Modulation of the activation of endothelial nitric oxide synthase and nitrosative stress biomarkers by aspirin triggered lipoxins: A possible mechanism of action of aspirin in the antiphospholipid syndrome.

PROBLEM: Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. METHODS: We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. RESULTS: Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. CONCLUSIONS: Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.

From gut to placenta: understanding how the maternal microbiome models life-long conditions.

The microbiome -defined as the microbiota (bacteria, archaea, lower and higher eukaryotes), their genomes, and the surrounding environmental conditions- has a well-described range of physiological functions. Thus, an imbalance of the microbiota composition -dysbiosis- has been associated with pregnancy complications or adverse fetal outcomes. Although there is controversy about the existence or absence of a microbiome in the placenta and fetus during healthy pregnancy, it is known that gut microbiota can produce bioactive metabolites that can enter the maternal circulation and may be actively or passively transferred through the placenta. Furthermore, the evidence suggests that such metabolites have some effect on the fetus. Since the microbiome can influence the epigenome, and modifications of the epigenome could be responsible for fetal programming, it can be experimentally supported that the maternal microbiome and its metabolites could be involved in fetal programming. The developmental origin of health and disease (DOHaD) approach looks to understand how exposure to environmental factors during periods of high plasticity in the early stages of life (e.g., gestational period) influences the program for disease risk in the progeny. Therefore, according to the DOHaD approach, the influence of maternal microbiota in disease development must be explored. Here, we described some of the diseases of adulthood that could be related to alterations in the maternal microbiota. In summary, this review aims to highlight the influence of maternal microbiota on both fetal development and postnatal life, suggesting that dysbiosis on this microbiota could be related to adulthood morbidity.

Mentalidad machista, estilos de crianza y vulnerabilidad social en cuidadores primarios. Una comparación transcultural entre Argentina y Perú / Sexist mentality, parenting styles and social vulnerability in primary caregivers. A cross-cultural comparison between Argentina and Peru

Resumen Introducción: la mentalidad machista es un fenómeno persistente en Latinoamérica. Sin embargo, no se tienen claros los factores que la generan, por ello, se realizó el estudio para analizar la mentalidad machista en función de factores como los estilos parentales y la vulnerabilidad social. Método: la muestra estuvo constituida por 389 (M.edad = 35.87, DE = 10.13) cuidadores primarios de niños, niñas y adolescentes de 4-16 años (M.edad= 9.33, DE = 4.66, femenino = 196) de diferentes regiones de Perú y Argentina. Se utilizaron (a) la subescala de Machismo de la Evaluación Multifásica de las Culturas (MACC-SF), (b) la Adaptación Española del Cuestionario de Crianza Parental y (c) una ficha sociodemográfica ad hoc, aplicadas través de las redes sociales mediante un formulario. Resultados: en ambas muestras, los niveles de machismo son relativamente bajos, aunque la muestra argentina presentó menores niveles y hábitos más positivos de crianza, en comparación con Perú. A su vez, se encontró asociación negativa entre machismo y estilos parentales, con mayor intensidad en las dimensiones; satisfacción con la crianza y disciplina. Finalmente, el machismo se asoció de forma negativa con la vulnerabilidad social y los estilos de crianza. Conclusión: las creencias machistas estarían asociadas con menor nivel socioeconómico y estilos de crianza más autoritarios, los que también se rigen por sus tradiciones y a un conservadurismo del legado cultural, en comparación a culturas más flexibles y democráticas.

Abstract Introduction: the macho mentality is a phenomenon that persists in the Latin American population; however, the factors that generate it are not clear. Therefore, the study is carried out with the objective of analyzing the macho mentality, based on factors such as parental styles and social vulnerability; and comparing according to country of origin: Argentina and Peru, respectively. Method: the sample consisted of 389 (M.age = 35.87, SD = 10.13) primary caregivers of children and adolescents from 4 to 16 (M.age = 9.33, SD = 4.66, feminine = 196) years of age from different regions of Peru and Argentina. The instruments used were the Machismo subscale of the Multiphasic Evaluation of Cultures (MACC-SF), the Spanish Adaptation of the Parental Upbringing Questionnaire, and an ad-hoc sociodemographic record, which were all applied through social networks using a Google® form. Results: in both samples, the levels of machismo are relatively low, although the Argentine sample presented lower levels of machismo and more positive parenting habits compared to that of Peru. In turn, a negative association was found between machismo and parenting styles, with greater intensity in the dimensions: satisfaction with parenting and discipline. Finally, machismo was negatively associated with social vulnerability and parenting styles. Conclusions: macho beliefs would be associated with a lower socioeconomic level and more authoritarian and inflexible parenting styles, which are also governed by their traditions and a cultural legacy of conservatism in comparison to more flexible and democratic cultures.

Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.

Catalytically active phospholipase A2 myotoxin from Crotalus durissus terrificus induces proliferation and differentiation of myoblasts dependent on prostaglandins produced by both COX-1 and COX-2 pathways.

Although crotoxin B (CB) is a well-established catalytically active secretory phospholipase A2 group IIA (sPLA2-IIA) myotoxin, we investigated its potential stimulatory effect on myogenesis with the involvement of prostaglandins (PGs) produced by cyclooxygenase (COX)-1 and -2 pathways. Myoblast C2C12 were cultured in proliferation or commitment protocols and incubated with CB followed by lumiracoxib (selective COX-2 inhibitor) or valeryl salicylate (selective COX-1 inhibitor) and subjected to analysis of PG release, cell proliferation and activation of myogenic regulatory factors (MRFs). Our data showed that CB in non-cytotoxic concentrations induces an increase of COX-2 protein expression and stimulates the activity of both COX isoforms to produce PGE2, PGD2 and 15d-PGJ2. CB induced an increase in the proliferation of C2C12 myoblast cells dependent on PGs from both COX-1 and COX-2 pathways. In addition, CB stimulated the activity of Pax7, MyoD, Myf5 and myogenin in proliferated cells. Otherwise, CB increased myogenin activity but not MyoD in committed cells. Our findings evidence the role of COX-1- and COX-2-derived PGs in modulating CB-induced activation of MRFs. This study contributes to the knowledge that CB promote early myogenic events via regulatory mechanisms on PG-dependent COX pathways, showing new concepts about the effect of sPLA2-IIA in skeletal muscle repair.

IL-1ß and TNF-α Modulation of Proliferated and Committed Myoblasts: IL-6 and COX-2-Derived Prostaglandins as Key Actors in the Mechanisms Involved.

In this study, we investigated the effects and mechanisms of the pro-inflammatory cytokines IL-1ß and TNF-α on the proliferation and commitment phases of myoblast differentiation. C2C12 mouse myoblast cells were cultured to reach a proliferated or committed status and were incubated with these cytokines for the evaluation of cell proliferation, cyclooxygenase 2 (COX-2) expression, release of prostaglandins (PGs) and myokines, and activation of myogenic regulatory factors (MRFs). We found that inhibition of the IL-6 receptor reduced IL-1ß- and TNF-α-induced cell proliferation, and that the IL-1ß effect also involved COX-2-derived PGs. Both cytokines modulated the release of the myokines myostatin, irisin, osteonectin, and IL-15. TNF-α and IL-6 reduced the activity of Pax7 in proliferated cells and reduced MyoD and myogenin activity at both proliferative and commitment stages. Otherwise, IL-1ß increased myogenin activity only in committed cells. Our data reveal a key role of IL-6 and COX-2-derived PGs in IL-1ß and TNF-α-induced myoblast proliferation and support the link between TNF-α and IL-6 and the activation of MRFs. We concluded that IL-1ß and TNF-α induce similar effects at the initial stages of muscle regeneration but found critical differences between their effects with the progression of the process, bringing new insights into inflammatory signalling in skeletal muscle regeneration.

The limited knowledge of placental damage due to neglected infections: ongoing problems in Latin America.

