MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Clinical and Imaging Findings in Children with Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD): From Presentation to Relapse.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) is an increasingly recognized cause of demyelinating disease in children. The purpose of this study is to characterize the CNS imaging manifestations of pediatric MOGAD and identify clinical and imaging variables associated with relapse. MATERIALS AND METHODS: We retrospectively identified children with serum antibody-positive MOGAD evaluated at our institution between 1997 and 2020. Clinical and demographic data were collected. MRIs of the brain, orbit, and spine at presentation and relapse were reviewed for location and pattern of abnormality. RESULTS: Among 61 cases (34 girls), mean age at presentation was 7 years (IQR 4-11). At presentation, there was imaging involvement of the brain in 78.6% (44/56), optic pathway in 55.4% (31/56), and spine in 19.6% (11/56). Brain involvement was commonly in the frontal (70.5%, 31/44) and subcortical (75%, 33/44) white matter, with involvement of the thalamus and pons in 47.7% each (21/44). Optic neuritis (ON) was commonly bilateral (80.6%, 25/31) involving intraorbital segments (77.4%, 24/31). Spinal cord lesions were typically cervical (72.7%, 8/11) and multifocal (72.7%, 8/11).The imaging patterns were age-dependent; children ≤9 years more commonly demonstrated ADEM-like imaging pattern at presentation (39.4%, 13/33) and first relapse (8/23, 34.8%), while children >9 years more commonly had ON at presentation (34.8%, 8/23, P = .001) and FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures at first relapse (5/18, 27.8%, P = .008). CONCLUSIONS: We describe the CNS imaging findings in pediatric MOGAD. The imaging pattern is age-dependent at presentation and first relapse. Younger age at presentation is associated with longer time to relapse.

Coumarin/ß-Cyclodextrin Inclusion Complexes Promote Acceleration and Improvement of Wound Healing.

Coumarins have great pharmacotherapeutic potential, presenting several biological and pharmaceutical applications, like antibiotic, fungicidal, anti-inflammatory, anticancer, anti-HIV, and healing activities, among others. These molecules are practically insoluble in water, and for biological applications, it became necessary to complex them with cyclodextrins (CDs), which influence their bioavailability in the target organism. In this work, we studied two coumarins, and it was possible to conclude that there were structural differences between 4,7-dimethyl-2H-chromen-2-one (DMC) and 7-methoxy-4-methyl-2H-chromen-2-one (MMC)/ß-CD that were solubilized in ethanol, frozen, and lyophilized (FL) and the mechanical mixtures (MM). In addition, the inclusion complex formation improved the solubility of DMC and MMC in an aqueous medium. According to the data, the inclusion complexes were formed and are more stable at a molar ratio of 2:1 coumarin/ß-CD, and hydrogen bonds along with π-π stacking interactions are responsible for the better stability, especially for (MMC)2@ß-CD. In vivo wound healing studies in mice showed faster re-epithelialization and the best deposition of collagen with the (DMC)2@ß-CD (FL) and (MMC)2@ß-CD (FL) inclusion complexes, demonstrating clearly that they have potential in wound repair. Therefore, (DMC)2@ß-CD (FL) deserves great attention because it presented excellent results, reducing the granulation tissue and mast cell density and improving collagen remodeling. Finally, the protein binding studies suggested that the anti-inflammatory activities might exert their biological function through the inhibition of MEK, providing the possibility of development of new MEK inhibitors.

Synthesis of novel psoralen analogues and their in vitro antitumor activity.

New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.

High serum neurofilament levels are observed close to disease activity events in pediatric-onset MS and MOG antibody-associated diseases.

