Translation, cross-cultural adaptation and validation of the Portuguese version of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis

Translation, cross-cultural adaptation and validation of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis. The original English version of the DYMUS was translated using the forward-backward technique, cross-culturally adaptated, pilot-tested in 40 patients, and then applied to 100 multiple sclerosis patients to assess the reliability and construct validity. Construct validity was assessed by Mann–Whitney test and Spearman’s correlation coefficient (rs). The internal consistency of the questionnaire was evaluated using Cronbach’s alpha coefficient and inter-item correlation. DYMUS-BR internal consistency was high (Cronbach’s alpha= 0.72); Cronbach’s alpha was 0.65 for the ‘dysphagia for solids’ subscale and 0.67 for the ‘dysphagia for liquids’ subscale and positive inter-item correlations was found between all items, except for weight loss question. Significant association (p<0.001) and correlation (rs = 0,357; p = 0.01) was found between DYMUS-BR and dysphagia self-assessment. The DYMUS-BR questionnaire maintained the characteristics of that originally described, demonstrating to be a reliable, valid, easy and consistent tool to be used by health professionals for preliminary selection of Brazilian MS patients who need more specific instrumental analyses of swallowing.

Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Modulation of synaptic transmission in hippocampal CA1 neurons by a novel neurotoxin (beta-pompilidotoxin) derived from wasp venom

We examined the effects of beta-pompilidotoxin (beta-PMTX), a neurotoxin derived from wasp venom. on synaptic transmission in the mammalian central nervous system (CNS). Using hippocampal slice preparations of rodents, we made both extracellular and intracellular recordings from the CA1 pyramidal neurons in response to stimulation of the Schaffer collateral/commissural fibers. Application of 5-10 muM beta-PMTX enhanced excitatory postsynaptic potentials (EPSPs) but suppressed the fast component of the inhibitory postsynaptic potentials (IPSPs). In the presence of 10 muM bicuculline, beta-PMTX potentiated EPSPs that were composed of both non-NMDA and NMDA receptor-mediated potentials. Potentiation of EPSPs was originated by repetitive firings of the prosynaptic axons, causing Summation of EPSPs. In the presence of 10 muM CNQX and 50 muM APV, beta-PMTX suppressed GABA(A) receptor-mediated fast IPSPs but retained GABA(B) receptor-mediated slow IPSPs. Our results suggest that beta-PMTX facilitates excitatory synaptic transmission by a presynaptic mechanism and that it causes overexcitation followed by block of the activity of some population of interneurons which regulate the activity of GABA(A) receptors. (C) 2001 Published by Elsevier B.V. Ireland Ltd and the Japan Neuroscience Society.

Chromatic discrimination losses in multiple sclerosis patients with and without optic neuritis using the Cambridge Colour Test

We assessed chromatic discrimination in multiple sclerosis (MS) patients both with (ON) and without (no ON) a history of optic neuritis using the Cambridge color test (CCT). Our goal was to determine the magnitude and chromatic axes of any color vision losses in both patient groups, and to evaluate age-related changes in chromatic discrimination in both patient groups compared to normals. Using the CCT, we measured chromatic discrimination along the protan, deutan and tritan axes in 35 patients with MS (17 ON eyes) and 74 age matched controls. Color thresholds for both patient groups were significantly higher than controls` along the protan and tritan axes (P < 0.001). In addition, the ON and no-ON groups differed significantly along all three-color axes (p < 0.001). MS patients presented a progressive color discrimination impairment with age (along the deutan and tritan axes) that was almost two times faster than controls, even in the absence of ON. These findings suggest that demyelinating diseases reduce sensitivity to color vision in both red-green and blue-yellow axes, implying impairment in both parvocellular and koniocellular visual pathways. The CCT is a useful tool to help characterize vision losses in MS and the relationship between these losses and degree of optic nerve involvement.

Does Lithium Prevent Alzheimer's Disease?

Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.

