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.

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.

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.

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.

Screening for preeclampsia in the first trimester and aspirin prophylaxis: our first year / Rastreio de pré-eclâmpsia no primeiro trimestre e profilaxia com aspirina: o nosso primeiro ano

Abstract 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 weremultiple pregnancy andmajor 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 earlyonset preeclampsia (before 34 weeks), in which cases low-dose aspirin (150mg 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.

Resumo 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 préeclâmpsia (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 préeclâmpsia precoce.

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.

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.

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.

A retrospective cohort study of plasma exchange in central nervous system demyelinating events in children.

BACKGROUND: Plasma exchange (PLEX) may improve recovery of acute central nervous system (CNS) demyelinating events related to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), and MOG-antibody associated demyelination (MOG) if recovery with pulse steroids (PS) is incomplete. Although there is a single randomized controlled trial in adults, there are limited case series in children. We aimed to describe the effectiveness and safety of PLEX in children with acute events of MS, NMOSD, TM, ADEM, and MOG with limited improvement after PS. METHODS: This was a retrospective cohort study of children with acute CNS demyelinating events seen at a single tertiary referral center who received PLEX as a second- or third-line therapy between 2006 and 2018. Through chart review of clinical notes, presence of clinical improvement by physician assessment was recorded pre- and post-PS and pre- and post-PLEX. Expanded Disability Status Scale (EDSS) scores were collected pre- and post-PLEX. We evaluated the number who improved clinically with PLEX and compared pre- and post-PLEX EDSS with Wilcoxon matched pairs signed-rank test. RESULTS: 26 patients followed at the Pediatric MS Center at the University of California, San Francisco received PLEX for acute events of MS (n = 15), NMOSD (n = 7), MOG (n = 2), TM (n = 1), and ADEM (n = 1). At time of PLEX initiation, median age was 13.5 years (range 3-17) and median time between the acute event onset and PLEX initiation was 22 days (range 3-94). 14 of 24 patients had documented clinical improvement after PS. Of those who improved during PS (n = 14), 13 had additional improvement after PLEX. Of those with no improvement after PS (n = 10), 8 improved after PLEX. 16 of 26 patients had pre- and post-PLEX EDSS scores available. Median pre-PLEX EDSS score was 4.0 (range 3.0-8.0), and median post-PLEX EDSS score was 3.75 (range 0-8.0) (p = 0.062). 5 patients had improved EDSS scores by 1 or more points. Adverse events during PLEX included hypotension (n = 3), nausea (n = 2), headache (n = 2), hypocalcemia (n = 2), hypofibrinogenemia (n = 2), thrombocytopenia (n = 1), spinal cord hemorrhage (n = 1), acute non-occlusive thrombosis of internal jugular vein (n = 1), occlusion of the central line (n = 1), edema of the neck (n = 1), and gastrointestinal discomfort (n = 1). CONCLUSIONS: PLEX is an overall well-tolerated second-line treatment option for pediatric patients with severe acute CNS demyelinating events with limited response to PS.

Biopsy-Supported Tumefactive Demyelination of the Central Nervous System in Children.

Pediatric tumefactive lesions remains challenging to clinicians in terms of diagnosis and treatment. The authors describe 11 children with biopsy-proven central nervous system tumefactive demyelination. The mean age of onset was 11 years. Clinical and radiological data coupled with biopsy aided in the diagnosis of tumefactive demyelination. Of the 6 cases in which oligoclonal band data were available, only 3 showed oligoclonal band in the cerebrospinal fluid. Due to poor recovery despite treatment with high-dose glucocorticosteroids, intravenous immunoglobulin, and/or plasmapheresis, 6 cases went on to receive cyclophosphamide with marked improvement. Long-term data were available on 9 cases. Eight of 9 cases were started on preventative multiple sclerosis therapy after initial presentation; 1 is pending discussion with family. Five of the 8 cases had clinical relapse during treatment. Seven cases met 2010 McDonald criteria for multiple sclerosis at follow-up, (1 developed secondary progressive multiple sclerosis), and 2 cases remained as clinically isolated syndrome on treatment.

Novel benzopsoralen analogues: synthesis, biological activity and molecular docking studies.