BACKGROUND: Serum neurofilament light chain (sNfL) is an emerging multiple sclerosis (MS) biomarker which measures neuro-axonal damage. However, understanding its temporal association with disease activity in pediatric-onset MS (POMS) and Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains limited. OBJECTIVE: To investigate the association of sNfL levels and time from disease activity in children with MS and MOGAD. METHODS: POMS and MOGAD cases with onset before 18 years of age were enrolled at the University of California San Francisco (UCSF) Regional Pediatric MS Center. Frequency-matched healthy subjects were recruited from general pediatric clinics. Serum samples were tested for MOG-IgG at Mayo Clinic using a live cell-based fluorescent activated cell sorting assay. sNfL levels were measured using single-molecule array (Simoa) technology measured in pg/mL. Data on demographics, clinical features, MRI, CSF, and treatment data were collected by chart review. RESULTS: We included 201 healthy controls healthy controls, 142 POMS, and 20 confirmed MOGAD cases with available sNfL levels. The median (IQR) age at the time of sampling was 15.6 (3.9), 15.5 (3.1), and 8.8 (4.1) years for controls, POMS, and MOGAD, respectively. Median sNfL levels (pg/ml) were higher in POMS (19.6) and MOGAD (32.7) cases compared to healthy controls (3.9) (p<0.001). sNfL levels ≥100 pg/ml were only detected within four months of a clinical event or MRI activity in both POMS and MOGAD cases. In addition, sNfL levels were higher in POMS patients with new/enlarged T2 and gadolinium-enhanced lesions than those without MRI activity within four months of sampling in POMS cases. CONCLUSION: High sNfL levels were observed close to clinical or MRI events in POMS and MOGAD. Our findings support sNfL as a biomarker of disease activity in pediatric demyelinating disorders.

Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain.

Tacrine is an acetylcholinesterase (AChE) inhibitor used as a cognitive enhancer in the treatment of Alzheimer's disease (AD). However, its low therapeutic efficiency and a high incidence of side effects have limited its clinical use. In this study, the molecular mechanisms underlying the impact on brain activity of tacrine and two novel tacrine analogues (T1, T2) were approached by focusing on three aspects: (i) their effects on brain cholinesterase activity; (ii) perturbations on electron transport chain enzymes activities of non-synaptic brain mitochondria; and (iii) the role of mitochondrial lipidome changes induced by these compounds on mitochondrial bioenergetics. Brain effects were evaluated 18 h after the administration of a single dose (75.6 µmol/kg) of tacrine or tacrine analogues. The three compounds promoted a significant reduction in brain AChE and butyrylcholinesterase (BuChE) activities. Additionally, tacrine was shown to be more efficient in brain AChE inhibition than T2 tacrine analogue and less active than T1 tacrine analogue, whereas BuChE inhibition followed the order: T1 > T2 > tacrine. The studies using non-synaptic brain mitochondria show that all the compounds studied disturbed brain mitochondrial bioenergetics mainly via the inhibition of complex I activity. Furthermore, the activity of complex IV is also affected by tacrine and T1 treatments while FoF(1) -ATPase is only affected by tacrine. Therefore, the compounds' toxicity as regards brain mitochondria, which follows the order: tacrine >> T1 > T2, does not correlate with their ability to inhibit brain cholinesterase enzymes. Lipidomics approaches show that phosphatidylethanolamine (PE) is the most abundant phospholipids (PL) class in non-synaptic brain mitochondria and cardiolipin (CL) present the greatest diversity of molecular species. Tacrine induced significant perturbations in the mitochondrial PL profile, which were detected by means of changes in the relative abundance of phosphatidylcholine (PC), PE, phosphatidylinositol (PI) and CL and by the presence of oxidized phosphatidylserines. Additionally, in both the T1 and T2 groups, the lipid content and molecular composition of brain mitochondria PL are perturbed to a lesser extent than in the tacrine group. Abnormalities in CL content and the amount of oxidized phosphatidylserines were associated with significant reductions in mitochondrial enzymes activities, mainly complex I. These results indicate that tacrine and its analogues impair mitochondrial function and bioenergetics, thus compromising the activity of brain cells.

Screening for preeclampsia in twin pregnancies.

Twin pregnancies are an important risk factor for preeclampsia, a hypertensive disorder of pregnancy that is associated with a significant risk of maternal and perinatal morbidity. Given the burden of preeclampsia, the identification of women at high risk in early pregnancy is essential to allow for preventive strategies and close monitoring. In singleton pregnancies, the risk factors for preeclampsia are well established, and a combined first-trimester prediction model has been shown to adequately predict preterm disease. Furthermore, intervention with low-dose aspirin at 150 mg/day in those identified as high-risk reduces the rate of preterm preeclampsia by 62%. In contrast, risk factors for preeclampsia in twin pregnancies are less established, the proposed screening models have shown poor performance with high false-positive rates, and the benefit of aspirin for the prevention of preeclampsia is not clearly demonstrated. In this review, we examine the literature assessing prediction and prevention of preeclampsia in twin pregnancies.

