Polycyclic aromatic hydrocarbons in seawater after the mysterious oil spill of 2019 on the Pernambuco coast, northeast Brazil.

In 2019, one of Brazil's most significant environmental disasters occurred, involving an oil spill that directly affected Pernambuco state. Contamination along the coast was evaluated by the quantification of polycyclic aromatic hydrocarbons (PAHs) in fifty seawater samples collected in the summer and winter of 2021. Analysis using fluorescence spectroscopy revealed that for all the samples, levels of dissolved/dispersed petroleum hydrocarbons (DDPHs) were higher than the regional baseline for tropical western shores of the Atlantic Ocean. GC-MS analyses quantified 17 PAHs in the samples, with highest total PAHs concentrations of 234 ng L-1 in summer and 33.3 ng L-1 in winter, which were consistent with the highest risks observed in ecotoxicity assays. The use of diagnostic ratios showed that the coast was impacted by a mixture of PAHs from petrogenic and pyrolytic sources. The results indicated the need for continuous monitoring of the regions affected by the 2019 spill.

Efficacy and safety of transcranial direct current stimulation over the left dorsolateral prefrontal cortex in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, triple-blinded, sham-controlled, crossover trial.

Introduction: Although pharmacological treatment for Attention-Deficit/Hyperactivity Disorder (ADHD) has demonstrated efficacy, several individuals persist in experiencing social and academic impairment. Additionally, the occurrence of significant side effects may render the use of psychotropic medications untenable. However, Transcranial Direct Current Stimulation (tDCS), a non-invasive brain stimulation technique, shows promising results in treating ADHD. Objectives: To investigate the efficacy and safety of tDCS on the performance of children and adolescents with ADHD in neuropsychological tests involving visual attention, visual and verbal working memory, and inhibitory control. Methodology: This study was a triple-blind, randomized, sham-controlled, crossover clinical trial. The intervention consisted of a daily session of tDCS (2 mA) or sham targeting the left dorsolateral prefrontal cortex (L-DLPFC), for 30 min, on five consecutive days. The primary outcome was change in the Visual Attention Test, Fourth Edition (TAVIS-4) before and after each intervention. Subjects were also evaluated pre and post-tDCS using the Digit Span subtest of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V), the Developmental Neuropsychological Assessment, Second Edition (NEPSY-II) Inhibiting Response (IR) subtest, and the Corsi Block-Tapping Task. Results: Fifteen individuals were included, and no statistically significant difference was observed when comparing the results of the TAVIS-4, the IR of NEPSY-II, and the intragroup Digit Span subtest of WISC-V undertaken before and after the procedure. Adverse events were mainly self-limiting and transient. The participants did not perceive any benefit from tDCS when measured on the Patient Global Impression of Improvement (PGI-I) Scale. Conclusion: This study did not meet its primary endpoint and found no performance enhancement in any investigated neuropsychological outcomes relating to the intervention group.

A Novel PACS1 Variant Associated With Schuurs-Hoeijmakers Syndrome Phenotype in an Indigenous Descendant in Brazil: A Case Report.

Schuurs-Hoeijmakers syndrome, an autosomal dominant disorder associated with mutations in the PACS1 gene, was initially identified in two unrelated children of European descent from a cohort of individuals with intellectual disabilities. This gene alteration significantly reduced cranial cartilaginous structures, inducing craniofacial alterations predominantly in a dominant-negative fashion. In this paper, we report a novel variant of PACS1 associated with Schuurs-Hoeijmakers syndrome: a boy aged two years and nine months of indigenous descent presenting with motor stereotypies, atypical sensory searches, language delay, and low socio-interactional reciprocity. Whole exome sequencing confirmed the presence of a heterozygous missense mutation c.943C>T p. (Arg315Trp) in the PACS1 gene. The phenotypic profile identified was similar to the other cases of Schuurs-Hoeijmakers syndrome described in the literature. This report highlights the importance of considering the possibility of PACS1 gene alterations and a diagnosis of Schuurs-Hoeijmakers syndrome in patients presenting craniofacial alterations associated with autistic features, psychomotor and language development delay.

Botulinum Toxin Type A in the Spasticity of Cerebral Palsy Related to Congenital Zika Syndrome: An Observational Study.