The placenta works as a selective barrier, protecting the fetus from potential infections that may affect the maternal organism during pregnancy. In this review, we will discuss several challenging infections that are common within Latin American countries and that may affect the maternal-fetal interface and pose risks to fetal development. Specifically, we will focus on emerging infectious diseases including the arboviruses, malaria, leishmaniasis, and the bacterial foodborne disease caused by Shiga toxin-producing Escherichia coli. We will also highlight some topics of interest currently being studied by research groups that comprise an international effort aimed at filling the knowledge gaps in this field. These topics address the relationship between exposure to microorganisms and placental abnormalities, congenital anomalies, and complications of pregnancy. ABBREVIATIONS: ADE: antibody-dependent enhancement; CCL2: monocyte chemoattractant protein-1; CCL3: macrophage inflammatory protein-1 α; CCL5: chemokine (C-C motif) ligand 5; CHIKV: chikungunya virus; DCL: diffuse cutaneous leishmaniasis; DENV: dengue virus; Gb3: glycolipid globotriaosylceramyde; HIF: hypoxia-inducible factor; HUS: hemolytic uremic syndrome; IFN: interferon; Ig: immunoglobulins; IL: interleukin; IUGR: intrauterine growth restriction; LCL: localized cutaneous leishmaniasis; LPS: lipopolysaccharid; MCL: mucocutaneous leishmaniasis; NO: nitric oxide; PCR: polymerase chain reaction; PGF: placental growth factor; PM: placental malaria; RIVATREM: Red Iberoamericana de Alteraciones Vasculares em transtornos del Embarazo; sVEGFR: soluble vascular endothelial growth factor receptor; STEC: shiga toxin-producing Escherichia coli; stx: shiga toxin protein; TNF: tumor necrosis factor; TOAS: T cell original antigenic sin; Var2CSA: variant surface antigen 2-CSA; VEGF: vascular endothelial growth factor; VL: visceral leishmaniasis; WHO: world health organization; YFV: yellow fever virus; ZIKV: Zika virus.

Role of aspirin-triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia.

PROBLEM: Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. METHOD OF STUDY: Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. RESULTS: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. CONCLUSION: Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.

Evaluación de estrés nitrosativo y oxidativo en mujeres con diferentes manifestaciones clínicas del síndrome antifosfolipídico / Evaluation of nitrosative stress and oxidative in women with different clinical manifestations of the antiphospholipid syndrome

Introducción:El síndrome antifosfolipídico (SAF) es una enfermedad autoinmune caracterizada por la presencia persistente de anticuerpos antifosfolípidos (aAFL) y manifestaciones clínicas de trombosis y/o morbilidad gestacional que se asocian con estrés nitrosativo/ oxidativo y disminución de la capacidad antioxidante, alterando el desarrollo gestacional. Objetivo: Evaluar algunos biomarcadores de estrés nitrosativo/oxidativo del suero de mujeres con diferentes manifestaciones clínicas del SAF y sus efectos en células endoteliales. Métodos: Se incluyeron sueros de 48 mujeres divididas en dos grupos con y sin aAFL. Se evaluó la concentración de nitritos, la capacidad antioxidante y la actividad de la enzima paraoxonasa

Remodelación vascular como modelo in vitro para el estudio del síndrome antifosfolipídico obstétrico / Vascular remodeling as in vitro model for the study of the obstetrical antiphospholipid syndrome

Introducción y Objetivo: Los anticuerpos antifosfolípidos (aAFL) se pueden unir a las células trofoblásticas o a las endoteliales, alterando la remodelación vascular y consecuentemente la placentación normal. El objetivo fue evaluar el efecto del suero de pacientes con síndrome antifosfolipídico (SAF) obstétrico en la interacción endotelio-trofoblasto utilizando un modelo in vitro tridimensional de remodelación vascular. Métodos: Las pacientes con aAFL fueron clasificadas en dos grupos: morbilidad gestacional y trombosis (MG/TV, n=7) y morbilidad gestacional sola (MG, n=8). Como control, se incluyeron mujeres sin aAFL con MG (MG/ aAFL-, n=10), y mujeres sanas (SHN, n=7). Células endoteliales HUVEC fueron cultivadas en Matrigel™ hasta formar estructuras tubulares (angiogénesis) y luego se adicionaron células trofoblásticas HTR8; estas células invaden las estructuras tubulares de las células endoteliales mejorando su estabilidad. Se evaluó el efecto de 10% del suero de las mujeres del estudio sobre esta interacción.

Encefalopatía epiléptica de inicio precoz en un paciente con mutación en SCN8A / Early onset epileptic encephalopathy in a patient with mutation in SCN8A

No disponible

Serum Protein Profile in Women With Pregnancy Morbidity Associated With Antiphospholipid Syndrome.