Obstetric outcomes after treatment for cervical intraepithelial neoplasia: six years of experience.

OBJECTIVE: : The purpose of this study was to assess the effect of cervical conization on subsequent pregnancy and delivery outcomes. MATERIALS AND METHODS: : A retrospective case-control study was performed in patients who underwent conization from 2000 to 2005 and had a subsequent delivery. Two case controls were matched for each case studied. The obstetric outcomes of the 2 groups were compared. A subsequent analysis comparing the 2 excisional techniques used was performed. RESULTS: : The study population group included 87 women (29 cases and 58 controls). Overall, the mean gestation age at delivery (38 vs 39 wk, p = .003), prevalence of preterm birth (20.7% vs 5.2%, p = .025), mean birth weight (3,035 vs 3279 g, p = .018), and low birth weight (20.7% vs 1.7%, p = .02) were statistically different among the cases and controls.In the study group (n = 29), large loop excision of the transformation zone was used in 62% (n = 18) and laser was used in 38% (n = 11) of the cases. There was no significant difference in the medium depth of the excised tissue, the prevalence of preterm birth, low birth weight, and the cesarean delivery rate between the 2 techniques. CONCLUSIONS: : Despite the small number of cases, this study indicates that excision of the transformation zone is associated with an increased risk of overall preterm delivery and low-birth weight infants in subsequent pregnancies. No significant difference was found between the 2 cervical excision procedures.

High titers of myelin oligodendrocyte glycoprotein antibody are only observed close to clinical events in pediatrics.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis. OBJECTIVE: To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers. METHODS: Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity. RESULTS: We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics. CONCLUSION: Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.

Thymol as an Interesting Building Block for Promising Fungicides against Fusarium solani.

The semisynthesis of 15 new thymol derivatives was achieved through Williamson synthesis and copper-catalyzed azide-alkyne cycloaddition (CuAAC) approaches. The reaction of CuAAC using the "Click Chemistry" strategy, in the presence of an alkynyl thymol derivative and commercial or prepared azides, provided nine thymol derivatives under microwave irradiation. This procedure reduces reaction time and cost. All molecular entities were elucidated by 1H and 13C NMR, IR, and HRMS data. These derivatives were evaluated in vitro for their fungicidal activity against Fusarium solani sp. Among the nine triazolic thymol derivatives obtained, seven of them were found to have moderated antifungal activity. In contrast, naphthoquinone/thymol hybrid ether 2b displayed activity comparable with that of the commercial fungicide thiabendazole. The structure-activity relationship for the most active compound 2b was discussed, and the mode of action was predicted by a possible binding to the fungic ergosterol and interference of osmotic balance of K+ into the extracellular medium.

Flavonoid Derivatives Targeting BCR-ABL Kinase: Semisynthesis, Molecular Dynamic Simulations and Enzymatic Inhibition.

BACKGROUND: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. OBJECTIVE: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. METHODS: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. RESULTS: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). CONCLUSION: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.

Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms.

Importance: Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population. Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. Design, Setting, and Participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test. Main Outcomes and Measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies. Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. Conclusions and Relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

Autoimmune Encephalitis in Children: A Case Series at a Tertiary Care Center.

Autoimmune encephalitis is the third most common cause of encephalitis in children. We provide a detailed account of presenting symptoms, diagnosis, and response to treatment in pediatric autoimmune encephalitis patients evaluated at University of California San Francisco within a 2.5-year period. Eleven were identified: anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis (n = 4), antibody-negative autoimmune encephalitis (n = 4), steroid-responsive encephalopathy associated with thyroiditis (SREAT) (n = 2), and glial fibrillary acidic protein (GFAP)-associated encephalitis (n = 1). Most common presenting symptoms included seizures and behavior changes (54%). More than 90% of patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin, and/or plasma exchange). A total of 64% received second-line treatment with rituximab, cyclophosphamide, or mycophenolate mofetil. One patient with NMDAR encephalitis died despite escalating immunotherapy. None of the patients showed complete recovery after median follow-up of 9 months (range 0.5-66). Children with autoimmune encephalitis have a diverse clinical presentation and may lack an identifiable autoantibody. Majority of patients show a good response to immunotherapy; however, recovery can be delayed.