PURPOSE: Investigate the effect of botulinum toxin type-A (BoNT-A) on spasticity and motor performance in children with Cerebral Palsy (CP) related to Congenital Zika Syndrome (CZS). METHODS: Prospective longitudinal observational study of 34 children with CP referred for BoNT-A treatment. Outcomes were evaluated with a muscle tone assessment scale (Modified Ashworth Scale - MAS) and the Patients' Global Impression of Improvement (PGI-I) scale. RESULTS: Mean age was 32.06 ± 3.07 months and 85% were classified as Gross Motor Function Classification System (GMFCS) V. Primitive reflexes were present in 56% of the sample. The majority of the parents (97.9%) reported improvement in range of motion or reduction in spasticity after treatment with botulinum toxin. No side effects were recorded. When compared to the baseline, median reduction in the MAS was 0.5 (IQR = 0). CONCLUSIONS: The findings of this study suggest that BoNT-A may effectively promote functional improvements and reduce muscle tone, improving the child's and family's quality of life.

The effects of transcranial direct current stimulation on attention and inhibitory control of children and adolescents with attention-deficit/hyperactivity disorder (ADHD): Study protocol for a randomized, sham-controlled, triple-blind, cross-over trial.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is characterized by a persistent pattern of inattention and hyperactivity/impulsivity. Despite the proven efficacy of pharmacological treatment, many individuals continue to suffer socially and academically and some experience significant side effects that negate the use psychotropic drugs. Transcranial direct current stimulation (tDCS) is a cortical neuromodulation feature that has shown positive results in the treatment of various neuropsychiatric conditions. OBJECTIVES: To investigate the effect of tDCS on the performance of children and adolescents with ADHD in the neuropsychological tests of visual attention, verbal, and inhibitory control. METHODOLOGY: Triple blind, randomized, sham-controlled, cross-over trial involving tDCS in children and adolescents with ADHD. Initial screening will be performed using Swanson, Nolan, and Pelham - IVand Wechsler intelligence scale for children fourth edition vocabulary and cube subtests. Individuals will be evaluated pre-tDCS and post-tDCS with the Wechsler intelligence scale for children fourth edition Digitus subtest, neuropsychological assessment battery second edition inhibiting responses subtest, Corsi cubes, and visual attention test-4.

The impact of botulinum toxin type A in the treatment of drooling in children with cerebral palsy secondary to Congenital Zika Syndrome: an observational study.

OBJECTIVE: The main aim of this study was to determine the impact of botulinum toxin A (BTX-A) on severity and frequency of drooling in children with Cerebral Palsy (CP) secondary to Congenital Zika Syndrome (CZS). METHODS: This is a prospective longitudinal observational study including 23 children who received bilateral injections of BTX in the parotid and submandibular glands. The Thomas-Stonell & Greenberg Drooling Severity and Frequency Scale was applied by a multidisciplinary team including Speech, Language and Hearing professionals. The Global Impression of Improvement (GII) Scale was also applied to assess parents' subjective perceptions of therapeutic response. Swallowing was assessed using Doppler ultrasonography. Univariate logistic regression was used to analyse differences between responders and non-responders. RESULTS: Participant age varied from 27 to 38 months (mean 31.78, SD = 2.61) all presented with Gross Motor Function Classification System (GMFCS) V. Drooling Severity and Frequency Scale scores ranged from 7 to 9 points (median = 9) prior to BTX administration and from 4 to 6 (median = 6) after. Pre- and post-treatment reduction in drooling severity occurred (Z = -3.746; p < 0.001). No cases of drooling worsening were reported. Only two subjects presented adverse effects attributed to BTX administration. Correlation was only confirmed with GII. DISCUSSION: This article presents the safe and positive impact of BTX-A administration guided by anatomical references described in the literature, even on children with microcephaly. Further studies are needed to facilitate the use of Doppler ultrasonography as a tool to characterize changes in sensory processing and motor response following intraoral input in children with CP.

