REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal.

BACKGROUND: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. METHODS: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. RESULTS: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. CONCLUSIONS: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.

Malignant transformation of oral leukoplakia: a multicentric retrospective study in Brazilian population.

BACKGROUND: Among the oral potentially malignant disorders, leukoplakia stands out as the most prevalent. The purpose of this study was to analyse the clinical-pathological features of oral leukoplakia in groups of patients from three major pathology centers in two different regions of Brazil, in order to determine which factors would be associated to the clinical risk of malignant transformation. MATERIAL AND METHODS: A total of 148 patients was analyzed, and data regarding gender, age, site, classification of the clinical subtype, harmful habits such as use of tobacco and alcohol, time of evolution and presence of dysplasia were collected. The association between risk factors and malignant transformation was investigated using the chi-square test and Fischer's exact test for correlation of variables. A significance level of 5% (p≤0.05) was used. RESULTS: The mean age of the patients was 60 years, and 56% were female. Most of the lesions (34,5%) were located in the lateral and ventral regions of the tongue. Of the 148 patients, ninety had clinical follow-up. Malignant transformation occurred in 13 patients (8.8%), with an average of 44 months of follow up. CONCLUSIONS: Non-smoker, nonhomogeneous clinical presentation, location at the tongue, and the presence of high degree of dysplasia were statistically relevant factors associated with a higher risk of transformation transformation.

The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome.

Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were classified as high and low responders to stress. We reveal that susceptible animals (high responders) develop local atrophy of the ventral tegmental area and an increase in functional connectivity between this area and the thalamus, further spreading to other areas that link the cognitive system with the fight-or-flight system. Through a longitudinal approach we were able to establish two distinct patterns, with functional changes occurring during the exposure to stress, but with an inflection point after the first week of stress when more prominent changes were seen. Finally, our study revealed differences in functional connectivity in a brainstem-limbic network that distinguishes resistant and susceptible responders before any exposure to stress, providing the first potential imaging-based predictive biomarkers of an individual's resilience/vulnerability to stressful conditions.

The impact of chronic stress on the rat brain lipidome.

Chronic stress is a major risk factor for several human disorders that affect modern societies. The brain is a key target of chronic stress. In fact, there is growing evidence indicating that exposure to stress affects learning and memory, decision making and emotional responses, and may even predispose for pathological processes, such as Alzheimer's disease and depression. Lipids are a major constituent of the brain and specifically signaling lipids have been shown to regulate brain function. Here, we used a mass spectrometry-based lipidomic approach to evaluate the impact of a chronic unpredictable stress (CUS) paradigm on the rat brain in a region-specific manner. We found that the prefrontal cortex (PFC) was the area with the highest degree of changes induced by chronic stress. Although the hippocampus presented relevant lipidomic changes, the amygdala and, to a greater extent, the cerebellum presented few lipid changes upon chronic stress exposure. The sphingolipid and phospholipid metabolism were profoundly affected, showing an increase in ceramide (Cer) and a decrease in sphingomyelin (SM) and dihydrosphingomyelin (dhSM) levels, and a decrease in phosphatidylethanolamine (PE) and ether phosphatidylcholine (PCe) and increase in lysophosphatidylethanolamine (LPE) levels, respectively. Furthermore, the fatty-acyl profile of phospholipids and diacylglycerol revealed that chronic stressed rats had higher 38 carbon(38C)-lipid levels in the hippocampus and reduced 36C-lipid levels in the PFC. Finally, lysophosphatidylcholine (LPC) levels in the PFC were found to be correlated with blood corticosterone (CORT) levels. In summary, lipidomic profiling of the effect of chronic stress allowed the identification of dysregulated lipid pathways, revealing putative targets for pharmacological intervention that may potentially be used to modulate stress-induced deficits.

The impact of stress in decision making in the context of uncertainty.

For a number of decades, different fields of knowledge, including psychology, economics, and neurosciences, have focused their research efforts on a better understanding of the decision-making process. Making decisions based on the probability of future events is routine in everyday life; it occurs whenever individuals select an option from several alternatives, each one associated with a specific value. Sometimes subjects decide knowing the precise outcomes of each option, but commonly they have to decide without knowing the consequences (because either ambiguity or risk is involved). Stress has a broad impact on animal behaviors, affects brain regions involved in decision-making processes, and, when maladaptive, is a trigger for neuropsychiatric disorders. This Mini-Review provides a comprehensive overview on how stress impacts decision-making processes, particularly under uncertain conditions. Understanding this can prove to be useful for intervention related to impairments to decision-making processes that present in several stress-triggered neuropsychiatric disorders.