Chorionic villus sampling: 10 years of experience in a University referral center.

OBJECTIVES: The purpose of this study was to estimate our center-specific CVS-related miscarriage rate. METHODS: This is an observational retrospective study of women submitted to a CVS in our hospital, between January 1st, 2007 and December 31st, 2016. Maternal and pregnancy characteristics, procedure details, genetic results and pregnancy outcomes of all patients were collected. The FMF miscarriage risk algorithm was used to estimate our population expected risk of miscarriage. To establish the procedure-related risk of miscarriage, we compared the observed with the expected miscarriage rate. RESULTS: We had a total number of 1523 women with a singleton pregnancy who did a CVS over the 10-year period. The mean maternal age was 34 years old; the majority of the women was Caucasian, multiparous and had a spontaneous pregnancy. The most common indication for CVS was a high-risk result in the 1st trimester combined screening test. The karyotype was normal in 72,7% of cases, 11,1% were T21 and 7,2% were T13 or T18. In the study group, 33 women were diagnosed with a fetal demise, 435 had a TOP and there were 4 intrauterine deaths and 34 miscarriages. The rate of miscarriage in our population was 3,2% and the expected patient specific risk for miscarriage was 3,0%. There was no statistical significance between the two miscarriage rates p = 0,705. CONCLUSION: In our study the risk of miscarriage in the CVS group was not significantly different from that the expected patient specific risk (3.2 % vs 3%, p = 0.7). The procedure-related risk of miscarriage was 0,2%, similar to the rates describe in the literature. An accurate risk of pregnancy loss should be used when counseling women for CVS to allow an informed decision.

Screening for Preeclampsia in the First Trimester and Aspirin Prophylaxis: Our First Year.

OBJECTIVE: Preeclampsia is a major cause of perinatal and maternal morbidity and mortality. Our objective is to assess the performance of a combined screening test for preeclampsia in the first trimester and the prophylactic use of low-dose aspirin. METHODS: Prospective study of all women attending our hospital for the first-trimester screening of aneuploidies, between March 2017 and February 2018 (n = 1,297). The exclusion criteria were multiple pregnancy and major fetal abnormalities. Preeclampsia screening was performed with an algorithm that includes maternal characteristics, and biophysical and biochemical biomarkers. High-risk was defined as a risk ≥ 1:50 of early-onset preeclampsia (before 34 weeks), in which cases low-dose aspirin (150 mg at night) was offered to these women from screening until 36 weeks. RESULTS: From the 1,272 enrolled participants, the majority were Caucasian (1,051; 82.6%) and multiparous (658, 51.7%). Fifty patients (3.9%) screened high-risk for preeclampsia, and all started a low-dose aspirin regimen, with good compliance (96%). Early-onset preeclampsia was found in 3 pregnant women (0.24%), and total preeclampsia was diagnosed in 25 (2.02%), compared with 28 (0.75%) cases of early preeclampsia (p = 0.0099) and 98 (2.62%) of total preeclampsia (p = 0.2904) before the implementation of screening. CONCLUSION: There was a lower incidence of both, early-onset and total preeclampsia, after the introduction of universal screening and prophylactic use of low-dose aspirin. This reduction was statistically significant in early-onset preeclampsia. The association of a first-trimester combined screening model and aspirin prophylaxis appears to be useful in predicting and reducing the incidence of early-onset preeclampsia, in a routine care setting.