Suicidal behavior in individuals with amyotrophic lateral sclerosis: A systematic review.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) leads to a drastic reduction in quality of life, generating intense psychological distress and predisposing those affected to mental illness and, in more severe cases, suicidal behavior. OBJECTIVE: This is a systematic review aiming to estimate the frequency of wish to die, suicide ideation and suicide in individuals with ALS using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). METHODS: The following databases were used: Pubmed/MEDLINE, PsycINFO, Embase, SciELO, Biblioteca Virtual de Saúde (BVS), and Cochrane Library. The choice of appropriate descriptors, or their equivalents, to define the search terms was based on the technical and scientific vocabulary of each database. RESULTS: 13 articles were included in the present systematic review, of which three were cross-sectional studies, nine were cohort-type and there was one case-control study. The studies show that individuals with ALS have a higher risk of suicide in relation to the general population, and there is evidence that this risk is even higher in the early stages of the disease. Major Depressive Disorder was the most prevalent mental disorder in the studies included. This mental health concern is often undertreated, leading to the increased susceptibility of this population to suicide. LIMITATIONS: In general, the study samples represent a highly heterogeneous population while many instruments used in the data collection were not uniform. CONCLUSIONS: The high degree of psychological vulnerability of this population, associated with a greater predisposition to suicidal behavior, should be minimized through public health measures.

Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer.

Evasion from apoptosis is one of the hallmarks of cancer. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptosis by inhibiting caspases and ubiquitinating target proteins. XIAP is mainly found at the cytoplasm, but recent data link nuclear XIAP to poor prognosis in breast cancer. Here, we generated a mutant form of XIAP with a nuclear localization signal (XIAPNLS-C-term) and investigated the oncogenic mechanisms associated with nuclear XIAP in breast cancer. Our results show that cells overexpressing XIAPΔRING (RING deletion) and XIAPNLS-C-term exhibited XIAP nuclear localization more abundantly than XIAPwild-type. Remarkably, overexpression of XIAPNLS-C-term, but not XIAPΔRING, conferred resistance to doxorubicin and increased cellular proliferative capacity. Interestingly, Survivin and c-IAP1 expression were not associated with XIAP oncogenic effects. However, NFκB expression and ubiquitination of K63, but not K48 chains, were increased following XIAPNLS-C-term overexpression, pointing to nuclear signaling transduction. Consistently, multivariate analysis revealed nuclear, but not cytoplasmic XIAP, as an independent prognostic factor in hormone receptor-negative breast cancer patients. Altogether, our findings suggest that nuclear XIAP confers poor outcome and RING-associated breast cancer growth and chemoresistance.

KPTN gene homozygous variant-related syndrome in the northeast of Brazil: A case report.

Alteration of the KPTN gene, responsible for the coding of kaptin (a protein involved in actin cytoskeletal dynamics), causes a syndrome characterized by macrocephaly, neurodevelopmental delay and epileptic seizures. We report the first Brazilian case of KPTN gene variation, previously described in nine subjects from four interlinked families from an Amish community in Ohio, two Estonian siblings and a 9-year-old boy from Kansas City. We report a case of KPTN-related syndrome in a 5-year-old child which presented macrocephaly, muscular hypotonia, and global development delay. The neurological examination revealed below-expected performance in coordination and balance tests, dyspraxia, and hand-mouth synkinesia. Expressive language was characterized by phono-articulatory imprecision, abundance of phonological processes and morphosyntactic immaturity. Neuropsychological assessment revealed intellectual disability with impairment of verbal and executive functions. Exome sequencing was performed. Analysis revealed a homozygous 2-nucleotide duplication c.597_598dup p.(Ser200Ilefs*55) in the KPTN gene, which is predicted to lead to a translational frameshift and formation of a premature stop codon. The phenotypic profile is similar to the cases described in the other families. Presence of macrocephaly and delayed development indicate the possibility of KPTN gene variation. Genetic testing should be carried out at an early stage in order to reach a timely diagnosis.