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats.

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron-astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-α-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.

Endogenous sex hormones are not associated with subclinical atherosclerosis in menopausal women.

AIM: The aim of this paper was to compare the carotid intima-media thickness (IMT) in pre- and postmenopausal women and to evaluate the association between endogenous sex hormones, body fat distribution, and insulin resistance and the IMT. METHODS: This cross-sectional study included 145 women aged 45-65 yr, comprising 56 premenopausal (FSH<20IU/mL and regular menstrual cycles) and 89 postmenopausal (FSH>40IU/ml and amenorrheic). All patients were evaluated for lipid profile, estradiol and testosterone, insulin ratio (G/I), HOMA-IR, and ultrasound measurement of IMT. Each variable was assessed for correlation with IMT using the univariate model. RESULTS: No difference was observed in IMT between pre- and postmenopausal women. A positive and statistically significant correlation was found between IMT and FSH levels (rs=0.21, P<0.009) and HOMA (rs=0.16, P<0.04). A positive and statistically significant correlation was observed between testosterone and waist (rs=0.3, P<0.04). No correlation was found between IMT and time of menopause (r=0.02, P=0.19). CONCLUSION: Estradiol and testosterone are not associated with subclinical atherosclerosis in menopausal women. A positive correlation between IMT and FSH may reflect an association between low estrogen and IMT. Abdominal fat can be an important link between androgenic levels and cardiovascular risk.

Local People Standings on Existing Farm Animal Welfare Legislation in the BRIC Countries and the USA. Comparison with Western European Legislation.

This study explored the demand for improved farm animal welfare (FAW) legislation in the BRIC countries and the USA. Results are discussed in comparison to Europe. Interviewees ranked their willingness to support or oppose introduction of more FAW-friendly laws in their country. A multinomial logistic regression was fit to the data (p < 0.001), with the parameters "country × gender" (p < 0.001) and "country × age" (p < 0.001) found significant. Americans, Russian women, and older Brazilian men are very supportive. The age effect is also felt in India, where older people are more supportive. Chinese, American men, and younger Indians are less supportive. Russian males are the group that oppose the most, followed by younger Brazilians and Indians. The law and its application vary a lot between countries. Nevertheless, the societal willingness to improve FAW legislation is high in all countries. The willingness is higher in Europe. The different cultural backgrounds, the socio-economic factors, and the social, economic, and environmental sustainability are enough reasons to create barriers to policy harmonization in the global trade of farm animal products.

Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population.

Large normal ('intermediate') alleles may produce de novo expansions in Huntington disease; nevertheless, there is very little evidence about their population prevalence and impact in daily practice, and there are conflicting reports about the extent of their instability. We estimated the frequency of large normal alleles (27-35 CAGs) and of reduced penetrance alleles (36-39 CAGs), as well as the frequency of genotypes carrying them, in (i) a diagnostic laboratory, (ii) a genetic counselling clinic and (iii) the general population. Large normal alleles were present in 6% of a large control sample, 7% of consultands who took pre-symptomatic testing and 7% of samples in the laboratory. Reduced penetrance alleles were found in 1 of 1772 control chromosomes (0.1% of individuals), 5% of 146 pre-symptomatic testees and over 2% of 1214 diagnostic samples (350 families). All 16 alleles sized 27-32 CAGs seemed to be transmitted stably; alleles ≥ 36 repeats were unstable in five families. Seven small full penetrance alleles contracted into the reduced penetrance range, but none into the large normal range. Evidence showed that large normal alleles are relatively frequent and that those with reduced penetrance are not a rare event, either at the laboratory or the clinic. This reinforces the need to understand the genomic context of repeat instability in each family and population.

The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

The SIGMA rat brain templates and atlases for multimodal MRI data analysis and visualization.

Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized neuroimaging tools, namely brain templates and descriptive atlases. Here, we present two rat brain MRI templates and their associated gray matter, white matter and cerebrospinal fluid probability maps, generated from ex vivo [Formula: see text]-weighted images (90 µm isotropic resolution) and in vivo T2-weighted images (150 µm isotropic resolution). In association with these templates, we also provide both anatomical and functional 3D brain atlases, respectively derived from the merging of the Waxholm and Tohoku atlases, and analysis of resting-state functional MRI data. Finally, we propose a complete set of preclinical MRI reference resources, compatible with common neuroimaging software, for the investigation of rat brain structures and functions.

Stress and glucocorticoid footprints in the brain-the path from depression to Alzheimer's disease.