Systemic sclerosis sine scleroderma associated with antiphospholipid syndrome

The antiphospholipid syndrome (APS) can be primary, when it occurs alone, or secondary, when it is associated with another autoimmune disease, mainly systemic lupus erythematosus and rarely other autoimmune diseases. Cases described in literature (Medline 1966 to December 2009) associate the presence of antiphospholipid antibodies with the presence of APS and systemic sclerosis (SS). Currently, however, no cases of the SS variant sine scleroderma with APS have been described. In this study, the authors describe the case of a patient with APS characterised by thrombosis of the retinal veins, in May 2006, the presence of lupus anticoagulant and an anticardiolipin IgG antibody. In May 2007, this patient developed Raynaud's phenomenon, a lack of oesophageal motility and nailfold capillaroscopy with a scleroderma pattern. The patient was positive for the anti-centromere antibody but lacked any evidence of cutaneous thickening or involvement. In summary, the authors describe the first case of a patient with APS associated with SS sine scleroderma.

Neuropathology and behavioral impairments after three types of global ischemia surgery in Meriones unguiculatus: Evidence in motor cortex, hippocampal CA1 region and the neostriatum

The effects of three types of global ischemia by occlusion of carotid artery on motor and exploratory behaviors of Gerbils were evaluated by the Activity Cage and Rota rod tests. Animals were divided based on two surgical criteria: unilateral (UNI) or bilateral (BIL) carotid occlusion, with (REP) or without (OCL) reperfusion; and their behavior was evaluated on the fourth (4) or sixth (6) day. There was reduction of cell number in striatum, motor cortex M1 area, and hippocampal CA1 area in all groups in comparison to control animals. For M1 area and striatum, the largest reduction was observed in UNI6, UNI4, and BIL4 groups. Neuronal loss was also observed in CA1 area of BIL4 rodents. There was a decrease in crossings and rearings in all groups in activity cage test, compared to control. Reperfusion, unilateral and bilateral occlusion groups showed decrease in crossings. Only the BIL4 showed a decrease of rearing. In the Rota rod test, except the UNIOCL6, the groups showed a decrease in the balance in comparison to control. Both groups with REP4 showed a major decrease in balance. These findings suggest that both unilateral and bilateral carotid occlusions with reperfusion produce impairments of motor and exploratory behavior. (C) 2011 Elsevier B.V. All rights reserved.

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C- T-1562 and (CA)(n) polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4 +/- 0.18 versus 0.93 +/- 0.18 A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96 +/- 0.25 versus 1.21 +/- 0.09 A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT + TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL Drug therapy resistance, disease severity. MMP-9 plasma activity and polymorphisms are associated with MS. (C) 2012 Elsevier B.V. All rights reserved.

Changes in hippocampal gene expression by 7-nitroindazole in rats submitted to forced swimming stress

Nitric oxide (NO) is an atypical neurotransmitter that has been related to the pathophysiology of major depression disorder. Increased plasma NO levels have been reported in depressed and suicidal patients. Inhibition of neuronial nitric oxide synthase (nNOS), on the other hand, induces antidepressant effects in clinical and pre-clinical trials. The mechanisms responsible for the antidepressant-like effects of nNOS inhibitors, however, are not completely understood. In this study, genomic and proteomic analyses were used to investigate the effects of the preferential nNOS inhibitor 7-nitroindazole (7-NI) on changes in global gene and protein expression in the hippocampus of rats submitted to forced swimming test (FST). Chronic treatment (14 days, i.p.) with imipramine (15 mg/kg daily) or 7-NI (60 mg/kg daily) significantly reduced immobility in the FST. Saturation curves for Serial analysis of gene expression libraries showed that the hippocampus of animals submitted to FST presented a lower number of expressed genes compared to non-FST stressed groups. Imipramine, but not 7-NI, reverted this effect. GeneGo analyses revealed that genes related to oxidative phosphorylation, apoptosis and survival controlled by HTR1A signaling and cytoskeleton remodeling controlled by Rho GTPases were significantly changed by FST. 7-NI prevented this effect. In addition, 7-NI treatment changed the expression of genes related to transcription in the cAMP response element-binding pathway. Therefore, this study suggests that changes in oxidative stress and neuroplastic processes could be involved in the antidepressant-like effects induced by nNOS inhibition.