OBJETIVO: A pré-eclâmpsia é uma causa importante de morbi-mortalidade materna e perinatal. Os objetivos do nosso estudo foram avaliar a implementação do rastreio combinado de pré-eclâmpsia no primeiro trimestre e o uso profilático de aspirina em baixa dose. MéTODOS: Estudo prospetivo das mulheres referenciadas ao nosso hospital para realização do rastreio do primeiro trimestre de aneuploidias, entre março de 2017 e fevereiro de 2018 (n = 1.297). Os critérios de exclusão foram gravidez múltipla e anomalias fetais graves. O algoritmo usado no rastreio da pré-eclâmpsia combina características maternas, e marcadores biofísicos e bioquímicos. Definiu-se alto risco como risco de pré-eclâmpsia precoce (antes das 34 semanas) ≥ 1:50, tendo sido recomendada aspirina em baixa dose (150 mg à noite) desde o rastreio até às 36 semanas. RESULTADOS: Das 1.272 participantes, a maioria era caucasiana (1.051; 82,6%) e multípara (658; 51,7%). Cinquenta grávidas (3,9%) foram consideradas de alto risco para pré-eclâmpsia e todas iniciaram aspirina em baixa dose, com boa adesão (96%). Pré-eclampsia precoce foi diagnosticada em 3 grávidas (0,24%), e no total foram diagnosticados 25 casos de pré-eclâmpsia (2,02%), comparativamente com 28 (0,75%) casos de pré-eclampsia precoces (p = 0,0099) e 98 (2,62%) casos totais de pré-eclâmpsia (p = 0,2904) observados antes da implementação do rastreio. Verificou-se uma menor incidência de pré-eclâmpsia precoce e total após introdução do rastreio universal e uso profilático de aspirina. A redução da pré-eclâmpsia precoce foi estatisticamente significativa. CONCLUSãO: A associação de um modelo de rastreio combinado no primeiro trimestre com o uso profilático de aspirina é aparentemente eficaz na redução do risco de pré-eclâmpsia precoce.

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3ß Enzyme Inhibition.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3ß isoforms is likely to represent an effective strategy against AD. OBJECTIVE: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3ß kinase inhibitors. METHODS: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3ß activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3ß complex [Protein Data Bank (PDB) code: 1Q3D]. RESULTS: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3ß inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3ß enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. CONCLUSION: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3ß inhibitors.

Pediatric glial fibrillary acidic protein meningoencephalomyelitis: A case report and review of the literature.

A novel autoantibody, glial fibrillary acidic protein (GFAP)-IgG, has recently been associated with cases of meningoencephalomyelitis. This entity is still being unraveled. Very few pediatric patients have been identified; thus, the clinical, biological and imaging phenotype remains to be defined. Herein we describe the clinical course of a 6-year-old patient initially suspected to have a demyelinating disease but ultimately diagnosed with GFAP-IgG positive autoimmune meningoencephalomyelitis. We also provide a review of the literature regarding this novel entity.

Cell-free DNA and contingent screening: Our first year.

INTRODUCTION: Analysis of cell-free DNA (cfDNA) from maternal blood has showed a great potential as a screening method for fetal aneuploidies. cfDNA can be used as a first line screening tool or in a contingent model, after the combined test. METHODS: Prospective study of women attending for first trimester combined screening in our Hospital, in the first year of contingent cfDNA screening. According to the combined screening test result patients were divided in high-risk (offered invasive test or routine follow-up), intermediate-risk (counselled for cfDNA, invasive or routine follow-up) or low-risk (routine ultrasound follow-up). Pregnancy outcomes and performance of screening were evaluated. A cost-effectiveness analysis was also done. RESULTS: The majority of the 1272 enrolled participants were Caucasian (82,6%), multiparous (51,7%) and the median maternal age was 30 years old. Thirty women screened high-risk and 83,3% of them opted for an invasive test. Forty-nine patients had an intermediate risk and 75,5% of them choose cfDNA testing. Our rate of invasive tests decreased from 3.5% to 2.4%. DISCUSSION: The cut-offs used to determine high and intermediate-risk are based on a compromise between detection rate, pregnancy lost rate and cost. Above a determined cut-off in the intermediate-risk group, the cost for each additional detected trisomy case is very high. One major benefit of this contingent model was the decrease in invasive testing. CONCLUSION: The contingent cfDNA screening model can be easily implemented in a public hospital with a low-risk population. Since cost/benefit is an important issue, further studies are needed to determine the ideal cut-off for our country.