Increasingly, stress is recognized as a trigger of depressive episodes and recent evidence suggests a causal role of stress in the onset and progression of Alzheimer's disease (AD) pathology. Besides aging, sex is an important determinant of prevalence rates for both AD and mood disorders. In light of a recent meta-analysis indicating that depressed subjects have a higher likelihood of developing AD, a key message in this article will be that both depression and AD are stress-related disorders and may represent a continuum that should receive more attention in future neurobiological studies. Accordingly, this review considers some of the cellular mechanisms that may be involved in regulating this transition threshold. In addition, it highlights the importance of addressing the question of how aging and sex interplay with stress to influence mood and cognition, with a bias towards consideration of neuroplastic events in particular brain regions, as the basis of AD and depressive disorders.

Dissociation of the morphological correlates of stress-induced anxiety and fear.

Chronic stress is a powerful modulator of emotional behaviour. Previous studies have shown that distinct neuronal pathways modulate different emotional behaviours: while the amygdala plays a key role in fear-conditioned-to-cue stimuli, the bed nucleus of stria terminalis (BNST) is implicated in anxiety behaviour and responses to contextual stimuli. In addition, the BNST is directly involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. In the present study, we assessed anxiety (measured in the elevated-plus maze and acoustic startle apparatus) and fear-conditioned responses to light stimuli in rats that had been exposed to either chronic unpredictable stress or corticosterone for 28 days; thereafter, stereological estimates of the BNST and amygdaloid complex were performed, followed by three-dimensional morphometric dendritic analysis. Results show that chronic stress induces hyperanxiety without influencing fear conditioning or locomotion and exploratory activity. Stress-induced hyperanxiety was correlated with increased volumes of the BNST but not of the amygdala. Dendritic remodelling was found to make a significant contribution to the stress-induced increase in BNST volume, primarily due to changes in the anteromedial area of the BNST, an area strongly implicated in emotional behaviour and in the neuroendocrine control of the stress response. Importantly, all of the effects of stress were recapitulated by exogenous corticosterone. In conclusion, this study shows that chronic stress impacts on BNST structure and function; its findings pertain to the modulation of emotional behaviour and the maladaptive response to stress.

Simultaneous supratentorial and brainstem abscesses due to Listeria monocytogenes.

Multiple supratentorial abscesses caused by Listeria monocytogenes are rare. We report the simultaneous occurrence of multiple supratentorial and brainstem abscesses due to Listeria, in a patient under corticotherapy for an exacerbation of ulcerative colitis. MR imaging features before and after successful conservative treatments are depicted. In immunocompromised patients with supratentorial listerial abscesses, the coexistence of brainstem abscedation is exceptional. Despite high mortality associated with listerial abscesses, this case illustrates the possibility of a good clinical outcome, if the appropriate antibiotic regimen is instituted and the immunosuppressant agent is discontinued.

Anxiety-like behavior and structural changes of the bed nucleus of the stria terminalis (BNST) in gestational protein-restricted male offspring.

Animal evidence has suggested that maternal emotional and nutritional stress during pregnancy is associated with behavioral outcomes in offspring. The nature of the stresses applied may differ, but it is often assumed that the mother's hippocampus-hypothalamic-pituitary-adrenal (HHPA) axis response releases higher levels of glucocorticoid hormones. The bed nucleus of the stria terminalis (BNST) is in a pivotal position to regulate the HHPA axis and the stress response, and it has been implicated in anxiety behavior. In the current study, to search whether BNST structural changes and neurochemical alterations are associated with anxiety-related behavior in adult gestational protein-restricted offspring relative to an age-matched normal protein diet (NP) rats, we conduct behavioral tests and, BNST dendritic tree analysis by Sholl analysis, associated to immunoblotting-protein quantification [11ß-HSD2, GR, MR, AT1R, 5HT1A and 5HT2A, corticotrophin-releasing factor (CRH) and CRH1]. Dams were maintained either on isocaloric standard rodent chow [with NP content, 17% casein or low protein content (LP), 6% casein] chow throughout their entire pregnancy. Here, in rats subjected to gestational protein restriction, we found: (a) a significant reduction in dendritic length and impoverished dendritic arborization in BNST neurons; (b) an elevated plasmatic corticosterone levels; and (c) associated with enhanced anxiety-like behavior when compared with age-matched NP offspring. Moreover, altered protein (11ß-HSD2, GR, MR and type 1 CRH receptors) expressions may underlie the increase in anxiety-like behavior in LP offspring. This work represents the first demonstration that BNST developmental plasticity by maternal protein restriction, resulting in fine structural changes and neurochemical alterations that are associated with modified behavioral states.

