Pregnancy effect on disease activity in women with multiple sclerosis treated with cladribine.

INTRODUCTION: Cladribine is an oral immune reconstitution therapy for relapsing multiple sclerosis (RMS). Hormonal and immune changes are responsible for the decline of disease activity in the third trimester of pregnancy and disease reactivation in the early post-partum period.We investigate the impact of pregnancy on disease activity in women with MS who conceived after cladribine treatment. METHODS: We recruited women of childbearing age with relapsing-remitting MS (RRMS) who became pregnant or not after being treated with cladribine. For both groups, demographic, clinical and radiological data were collected 1 year before and after treatment during a mean follow-up of 3.53 years. We compared disease activity over time between groups using variance analysis for repeated measures. RESULTS: 48 childbearing women were included. 25 women had a pregnancy after a mean of 1.75 years from the first treatment cycle. Women with or without pregnancy did not differ in demographics or pre-cladribine disease activity. No significant differences in disease activity or EDSS worsening were found between women with or without pregnancy. DISCUSSION: Our findings suggest that pregnancy does not appear to influence disease activity and disability in women previously treated with cladribine; further studies with larger numbers and longer follow-up are needed to confirm this finding.

Cortico-muscular coherence as an index of fatigue in multiple sclerosis.

BACKGROUND: Highly common in multiple sclerosis (MS), fatigue severely impacts patients' daily lives. Previous findings of altered connectivity patterns led to the hypothesis that the distortion of functional connections within the brain-muscle circuit plays a crucial pathogenic role. OBJECTIVE: The objective of this paper is to identify markers sensitive to fatigue in multiple sclerosis. METHODS: Structural (magnetic resonance imaging with assessment of thalamic volume and cortical thickness of the primary sensorimotor areas) and functional (cortico-muscular coherence (CMC) from simultaneous electroencephalo- and surface electromyographic recordings during a weak handgrip task) measures were used on 20 mildly disabled MS patients (relapsing-remitting course, Expanded Disability Status Scale score ≤ 2) who were recruited in two fatigue-dependent groups according to the Modified Fatigue Index Scale (MFIS) score. RESULTS: The two groups were similar in terms of demographic, clinical and imaging features, as well as task execution accuracy and weariness. In the absence of any fatigue-dependent brain and muscular oscillatory activity alterations, CMC worked at higher frequencies as fatigue increased, explaining 67% of MFIS variance (p=.002). CONCLUSION: Brain-muscle functional connectivity emerged as a sensitive marker of phenomena related to the origin of MS fatigue, impacting central-peripheral communication well before the appearance of any impairment in the communicating nodes.

Emotional processing in RRMS patients: Dissociation between behavioural and neurophysiological response.

BACKGROUNG: Multiple sclerosis (MS) results in a broad range of symptoms, including motor, visual, cognitive, and neuropsychiatric deficits. Some studies, considering affective facial expressions to study emotion processing, demonstrated emotion recognition difficulties in MS patients. OBJECTIVE: We investigated the impact of MS on the emotional-behaviour rating and neurophysiological response (Event Related Potentials-ERP) through a battery of affective visual stimuli selected from the International Affective Picture System (IAPS). METHODS: Twenty patients with diagnosis of Relapsing Remitting MS (RRMS) and 20 Healthy Controls (HC) matched by age, gender and education were enrolled. Each of them, after a neuropsychological assessment, were asked to evaluate arousal and valence of affective visual stimuli. RESULTS: Our results showed higher P300 amplitudes in RRMS patients than HC group for pleasant and unpleasant images. Moreover, RRMS patients showed lower Reaction Time (RT) respect HC in valence rating. No other effect did emerge between groups. CONCLUSION: Our study shows early compensatory cerebral mechanisms in RRMS patients throughout emotional information processing, particularly for unpleasant and pleasant stimuli. We hypothesize that this compensatory cerebral mechanism reduces the behavioural dissimilarity between patients and HC.

Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis Patients with Very Mild Clinical Disability.

Cognitive dysfunction affects 40-65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores ≤ 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS ≤ 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 ≤ EDSS ≤ 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation.

Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis.

OBJECTIVE: Fingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5mg/day. METHODS: Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5ms) and intracortical facilitation (at 7, 9, 11 and 13ms) were estimated at T0 and T1. RESULTS: Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. CONCLUSIONS: Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. SIGNIFICANCE: This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models.

[Sclerotic dentin: aetio-pathogenetic hypotheses]. / Dentina sclerotica: ipotesi eziopatogenetiche.