Quantification of Retinal Neural Loss in Patients with Neuromyelitis Optica and Multiple Sclerosis with or without Optic Neuritis Using Fourier-Domain Optical Coherence Tomography

PURPOSE. We compared retinal nerve fiber layer (RNFL) and macular thickness measurements in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) with or without a history of optic neuritis, and in controls using Fourier-domain (FD) optical coherence tomography (OCT). METHODS. Patients with MS (n = 60), NMO (n = 33), longitudinal extensive transverse myelitis (LETM, n = 28) and healthy controls (n = 41) underwent ophthalmic examination, including automated perimetry, and FD-OCT RNFL and macular thickness measurements. Five groups of eyes were compared: MS with or without previous optic neuritis, NMO, LETM, and controls. Correlation between OCT and visual field (VF) findings was investigated. RESULTS. With regard to most parameters, RNFL and macular thickness measurements were significantly smaller in eyes of each group of patients compared to controls. MS eyes with optic neuritis did not differ significantly from MS eyes without optic neuritis, but measurements were smaller in NMO eyes than in all other groups. RNFL (but not macular thickness) measurements were significantly smaller in LETM eyes than in controls. While OCT abnormalities were correlated significantly with VF loss in NMO/LETM and MS, the correlation was much stronger in the former. CONCLUSIONS. Although FD-OCT RNFL and macular thickness measurements can reveal subclinical or optic neuritis-related abnormalities in NMO-spectrum and MS patients, abnormalities are predominant in the macula of MS patients and in RFNL measurements in NMO patients. The correlation between OCT and VF abnormalities was stronger in NMO than in MS, suggesting the two conditions differ regarding structural and functional damage. (ClinicalTrials.gov number, NCT01024985.) Invest Ophthalmol Vis Sci. 2012;53:3959-3966) DOI:10.1167/iovs.11-9324

Survival, Causes of Death, and Prognostic Factors in Systemic Sclerosis: Analysis of 947 Brazilian Patients

Objective. To analyze survival, prognostic factors, and causes of death in a large cohort of patients with systemic sclerosis (SSc). Methods. From 1991 to 2010, 947 patients with SSc were treated at 2 referral university centers in Brazil. Causes of death were considered SSc-related and non-SSc-related. Multiple logistic regression analysis was used to identify prognostic factors. Survival at 5 and 10 years was estimated using the Kaplan-Meier method. Results. One hundred sixty-eight patients died during the followup. Among the 110 deaths considered related to SSc, there was predominance of lung (48.1%) and heart (24.5%) involvement. Most of the 58 deaths not related to SSc were caused by infection, cardiovascular or cerebrovascular disease, and cancer. Male sex, modified Rodnan skin score (mRSS) > 20, osteoarticular involvement, lung involvement, and renal crisis were the main prognostic factors associated to death. Overall survival rate was 90% for 5 years and 84% for 10 years. Patients presented worse prognosis if they had diffuse SSc (85% vs 92% at 5 yrs, respectively, and 77% vs 87% at 10 yrs, compared to limited SSc), male sex (77% vs 90% at 5 yrs and 64% vs 86% at 10 yrs, compared to female sex), and mRSS > 20 (83% vs 90% at 5 yrs and 66% vs 86% at 10 yrs, compared to mRSS <20). Conclusion. Survival was worse in male patients with diffuse SSc, and lung and heart involvement represented the main causes of death in this South American series of patients with SSc. (First Release Aug 15 2012; J Rheumatol 2012;39:1971-8; doi:10.3899/jrheum.111582)

Novelty, but Not Operant Aversive Learning, Enhances Fos and Egr-1 Expression in the Medial Prefrontal Cortex and Hippocampal Areas of Rats