Brain interference: Revisiting the role of IFNγ in the central nervous system.

Interferon gamma (IFNγ) is a pro-inflammatory cytokine, first described as a secreted molecule capable of interfering with viral replication. Since then, numerous other important actions in the context of the immune response to invading pathogens (including those invading the brain) have been ascribed to this pleiotropic cytokine. Nevertheless, the precise role of IFNγ in neuropsychiatric and neurodegenerative disorders, and its possible contribution to the regulation of normal brain function, remains enigmatic. This review integrates and considers current knowledge about IFNγ actions with accumulating evidence of its importance on neurocytogenesis, synaptic plasticity and neurodegeneration within the framework of brain health and disease.

Cyclic electron flow, NPQ and photorespiration are crucial for the establishment of young plants of Ricinus communis and Jatropha curcas exposed to drought.

Although plant physiological responses to drought have been widely studied, the interaction between photoprotection, photorespiration and antioxidant metabolism in water-stressed plants is scarcely addressed. This study aimed to evaluate the physiological adjustments preserving photosynthesis and growth in two plant species with different tolerance to drought: Jatropha curcas and Ricinus communis. We measured stress indicators, gas exchange, photochemistry of PSII and PSI, antioxidant enzymes, cyclic electron flow and photorespiration. Physiological stress indicators associated with reduction in growth confirmed R. communis as sensitive and J. curcas as tolerant to drought. Drought induced loss of photosynthesis in R. communis, whereas J. curcas maintained higher leaf gas exchange and photochemistry under drought. In addition, J. curcas showed higher dissipation of excess energy and presented higher cyclic electron flow when exposed to drought. Although none of these mechanisms have been triggered in R. communis, this species showed increases in photorespiration. R. communis displayed loss of Rubisco content while the Rubisco relative abundance did not change in J. curcas under drought. Accordingly, the in vivo maximum Rubisco carboxylation rate (Vcmax ) and the maximum photosynthetic electron transport rate driving RuBP regeneration (Jmax ) were less affected in J. curcas. Both species displayed an efficient antioxidant mechanism by increasing activities of ascorbate peroxidase (APX) and superoxide dismutase (SOD). Overall, we suggest that the modulation of different photoprotective mechanisms is crucial to mitigate the effects caused by excess energy, maintaining photosynthetic apparatus efficiency and promoting the establishment of young plants of these two species under drought.

Kidney Transplantation Using Gonadal Vein for Venous Anastomosis in Patients With Iliac Vein Thrombosis or Stenosis: A Series of Cases.

BACKGROUND: Kidney transplantation is the treatment of choice for patients with end-stage renal disease. The standard surgery uses the recipient's iliac vessels for vascular anastomosis. Thrombosis and/or stenosis of the iliac vein, which are possible complications of multiple vascular access points for dialysis, can be detected intraoperatively, constituting a surgical challenge. An infrequently reported option is the use of the gonadal vein. OBJECTIVES: This study aims to evaluate the outcomes of venous anastomosis in the gonadal vein in patients with iliac vein thrombosis and/or stenosis submitted to kidney transplantation. METHODS: We reviewed the records of five adult recipients with iliac vein thrombosis and/or stenosis detected intraoperatively during emergency kidney transplantation with deceased donor due to vascular access failure from February 2013 to December 2014. Antithrombotic prophylaxis was not performed. We evaluated the postoperative complications, length of stay, early graft echo-Doppler, and renal function during the first year postoperatively. RESULTS: Delayed graft function occurred in three cases. Two patients developed postoperative infection requiring antibiotics. One patient required reoperation due to post-renal biopsy complications. The mean length of stay was 31.2 days and the mean serum creatinine levels at discharge, at 6 months, and at 12 months postoperatively were 1.42 mg/dL, 0.86 mg/dL, and 0.82 mg/dL, respectively. All patients had normal ultrasonography. There were no losses of graft or deaths during follow-up. CONCLUSION: Venous anastomosis using the gonadal vein in kidney transplantation for patients with iliac vein thrombosis and/or stenosis showed good clinical and surgical results, showing this method to be a viable alternative to venous drainage in these complex patients.

Mismatch between anxiety status and morphometric parameters in the amygdala and bed nucleus of the stria terminalis.

Aging is associated with behavioral changes, including increased anxiety. In this study we confirmed a hyperanxious status in aged animals, measured in the elevated-plus maze and in the acoustic startle. Subsequently, we searched for age-related changes in the volume and cell numbers in the amygdala or in the bed nucleus of the stria terminalis, but failed to detect gross structural changes in these two brain areas, both implicated in emotionality.