Predictive equation for blood flow restriction training / Equação preditiva para o treinamento de restrição do fluxo sanguíneo / Ecuación predictiva para el entrenamiento de restricción del flujo sanguíneo

ABSTRACT Introduction No research has investigated predictive equations for application in blood flow restriction (BFR) training using a cuff with a circumference of 18 cm for the lower limbs, and including age and sex as predictor variables. Objectives To develop an equation to predict cuff pressure levels for use in BFR training for the lower limbs. Methods A total of 51 adults (age 23.23 ± 5.24 years) of both sexes (males, n= 32; females, n= 19) underwent a series of tests and anthropometric (body mass, height, body mass index - BMI, and thigh circumference - TC) and hemodynamic (brachial systolic - SBP - and diastolic - DBP - blood pressure) measurements. The arterial occlusion pressure (AOP) of the lower limbs was measured using a Doppler probe. Results The predictive equation was developed based on a hierarchical linear regression model consisting of six blocks, corresponding to TC (β = 0.380; p = 0.005), SBP (β = 0.091; p = 0.482), age (β = 0.320; p = 0.015), and sex (β = -0.207; p = 0.105), which explained 39.7% of the variation in arterial occlusion pressure. DBP and BMI were not associated with AOP. As a result, the predictive equation is as follows: AOP (mmHg) = 65.290 + 1.110 (TC in cm) + 0.178 (SBP in mmHg) + 1.153 (age in years) - 7.984 (sex, 1 - male and 2 - female), reporting values of r = 0.630, r2 = 0.397 and SEE = 15,289. Conclusion Cuff pressure for BFR training of the lower limbs may be selected based on TC, SBP, age and sex, and thigh circumference is considered the main predictor. Level of Evidence III, Non-consecutive studies, or studies without consistently applied reference standard.

RESUMO Introdução Nenhuma pesquisa investigou equações preditivas para aplicação no treinamento de restrição do fluxo sanguíneo (RFS) utilizando um manguito de 18 cm de circunferência para os membros inferiores e incluindo a idade e sexo como variáveis preditoras. Objetivos Desenvolver uma equação preditiva dos níveis de pressão do manguito para uso no treinamento de RFS para os membros inferiores. Métodos Um total de 51 adultos (23,23 ± 5,24 anos) de ambos os sexos (homens, n = 32; mulheres, n = 19) foram submetidos a uma série de testes e medidas antropométricas (massa corporal, altura, índice de massa corporal - IMC e circunferência da coxa - CC) e hemodinâmicas (pressão sistólica braquial - PSB e diastólica - PDB). A pressão de oclusão arterial (POA) dos membros inferiores foi medida com utilização de uma sonda Doppler. Resultados A equação preditiva foi desenvolvida a partir de um modelo hierárquico de regressão linear composto de seis blocos, correspondendo a CC (β = 0,380; p = 0,005), PSB (β = ٠,091; p = 0,482), idade (β = 0,320; p = 0,015) e sexo (β = -0,207; p = 0,105), explicando os 39,7% da variação na pressão de oclusão arterial. O IMC e a PDB não foram associados à POA. Como resultado, apresenta-se a seguinte equação: POA (mmHg) = 65,290 + 1,110 (CC em cm) + 0,178 (PSB em mmHg) + 1,153 (idade em anos) - 7,984 (sexo, 1 - masculino e 2 - feminino), com valores de r = 0,630, r2 = 0,397 e EPE = 15,289. Conclusão A pressão do manguito para utilização no treinamento de RFS dos membros inferiores pode ser selecionada com base nas medidas de CC, PSB, idade e sexo, sendo que, a circunferência da coxa é considerada o principal preditor. Nível de Evidência III, Estudos não consecutivos ou estudos sem padrão de referência consistentemente aplicado.

