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Acute ischemic stroke is a sudden neurological event caused by brain ischemia. Patients with large vessel occlusion are at high risk of developing significant cerebral edema, which can lead to rapid neurological decline. The optimal timing for decompressive hemicraniectomy to prevent further brain damage is still uncertain. This study aimed to identify potential predictors of severe brain edema. The data indicate that specific cytokines may help identify patients with a higher risk of developing life-threatening brain swelling in the early phase post-stroke. The association between a positive biomarker and the outcome was calculated, and three biomarkers—S100B protein, MMP-9, and IL-10—were found to be significantly associated with malignant edema. A model was derived for early predicting malignant cerebral edema, including S100B protein and IL-1 beta. These findings suggest that molecular biomarkers related to the ischemic cascade may be a helpful way of predicting the development of malignant cerebral edema in ischemic stroke patients, potentially widening the time window for intervention and assisting in decision-making. In conclusion, this study provides insights into the molecular mechanisms of severe brain edema and highlights the potential use of biomarkers in predicting the course of ischemic stroke. [ABSTRACT FROM AUTHOR]

This paper deals with the problem of modeling counterfactual reasoning in scenarios where, apart from the observed endogenous variables, we have a latent variable that affects the outcomes and, consequently, the results of counterfactuals queries. This is a common setup in healthcare problems, including mental health. We propose a new framework where the aforementioned problem is modeled as a multivariate regression and the counterfactual model accounts for both observed and a latent variable, where the latter represents what we call the patient individuality factor (φ ). In mental health, focusing on individuals is paramount, as past experiences can change how people see or deal with situations, but individuality cannot be directly measured. To the best of our knowledge, this is the first counterfactual approach that considers both observational and latent variables to provide deterministic answers to counterfactual queries, such as: what if I change the social support of a patient, to what extent can I change his/her anxiety? The framework combines concepts from deep representation learning and causal inference to infer the value of φ and capture both non-linear and multiplicative effects of causal variables. Experiments are performed with both synthetic and real-world datasets, where we predict how changes in people's actions may lead to different outcomes in terms of symptoms of mental illness and quality of life. Results show the model learns the individually factor with errors lower than 0.05 and answers counterfactual queries that are supported by the medical literature. The model has the potential to recommend small changes in people's lives that may completely change their relationship with mental illness. [ABSTRACT FROM AUTHOR]

Human T cell leukemia virus type-I (HTLV-1) infection courses with a myelopathy, the tropical spastic paraparesis (HAM/TSP). In a case-control study, we compared the neuropsychological profile and functional characteristics in two case HTLV-1-infected groups (asymptomatic and with HAM/TSP) with a control group negative for HTLV-1. Subjects were paired for age, sex, and educational features. The case group differed from control group in neuropsychological measures such as in episodic memory recall, executive functions, and fine motor dexterity measure. Individuals with HAM/TSP have more depressive symptoms and worst performance in activities of daily living (ADL) presenting a less functionality. In multivariate models, the fine motor performance, the executive functioning, the recognition memory, and the depressive symptoms explained part of the variance in functionality. Those findings may contribute to understand of everyday life impairments and limitations of HTLV-1-infected population and to organize the rehabilitation. Once more, based in neuropsychological and functional data, we can reaffirm that HTLV-1 is never a benign condition, but sometimes it is only in a stage coursing with less symptoms. [ABSTRACT FROM AUTHOR]

Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3β (Gsk3β) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3β had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity. [ABSTRACT FROM AUTHOR]

Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain. [ABSTRACT FROM AUTHOR]