New benzopsoralen analogues were synthesized and their inhibitory effect on the growth of tumourtumour cell lines (MDA MB231 and TCC-SUP) was evaluated. The in vitro antitumour activity of the new benzopsoralen analogues was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds to evaluate the potential of these molecules to interact with the haem group of the enzymes. The results demonstrated that the compounds that are able to interact with the iron ion of the haem cofactor and at the same time with active site Asn297 are those that have better anti-proliferative activity.

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.

Diabetic mastopathy: a case report.

Diabetic mastopathy (DMP) is an uncommon collection of clinical, radiological, and histological features, classically described in premenopausal women with long-term insulin-dependent diabetes mellitus. This entity can mimic breast carcinoma, but, in the appropriate clinical and imaging setting, the diagnosis can be made by core biopsy, avoiding unnecessary surgeries. We report the case of a 34-year-old female, with a 12-year history of type 1 diabetes, who presented with bilateral breast lumps. Mammography, ultrasonography, and magnetic resonance imaging could not exclude the suspicion of malignancy, and a core biopsy was performed showing the typical histologic features of DMP. The literature is briefly reviewed.

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.

Synthesis of novel benzofurocoumarin analogues and their anti-proliferative effect on human cancer cell lines.

The synthesis of five new tetracyclic benzofurocoumarin (benzopsoralen) analogues is described. Their inhibitory effects on the growth of three human tumor cell lines (MDA MB 231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma) were evaluated, and discussed in terms of structure-activity relationship.

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.

Pt(II) complexes with bidentate and tridentate pyrazolyl-containing chelators: synthesis, structural characterization and biological studies.

A series of four Pt(II) complexes anchored by bidentate or tridentate pyrazolyl-alkylamine chelators bearing different substituents at the azolyl rings has been prepared with the aim to assess their interest in the design of novel anticancer drugs. All complexes have been fully characterized by classical analytical methods and three of them were characterized also by X-ray diffraction analysis. Their solution behavior, together with lipophilicity measurements, cell uptake, antiproliferative properties, DNA interaction have been evaluated. Albeit all the complexes were less active than cisplatin on ovarian carcinoma A2780 cell line, greatly retained their activity in the cisplatin-resistant A2780cisR cell line and presented a lower resistance factor compared to cisplatin. Moreover, the Pt(II) complexes under investigation were less prone to undergo deactivation by glutathione, believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly.

[Ovarian hyperstimulation syndrome in a spontaneous pregnancy]. / Síndrome de hiperestimulação do ovário em gravidez espontânea.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is considered to be an iatrogenic complication of ovulation induction therapy. However, OHSS may rarely be associated with spontaneous ovulatory cycles, usually in multiple or molar gestations or hypothyroidism. Clinical manifestations vary and may be potentially fatal in severe cases. CASE REPORT: A 28-year-old primigravid, with no history of an infertility treatment, presented with enlarged ovaries and ascite. The patient had minor abdominal discomfort, without other complains. Ultrasound evaluation showed enlarged cystic ovaries and mild ascites. Hormonal profile revealed increased estradiol levels, with normal TSH and hCG. The patient was managed expectantly with no complications. DISCUSSION: Although spontaneous OHSS is a rare entity, it is important to consider it in cases of bilateral ovarian masses in pregnancy. Three different mechanisms responsible for the occurrence of spontaneous OHSS have been described. This syndrome is thought to be secondary to promiscuity of the FSH receptor for hCG and/or TSH. It may occur with normal or increased levels of hCG and/or TSH.

Fructose-1,6-bisphosphate preserves intracellular glutathione and protects cortical neurons against oxidative stress.

Fructose-1,6-bisphosphate (FBP), an endogenous intermediate of glycolysis, protects the brain against ischemia-reperfusion injury. The mechanisms of FBP protection after cerebral ischemia are not well understood. The current study was undertaken to determine whether FBP protects primary neurons against hypoxia and oxidative stress by preserving reduced glutathione (GSH). Cultures of pure cortical neurons were subjected to oxygen deprivation, a donor of nitric oxide and superoxide radicals (3-morpholinosydnonimine), an inhibitor of glutathione synthesis (L-buthionine-sulfoximine) or glutathione reductase (1,3-bis(2-chloroethyl)-1-nitrosourea) in the presence or absence of FBP (3.5 mM). Neuronal viability was determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. FBP protected neurons against hypoxia-reoxygenation and oxidative stress under conditions of compromised GSH metabolism. The efficacy of FBP depended on duration of hypoxia and was associated with higher intracellular GSH concentration, an effect partly mediated via increased glutathione reductase activity.