RESUMEN Introducción Ninguna pesquisa investigó las ecuaciones predictivas para aplicación en el entrenamiento de restricción del flujo sanguíneo (RFS) utilizando un manguito de 18 cm de circunferencia para los miembros inferiores e incluyendo la edad y sexo como variables predictoras. Objetivos Desarrollar una ecuación predictiva de los niveles de presión del manguito para uso en el entrenamiento de RFS para los miembros inferiores. Métodos Un total de 51 adultos (23,23 ± 5,24 años) de ambos sexos (masculino, n = 32, femenino, n = 19) fueron sometidos a una serie de pruebas y mediciones antropométricas (masa corporal, estatura, índice de masa corporal - IMC y circunferencia del muslo - CM) y hemodinámicas (presión sistólica braquial - PSB , y diastólica - PDB). La presión de oclusión arterial (POA) de los miembros inferiores se midió mediante una sonda Doppler. Resultados La ecuación predictiva se desarrolló a partir de un modelo jerárquico de regresión lineal compuesto de seis bloques, correspondiendo a CM (β = 0,380; p = 0,005), PSB (β = 0,091; p = 0,482), edad (β = 0,320; p = 0,015), y sexo (β = -0,207; p = 0,105), explicando 39,7% de la variación en la presión de oclusión arterial. El IMC y la PDB no fueron asociadas a la POA. Como resultado, se presenta la siguiente ecuación: POA (mmHg) = 65,290 + 1,110 (CM en cm) + 0,178 (PAS en mmHg) + 1,153 (edad en años) - 7,984 (sexo, 1 - Masculino y 2 - Femenino), con valores de r = 0,630, r2 = 0,397 y EEE = 15,289. Conclusión La presión del manguito para su uso en el entrenamiento de RFS de los miembros inferiores puede seleccionarse con base en las medidas de CM, PSB, edad y sexo, siendo que la circunferencia del muslo es considerada el principal predictor. Nivel de Evidencia III, Estudios no consecutivos o estudios sin estándar de referencia consistentemente aplicado.

Effect of Anodal tDCS on Articulatory Accuracy, Word Production, and Syllable Repetition in Subjects with Aphasia: A Crossover, Double-Blinded, Sham-Controlled Trial.

INTRODUCTION: Transcranial direct-current stimulation (tDCS) has been used to modulate and induce changes in brain function and excitability. tDCS is a promising tool for the treatment of aphasia. OBJECTIVE: To evaluate whether tDCS improves articulatory accuracy and speech production in patients with aphasia after stroke. METHODS AND RESULTS: Twelve right-handed subjects participated in a double-blind, sham-controlled, crossover offline trial. We assessed (1) articulatory accuracy at a naming task, (2) number of words correctly produced, (3) number of syllables repeated correctly, and (4) qualitative assessment of speech. Articulatory accuracy improved when using tDCS over Broca's area in subjects with aphasia post-stroke (p ≤ 0.05). Qualitative improvement in the naming and syllable repetition tasks was observed, but the difference was not statistically significant (respectively, p = 0.15 and p = 0.79). CONCLUSION: The current results corroborate the potential of tDCS to be used as an alternative and complementary treatment for individuals with aphasia.

Combining Fluoxetine and rTMS in Poststroke Motor Recovery: A Placebo-Controlled Double-Blind Randomized Phase 2 Clinical Trial.

Background. Although recent evidence has shown a new role of fluoxetine in motor rehabilitation, results are mixed. We conducted a randomized clinical trial to evaluate whether combining repetitive transcranial magnetic stimulation (rTMS) with fluoxetine increases upper limb motor function in stroke. Methods. Twenty-seven hemiparetic patients within 2 years of ischemic stroke were randomized into 3 groups: Combined (active rTMS + fluoxetine), Fluoxetine (sham rTMS + fluoxetine), or Placebo (sham rTMS + placebo fluoxetine). Participants received 18 sessions of 1-Hz rTMS in the unaffected primary motor cortex and 90 days of fluoxetine (20 mg/d). Motor function was assessed using Jebsen-Taylor Hand Function (JTHF) and Fugl-Meyer Assessment (FMA) scales. Corticospinal excitability was assessed with TMS. Results. After adjusting for time since stroke, there was significantly greater improvement in JTHF in the combined rTMS + fluoxetine group (mean improvement: -214.33 seconds) than in the placebo (-177.98 seconds, P = 0.005) and fluoxetine (-50.16 seconds, P < 0.001) groups. The fluoxetine group had less improvement than placebo on both scales (respectively, JTHF: -50.16 vs -117.98 seconds, P = 0.038; and FMA: 6.72 vs 15.55 points, P = 0.039), suggesting that fluoxetine possibly had detrimental effects. The unaffected hemisphere showed decreased intracortical inhibition in the combined and fluoxetine groups, and increased intracortical facilitation in the fluoxetine group. This facilitation was negatively correlated with motor function improvement (FMA, r2 = -0.398, P = 0.0395). Conclusion. Combined fluoxetine and rTMS treatment leads to better motor function in stroke than fluoxetine alone and placebo. Moreover, fluoxetine leads to smaller improvements than placebo, and fluoxetine's effects on intracortical facilitation suggest a potential diffuse mechanism that may hinder beneficial plasticity on motor recovery.