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Background: Adverse drug reactions (ADRs) associated with anti-tuberculosis (anti-TB) drug regimens have considerable impact on anti-TB treatment, potentially leading to unsuccessful outcomes. Nevertheless, the risk factors that play a role in anti-TB drug-induced ADRs are not well established. It is well documented that genetic polymorphisms in drug-metabolizing enzymes (DMEs) result in considerably complex variability in anti-TB drug disposition. In addition, the impact of pharmacogenetic variation on the metabolism of anti-TB drugs may be modifiable by environmental exposure. Thus, an assessment of pharmacogenetic variability combined with biomarkers of environmental exposure may be helpful for demonstrating the effect of the gene-environment interaction on susceptibility to ADRs induced by anti-TB drug therapy. Objective: The aim of the study was to investigate the impact of the interaction between environmental risk factors and pharmacogenetic polymorphisms in four common DMEs - N-acetyltransferase 2 (arylamine N-acetyltransferase) [NAT2], glutathione S-transferase theta 1 [GSTT1], glutathione S-transferase mu 1 [GSTM1], and cytochrome P450 2E1 [CYP2E1] - on commonly reported ADRs to first-line anti-TB drugs in 129 patients receiving homogeneous TB treatment. Methods: TB patients monitored during drug treatment were divided into subgroups according to the presence or absence of ADRs. Additionally, the patients' clinical and demographic characteristics were collected in order to identify the environmental factors that are potential triggers for ADRs induced by anti-TB drug treatment. Pharmacogenetic variability was determined by gene sequencing, TaqMan® assays, or polymerase chain reaction. Results: The findings of this study suggest that the NAT2 slow acetylator haplotype, female sex, and smoking are important determinants of susceptibility to ADRs induced by anti-TB drugs. Patients carrying multiple, but not single, polymorphisms in the NAT2, GSTM1, GSTT1, and CYP2E1 genes were found to have an increased risk of ADRs, as revealed by gene-gene interaction analysis. Moreover, we also identified meaningful gene-environment interaction models that resulted in the highest levels of ADR risk. Conclusion: The study findings provide evidence of the clinical impact of the interaction between pharmacogenetic variability and environmental factors on ADRs induced by anti-TB drug therapy. Predictive pharmacogenetic testing and a comprehensive clinical history would therefore be helpful for identification and careful monitoring of patients at high risk of this complication. [ABSTRACT FROM AUTHOR]

It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12-NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the cAMP/PKA pathway, with decreased levels of cAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/cAMP signaling pathway. Identification of the cellular mechanisms linking NCS-1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders. [ABSTRACT FROM AUTHOR]

Postpartum depression disorder (PPD) is a severe illness affecting around 15% of deliveries. Several evidences suggest that PPD is, at least, partially genetic determined. The gene encoding BDNF is a strong candidate for pathogenesis of PPD since that it has been observed decrease of serum BDNF in patients suffering from PPD. The gene encoding BDNF has a polymorphism (Val66Met) that alters the regulated protein secretion; the methionine variant being associated with insufficient secretion compared with the Valine variant. We hypothesized that BDNF gene Val66Met polymorphism could be associated with PPD. We assessed 227 subjects randomly selected who had delivery at a maternity hospital using EPDS. Differences in genotype frequency were calculated by χ2 test. Logistic Regression Analyses was performed to verify the existence of interaction between biological, psychiatric and environmental variables and PPD. Difference between groups was tested with Student’s t test. Tests were two-tailed and results significant when p ≤ 0.05. No difference in BDNF genotype distribution was observed between the depressed and non-depressed women. Educational level, stress during pregnancy, bipolar disorder and anxiety was strongly associated with PPD. We were not able to show an association between BDNF polymorphisms and PPD. Further studies are necessary to both of confirm our results and improve validity of PPD diagnosis. [ABSTRACT FROM AUTHOR]

A number of human and animal studies implicate GSK3 in the pathophysiology and genetics of schizophrenia. In general, the data suggest that phosphorylation levels of GSK3β are reduced in schizophrenia, resulting in increased GSK3β activity. Since GSK3β regulation is altered in schizophrenia, polymorphic variation in this gene may affect susceptibility to schizophrenia or treatment response. To analyze GSK3β genetic variants for association with schizophrenia and clozapine response. We examined GSK3β markers in 185 matched case–control subjects, 85 small nuclear families, and 150 schizophrenia patients treated with clozapine for 6 months. Three markers (rs7624540, rs4072520, and rs6779828) showed genotypic association with schizophrenia in the case–control sample. We did not observe any family and clozapine response association with a specific allele, genotype, or haplotype. Our results suggest that GSK3β polymorphisms might be involved in schizophrenia risk but do not appear to play a significant role in clozapine response. [ABSTRACT FROM AUTHOR]

Investigates the effect of ouabain on the release of [[sup 3]H]acetylcholine ([[sup 3]H]ACh) in rat brain cortical slices. Evidence that the ouabain-induced release of ([[sup 3]H]ACh) was calcium-independent and not blocked by EGTA; Suggestion that ouabain causes Ca[sup 2+] release from intracellular stores that can increase ([[sup 3]H]ACh) exocytosis from rat brain cortical slices.