The situation with regard to current knowledge concerning dentinal sclerosis is examined. SEM and TEM examination of specimens of sclerotic dentin showed changes in diameter and tubular content leading to various degrees of obstruction of the lumen. There is agreement that this is due to the neo-apposition of peri-tubular dentin associated with intra-tubular deposition of crystals of Whitelockite, although the debate is still open on how such deposition may come about. Sclerotic casts are created in the tubules that may completely occlude the lumen or present a central cavity. In general these casts are surrounded by a thin fissure that has been variously interpreted. Many agree that sclerotic dentin has an increased mineral component, but without clarifying whether this is only a quantitative increase or whether it is also due to hyper-mineralisation of pre-existing dentin. An examination of the literature reveals numerous hypotheses surrounding the genesis of sclerotic dentin: some say it is due to passive phenomena of dissolution and precipitation whereas others suggest active involvement of the odontoblastic processes and the pulp. Since no studies have confirmed or confuted these theses, we may continue to think of dentinal sclerosis as a multifactorial event, due both to an increase in the thickness of peri-tubular dentin and to intra-tubular precipitation of calcium salts associated with mineralisation of the organic structures present in the lumen.

[Bonding compatibility between adhesive systems and composite resins]. / Affinità di legame tra sistemi adesivi e resine composite.

AIM: The purpose of the present study was to analyse bonding compatibility between photo- and self-polymerising composite resins ad two-step total-etch (one component) adhesive systems with a different activation method. METHODS: Thirty healthy extracted molars were cut transversally to obtain sixty flat dentin surfaces. The acid conditioned surfaces were bonded with Scotchbond 1 (3M), Excite (Vivadent) or Excite DSC (Vivadent). A cylinder of composite resin (3 mm diameter and 4 mm height) was constructed on each adhesive layer using photopolymerised Tetric Ceram (Vivadend) and dual Luxacore (DMG) but activated only chemically. The samples were subjected to the shear bond test. The fracture surfaces obtained were classified by type and site in the stereomicroscope. Twelve samples representing each group were further prepared for the SEM. RESULTS: The data obtained from the test, the microscopic investigation and statistical analysis (ANOVA and Bonferroni) seem to confirm the presence of a reduced bonding compatibility between one-component adhesive systems and self-polymerising composites. This incompatibility is evident for the adhesive Scotchbond 1 and limited for Excite, while it seems to be overcome by Excite DSC which appears to bond well with both Tetric Ceram and Luxacore. CONCLUSIONS: Adhesive-composite incompatibility seems to depend on the activation method of the composite as well as on that of the adhesive system. The chemical compatibility bet-ween these two materials is influenced not only by the chemical composition of the adhesive, but also by that of the composite.

Cognition is related to resting-state small-world network topology: an magnetoencephalographic study.

Brain networks and cognition have recently begun to attract attention: studies suggest that more efficiently wired resting-state brain networks are indeed correlated with better cognitive performance. "Small-world" brain networks combine local segregation with global integration, hereby subserving information processing. Furthermore, recent studies implicate that gender effects may be present in both network dynamics and its correlations with cognition. This study reports on the relation between resting-state functional brain topology with overall and domain-specific cognitive performance in healthy participants and possible gender differences herein. Healthy participants underwent neuropsychological tests, of which individual scores were converted to z-scores. Network analysis was performed on resting-state, eyes-closed magnetoencephalography (MEG) data, after determining functional connectivity between each pair of sensors. The clustering coefficient (local specialization), average path length (overall integration and efficiency) and "small-world index" (i.e. ratio between clustering and path length) were calculated in six frequency bands. 14 male and 14 female participants were included. Better total cognitive performance was related to increased local connectivity in the theta band, higher clustering coefficient (in delta and theta bands) and higher small-worldness (in theta and lower gamma bands). Women showed less clustering and shorter path length in the delta band. There were no significant correlations between network topology and cognitive functioning in females. In contrast, higher cognitive scores in men were associated with increased theta band clustering and small-worldness. These results provide further evidence for the value of functional brain network topology for cognitive functioning and suggest that gender is an important factor in this respect.

An unusual cause of dementia: essential diagnostic elements of corticobasal degeneration-a case report and review of the literature.

Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease.

Estrogen receptor content in breast cancer: correlation between biochemical and immunohistochemical methods.

Estrogen receptor content of 26 consecutive cases of ductal breast carcinoma was evaluated by using both biochemical and immunohistochemical methods. Agreement was present in 20/26 cases (76.9%). The analysis of discordant cases shows that in 5 cases disagreement is due to sampling error or to prolonged storage before biochemical evaluation. Such cases may reasonably be excluded when correlating results. Linear regression of the remaining 21 cases shows a significant relationship (r = 0.931; p less than 0.001) between biochemical and immunohistochemical values. Results show that immunohistochemical and biochemical assays are largely comparable, and stress the important role of the pathologist in tumor sampling.