Immediate early genes (IEG) are presumed to be activated in response to stress, novelty, and learning. Evidence supports the involvement of prefrontal and hippocampal areas in stress and learning, but also in the detection of novel events. This study examined whether a previous experience with shocks changes the pattern of Fos and Egr-1 expression in the medial prefrontal cortex (mPFC), the hippocampal cornus ammonis 1 (CA1), and dentate gyrus (DG) of adult male Wistar rats that learned to escape in an operant aversive test. Subjects previously exposed to inescapable footshocks that learned to escape from Shocks were assigned to the treated group (EXP). Subjects from Group Novelty (NOV) rested undisturbed during treatment and also learned to escape in the test. The nonshock group (NSH) rested undisturbed in both sessions. Standard immunohistochemistry procedures were used to detect the proteins in brain sections. The results show that a previous experience with shocks changed the pattern of IEG expression, then demonstrating c-fos and egr-1 induction as experience-dependent events. Compared with NSH and EXP an enhanced Fos expression was detected in the mPFC and CA1 subfield of Group NOV, which also exhibited increased Egr-1 expression in the mPFC and DG in comparison to NSH. No differences were found in the DG for Fos, or in the CA1 for Egr-1. Novelty, and not the operant aversive escape learning, seems to have generated IEG induction. The results suggest novel stimuli as a possible confounding factor in studies on Fos and/or Egr-1 expression in aversive conditions.

Texture analysis of high resolution MRI allows discrimination between febrile and afebrile initial precipitating injury in mesial temporal sclerosis

A computational pipeline combining texture analysis and pattern classification algorithms was developed for investigating associations between high-resolution MRI features and histological data. This methodology was tested in the study of dentate gyrus images of sclerotic hippocampi resected from refractory epilepsy patients. Images were acquired using a simple surface coil in a 3.0T MRI scanner. All specimens were subsequently submitted to histological semiquantitative evaluation. The computational pipeline was applied for classifying pixels according to: a) dentate gyrus histological parameters and b) patients' febrile or afebrile initial precipitating insult history. The pipeline results for febrile and afebrile patients achieved 70% classification accuracy, with 78% sensitivity and 80% specificity [area under the reader observer characteristics (ROC) curve: 0.89]. The analysis of the histological data alone was not sufficient to achieve significant power to separate febrile and afebrile groups. Interesting enough, the results from our approach did not show significant correlation with histological parameters (which per se were not enough to classify patient groups). These results showed the potential of adding computational texture analysis together with classification methods for detecting subtle MRI signal differences, a method sufficient to provide good clinical classification. A wide range of applications of this pipeline can also be used in other areas of medical imaging. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc.

miR-15a and 16-1 Are Downregulated in CD4(+) T Cells of Multiple Sclerosis Relapsing Patients

The pathology of relapsing-remitting multiple sclerosis (RR-MS) is largely attributed to activated autoreactive effector T lymphocytes. The influence of microRNAs on the immune response has been shown to occur in different pathways of lymphocyte differentiation and function. Here, the expression of the miRNAs miR-15a/161 in PBMC, CD4(+), and CD8(+) from RR-MS patients has been investigated. BCL2, a known miR-15a/16-1 target, has also been analyzed. The results have shown that miR-15a/16-1 is downregulated in CD4(+) T cells, whereas BCL2 is highly expressed in RR-MS patients only. Our data suggest that miR-15a/16-1 can also modulate the BCL2 gene expression in CD4(+) T cells from RR-MS patients, thereby affecting apoptosis processes.

Comparison of Visual Acuity and Automated Perimetry Findings in Patients With Neuromyelitis Optica or Multiple Sclerosis After Single or Multiple Attacks of Optic Neuritis

Objective: To review the clinical characteristics of patients with neuromyelitis optica (NMO) and to compare their visual outcome with those of patients with optic neuritis (ON) and multiple sclerosis (MS). Methods: Thirty-three patients with NMO underwent neuro-ophthalmic evaluation, including automated perimetry along with 30 patients with MS. Visual function in both groups was compared overall and specifically for eyes after a single episode of ON. Results: Visual function and average visual field (VF) mean deviation were significantly worse in eyes of patients with NMO. After a single episode of ON, the VF was normal in only 2 of 36 eyes of patients with NMO compared to 17 of 35 eyes with MS (P < 0.001). The statistical analysis indicated that after a single episode of ON, the odds ratio for having NMO was 6.0 (confidence interval [CI]: 1.6-21.9) when VF mean deviation was worse than -20.0 dB while the odds ratio for having MS was 16.0 (CI: 3.6-68.7) when better than -3.0 dB. Conclusion: Visual outcome was significantly worse in NMO than in MS. After a single episode of ON, suspicion of NMO should be raised in the presence of severe residual VF deficit with automated perimetry and lowered in the case of complete VF recovery.