Searching for the optimal tDCS target for motor rehabilitation.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated over the years due to its short and also long-term effects on cortical excitability and neuroplasticity. Although its mechanisms to improve motor function are not fully understood, this technique has been suggested as an alternative therapeutic method for motor rehabilitation, especially those with motor function deficits. When applied to the primary motor cortex, tDCS has shown to improve motor function in healthy individuals, as well as in patients with neurological disorders. Based on its potential effects on motor recovery, identifying optimal targets for tDCS stimulation is essential to improve knowledge regarding neuromodulation as well as to advance the use of tDCS in clinical motor rehabilitation. METHODS AND RESULTS: Therefore, this review discusses the existing evidence on the application of four different tDCS montages to promote and enhance motor rehabilitation: (1) anodal ipsilesional and cathodal contralesional primary motor cortex tDCS, (2) combination of central tDCS and peripheral electrical stimulation, (3) prefrontal tDCS montage and (4) cerebellar tDCS stimulation. Although there is a significant amount of data testing primary motor cortex tDCS for motor recovery, other targets and strategies have not been sufficiently tested. This review then presents the potential mechanisms and available evidence of these other tDCS strategies to promote motor recovery. CONCLUSIONS: In spite of the large amount of data showing that tDCS is a promising adjuvant tool for motor rehabilitation, the diversity of parameters, associated with different characteristics of the clinical populations, has generated studies with heterogeneous methodologies and controversial results. The ideal montage for motor rehabilitation should be based on a patient-tailored approach that takes into account aspects related to the safety of the technique and the quality of the available evidence.

Clinical and neurodevelopmental features in children with cerebral palsy and probable congenital Zika.

OBJECTIVE: To describe the neurological and neurodevelopmental features at 1 year of age in children with cerebral palsy (CP) related to probable congenital Zika (CZ), followed in a referral neurorehabilitation hospital. METHODS: Data on 82 children with CP associated with probable CZ, who consecutively attended the neurodevelopmental and neurological assessment around one year of age, were collected. For neurodevelopmental evaluation, Bayley-III Scales of Infant and Toddler Development was used. Descriptive statistical analysis was performed. RESULTS: The children were admitted into the rehabilitation program at a young age (mean age: 4.8 months, SD 3.1), followed beyond the first year of life (mean age of follow up: 13.2 months, SD 2.1), born to young mothers (mean age: 28.1 years, SD 5.9), in their first pregnancy (62.2%). The majority had severe congenital microcephaly (62.0%), spastic CP (96.3%), epilepsy (63.4%), absent expected postural reactions (93.2%), abnormal persistence of primitive reflexes (94.7%), and severe neuroimaging abnormalities, predominantly calcifications (97.6%). Extremely low performances on cognitive (95.1%), language (97.6%) and motor (97.6%) developmental composite scores were observed. There was a correlation between the cognitive score with the birth head circumference (HC) (r = 0.3, p = 0.01) and with the follow up HC (r = 0.4, p < 0.01), as well as between the follow up HC with the motor score (r = 0.2, p = 0.03). CONCLUSION: Congenital Zika may be associated with a severe form of CP, mainly bilateral spastic, with a severe global neurodevelopmental impairment and early signs of a poor prognosis for independent walking. Head circumference may be a prognostic marker among those children. These results may help establish goals for the rehabilitation program and identify priority health services.

Transcranial direct current stimulation to prevent and treat surgery-induced opioid dependence: a systematic review.

Opioid misuse leading to dependence is a major health issue. Recent studies explored valid alternatives to treat pain in postsurgical settings. This systematic review aims to discuss the role of transcranial direct current stimulation (tDCS) in preventing and treating postoperative pain and opioid dependence. PubMed and Embase databases were screened, considering studies testing tDCS effects on pain and opioid consumption in surgical settings and opioid addiction. Eight studies met our inclusion criteria. Results showed a reduction of postoperative pain, opioid consumption and cue-induced craving following cortical stimulation. Despite the limited number of studies, this review shows preliminary encouraging evidence regarding the analgesic role of tDCS. However, future studies are needed to further investigate the application of tDCS in postsurgical settings.

NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains.

