastigmine, a new long-acting cholinesterase inhibitor, in patients with probable Alzheimer's disease. METHODS: This was a double-blind, randomized, placebo-controlled, unbalanced parallel-group study. One-hundred and three patients (83 in the eptastigmine group and 20 in the placebo group) were recruited by 10 centers. Patients received 20 mg eptastigmine or placebo for 4 weeks with twice-a-day or three-times-a-day regimens, depending on body weight (< or = 65 kg or > 65 kg, respectively). Patient performance on the Logical Memory Test, Semantic Word Fluency Test, Trail Making Test, Index of Independence in Activities of Daily Living, Instrumental Activities of Daily Living Scales (IADL), and the Physician and Caregiver Clinical Global Impression of Change (CGIC) was assessed at baseline and at the end of treatment. RESULTS: Nine patients, all from the eptastigmine group, did not complete treatment because of uncooperativeness (n = 3), adverse events (n = 3), protocol violations (n = 2), and clinical decline (n = 1). Twenty-five patients receiving eptastigmine (34%) reported adverse events mainly of the cholinergic type. Cholinergic side effects were generally associated with peak red blood cell cholinesterase inhibition exceeding 50% after the first dose, or 70% at steady state. At steady state, average daily acetylcholinesterase inhibition ranged from 13% to 54%. Overall, 34% of patients receiving eptastigmine versus 0% receiving placebo (p = 0.006) improved on the Physician CGIC. This percentage increased to 46% in the subgroup of patients with average daily acetylcholinesterase inhibition ranging from 30% to 35%. Patient performance on the IADL also improved significantly compared with the placebo group (p = 0.019). In the eptastigmine group, performances on all tests and scales improved with an inverted U-shaped relation to average daily acetylcholinesterase inhibition. CONCLUSIONS: This study shows that doses of 40 to 60 mg per day of eptastigmine are relatively safe and well tolerated and that moderate acetylcholinesterase inhibition is associated with maximal cognitive efficacy.
Aged↗
Alpha6 beta4 and alpha6 beta1 integrins in astrocytomas and other CNS tumors.
Laminin may alter the biological behavior of gliomas. Therefore, we investigated the expression of two laminin receptors, alpha6 beta1 and alpha6 beta4 integrins in normal brain, astrogliotic brain, and astrocytomas as compared to other central nervous system (CNS) tumors. In most CNS tumors, the expression of these integrins was unchanged in neoplastic as compared to normal counterpart cells. In contrast, increased numbers of reactive and neoplastic astrocytes expressed beta4 integrin as compared to normal astrocytes, whereas alpha6 and beta1 integrin expression did not change. Conversely, lower numbers of astrocytoma blood vessels expressed beta4, whereas all blood vessels in normal brain expressed beta4. These data suggest that the profile of laminin receptors changes in neoplastic astrocytes and in astrocytoma blood vessels; this change may play an important role in astrocytoma pathogenesis.
Astrocytoma↗
Correlation between brain MRI lesion volume and disability in patients with multiple sclerosis.
In this study we evaluated the relationships between clinical variables and lesion volumes measured from magnetic resonance imaging (MRI) scans in a large cohort of multiple sclerosis (MS) patients. One hundred and thirty patients with MS entered the study: 36 patients had relapsing-remitting (RR), 39 benign (B), 42 secondary progressive (SP) and 13 primary progressive (PP) courses. There was a significant correlation (r = 0.3; p = 0.0006) between the total lesion load and the EDSS score when the whole cohort of patients was considered. This correlation increased (r = 0.5) when only patients with RRMS and SPMS were considered. Our data indicate that a correlation between disability and MRI lesion volume in MS exists, but its strength is moderate.
Adult↗