Describes the effects of both scorpion and tityus neurotoxins on [H]acetylcholine (ACh) release from rat cerebrocortical synaptosomes in the presence or absence of the calcium channels blockers. Effect of different actions of calcium channel blockers on [H]ACh; Contribution of calcium channels in mediating tityus toxin-evoked [H]ACh release.

1. In this study we investigated the effect of 7-nitroindazole (7-NI), a preferential inhibitor of neuronal nitric oxide synthase (nNOS), on kainic acid (KA) induced neurotoxicity in rats. Choline acetyltransferase activity (CAT), a cholinergic marker, and histological changes were employed to assess neurotoxicity. 2. In control rats, the local intrastriatal injection of 0.5 µg of KA reduced CAT from 22.9 ± 2.2 to 14.7 ± 2.0 nmol/h/mg tissue ((38 ± 6)% reduction) (P < 0.001). Greater reductions in CAT were observed with 1 and 2 µg of KA ((70 ± 6)% and (80 ± 3)%, respectively). 7-NI aggravated KA-induced cholinergic and histological damage. KA reduced CAT by (68.2 ± 4)% in 7-NI-treated rats, by (38 ± 6)% in saline-treated controls, and by (41 ± 4)% in peanut-oil- (7-NI-vehicle-) treated rats (P = 0.0047). 3. After KA, CAT activity averaged 14.3 ± 2.0 in peanut-oil-treated rats and 7.9 ± 1.0 nmol/h/mg tissue in 7-NI- (peanut-oil-) treated rats (P = 0.015). Similarly to changes in CAT, 7-NI treatment aggravated KA-induced histological changes indicative of neuronal damage (acute ischemic neuronal changes, disorganization of myelinated fibers bundle, and vacuolation changes of the neuropil). Treatment with 7-NI was not associated with increased mortality. 4. Our findings suggest that neuronal NO plays a neuroprotective action on excitotoxicity. [ABSTRACT FROM AUTHOR]

1. The existence of functional interrelationships between dorsal and ventral regions of the rat striatum was investigated. Kainic acid (KA) was employed to induce neuronal lesions in the more dorsal striatum, the caudate-putamen (CP). Only one CP (one side) received KA. KA-induced neurotoxicity at the site of injection (CP) was evidenced by reductions in choline-acetyltransferase activity and in GABA levels, and by increases in the ratios metabolite/monoamine for dopamine (DA) and serotonin (5-HT). 2. In addition to the well-known local effects, direct stereotaxic injection of KA into the CP produced distant effects in the ipsilateral olfactory tubercle (OT). A dose-dependent increase in the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and decreases in DA and 5-HT concentrations were observed in the OT ipsilateral to the CP injected with KA. With 1, 2, 3, and 4 µg of KA, the ratio DOPAC+HVA/DA in the OT was 30, 79, 140, and 173% higher, respectively, than control levels. With 2, 3, and 4 µg of KA, the levels of 5-HIAA were approximately 30, 60, and 120% higher than control values, and the changes in 5-HIAA were associated with significant reductions in 5-HT concentrations. 3. Our results suggest that the dorsal part of the striatum exerts important regulatory functions over the most ventral striatal region, the OT Destruction of CP interneurons by KA leads to disinhibition of DA and 5-HT activities to the OT. The functional interactions between dorsal and ventral striatal regions may play a role in the integration of fundamental life-preserving, motivational, and goal-directed olfactory motor behaviors of rodents. [ABSTRACT FROM AUTHOR]

A letter to the editor about the frequency of postpartum depression and its relevance to clinical management is presented.