The NFAT (nuclear factor of activated T cells) family of transcription factors is composed of four calcium-responsive proteins (NFAT1 to -4). The NFAT2 (also called NFATc1) gene encodes the isoforms NFAT2α and NFAT2ß that result mainly from alternative initiation exons that provide two different N-terminal transactivation domains. However, the specific roles of the NFAT2 isoforms in cell physiology remain unclear. Because previous studies have shown oncogenic potential for NFAT2, this study emphasized the role of the NFAT2 isoforms in cell transformation. Here, we show that a constitutively active form of NFAT2α (CA-NFAT2α) and CA-NFAT2ß distinctly control death and transformation in NIH 3T3 cells. While CA-NFAT2α strongly induces cell transformation, CA-NFAT2ß leads to reduced cell proliferation and intense cell death through the upregulation of tumor necrosis factor alpha (TNF-α). CA-NFAT2ß also increases cell death and upregulates Fas ligand (FasL) and TNF-α in CD4(+) T cells. Furthermore, we demonstrate that differential roles of NFAT2 isoforms in NIH 3T3 cells depend on the N-terminal domain, where the NFAT2ß-specific N-terminal acidic motif is necessary to induce cell death. Interestingly, the NFAT2α isoform is upregulated in Burkitt lymphomas, suggesting an isoform-specific involvement of NFAT2 in cancer development. Finally, our data suggest that alternative N-terminal domains of NFAT2 could provide differential mechanisms for the control of cellular functions.

The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-α expression.

Nuclear factor of activated T cells (NFAT) was described as an activation and differentiation factor in T cells. NFAT1 protein is expressed in several cell types and has been implicated in the control of the cell cycle, death and migration. Overexpression or activation of NFAT1 has been demonstrated to induce cell death in different cell types, such as T lymphocytes, Burkitt's lymphoma, and fibroblasts. Although these findings indicate a role for NFAT1 transcription factor in control of cell death, the precise mechanisms involved in this process regulated by NFAT1 are still poorly understood. The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines that are important in driving proliferation and preventing apoptosis and is widely implicated in cell transformation and cancer development. We show that NFAT1 protein can cooperate with Ras/Raf/MEK/ERK, but not with the JNK, p38 or NFκB pathways in cell death induction. NFAT1 can induce a cell death pathway consistent with apoptosis, which can be shifted to programmed necrosis by caspase inhibitors. Finally, through screening genes involved in cell death regulation, although we determined that TNF-α, TRAIL and PAK7 genes were up-regulated, only TNF-α expression was responsible for cell death in this context. These data suggest that NFAT1 protein activation can shift oncogenic Ras/Raf/MEK/ERK signaling to acting as a tumor suppressor pathway. These data support a potential role for regulating NFAT1 expression in gene therapy in tumors that display an activated Ras pathway, which could lead to more specific, target-directed TNF-α expression and, thus, tumor suppression.

NFAT1 C-terminal domains are necessary but not sufficient for inducing cell death.

The proteins belonging to the nuclear factor of activated T cells (NFAT) family of transcription factors are expressed in several cell types and regulate genes involved in differentiation, cell cycle and apoptosis. NFAT proteins share two conserved domains, the NFAT-homology region (NHR) and a DNA-binding domain (DBD). The N- and C-termini display two transactivation domains (TAD-N and TAD-C) that have low sequence similarity. Due to the high sequence conservation in the NHR and DBD, NFAT members have some overlapping roles in gene regulation. However, several studies have shown distinct roles for NFAT proteins in the regulation of cell death. The TAD-C shows low sequence similarity among NFAT family members, but its contribution to specific NFAT1-induced phenotypes is poorly understood. Here, we described at least two regions of NFAT1 TAD-C that confer pro-apoptotic activity to NFAT1. These regions extend from amino acids 699 to 734 and 819 to 850 of NFAT1. We also showed that the NFAT1 TAD-C is unable to induce apoptosis by itself and requires a functional DBD. Furthermore, we showed that when fused to NFAT1 TAD-C, NFAT2, which is associated with cell transformation, induces apoptosis in fibroblasts. Together, these results suggest that the NFAT1 TAD-C includes NFAT death domains that confer to different NFAT members the ability to induce apoptosis.