CONTEXT: Antiphospholipid antibodies (aPL) are related with a high risk of pregnancy morbidity (PM) and also of vascular thrombosis. On the basis of recent studies, we expect that in women with PM associated with antiphospholipid syndrome (APS), further factors may be deregulated and involved in pathophysiology of the disease. Such factors may have the potential to become novel biomarkers for APS and its stages. SETTINGS AND DESIGN: Descriptive study from a recurrent pregnancy loss program. AIMS: To study the protein expression in sera from women with PM with or without aPL. MATERIALS AND METHODS: Protein profiles were determined by surface enhanced laser desorption and ionization - time of flight mass spectrometry (SELDI-TOF MS) in the serum samples from women with PM, 10 of them with aPL and 12 without aPL. On the basis of the mass-to-charge ratio (m/z) of the protein, signals differentially expressed between the two groups were compared with data banks to approach candidate proteins. STATISTICAL ANALYSIS USED: To determine the differential expression of each protein, a no paired t-test was performed using Ciphergen Express Client 3.1 software. RESULTS: SELDI-TOF analysis makes it possible to discriminate between several proteins in women with PM with and without aPL, although it does not allow protein identification. Nine proteins were found in significantly higher levels in aPL-positive women. CONCLUSION: The results underline that further factors beyond autoantibodies are involved in PM associated with APS and might lead to the development of new biomarkers.

Modulation of antiphospholipid antibodies-induced trophoblast damage by different drugs used to prevent pregnancy morbidity associated with antiphospholipid syndrome.

PROBLEM: Women with antiphospholipid antibodies (aPLs) present a risk of pregnancy morbidity (PM), vascular thrombosis (VT), or both (PM/VT). aPLs affect trophoblast function, and the aim of this study was to determine the modulation of this aPL-induced damage by different drugs. METHOD OF STUDY: IgG was obtained from women with PM and PM/VT positive to aPLs. Binding of IgG to trophoblastic cells, proliferation, mitochondrial membrane integrity, and trophoblast invasion were assessed. The effect of enoxaparin, aspirin, and aspirin-triggered lipoxin (ATL) were evaluated as well as signal transducer and activator of transcription 3 (STAT3) phosphorylation. RESULTS: IgG from women with aPLs strongly binds to trophoblastic cells. Integrity of mitochondrial membrane was reduced, and proliferation was increased by IgG-PM/VT. Both IgG-PM and IgG-PM/VT decreased trophoblast invasion, which was restored by enoxaparin, aspirin, and ATL. IgG-PM triggered reduction in STAT3 phosphorylation. CONCLUSION: Some drugs used to prevent aPL-induced PM modulated the alteration of trophoblast function.

Photoselective Vaporization with KTP 180-W Green Laser for the Treatment of Lower Urinary Symptoms Secondary to Benign Prostatic Enlargement: Effectiveness and Safety at Midterm Follow-Up.

OBJECTIVES: To determine safety, efficacy, and improvement in patient's quality of life (QoL) with 180-W green light laser prostate photovaporization in medium-term follow-up. METHODS: Observational descriptive analysis. All the patients who were treated with photoselective vaporization with potassium titanyl phosphate crystal 180-W green laser between January 2012 and February 2014 were included. The primary outcome was the change of the International Prostate Symptom Score (IPSS). A descriptive analysis was conducted. Statistic inference was made using nonparametric measurements according to the findings. The Wilcoxon signed-rank test was applied to paired data. Finally, survival curves were used to determine the effectiveness. RESULTS: Two hundred one subjects were included. The mean follow-up was 13.1 months (2-28). Prostate volume was 75.46 ml (30-240). Mean surgical time was 73.29±29.74 minutes, laser time was 44.27±21.03 minutes, and the mean energy used was 271.5±140.1 kJ. Postoperative indwelling catheter time was 15.81±8.87 hours. IPSS decreased 12.79 points, from 19.13±7.79 to 6.34±5.91 (p=0.0001). QoL question of the IPSS shows improvement from 4.16 to 1.27 (p=0.00001). In a maximum follow-up period of 28 months, 85.2% of patients showed an improvement of four points in IPSS. Visual scale of improvement perception showed an increase from 36.49 to 89.84 (p=0.0001). No major complications were reported. CONCLUSION: Prostate photoselective vaporization with a 180-W green light laser is a safe and effective treatment option for patients with lower urinary symptoms secondary to benign prostate enlargement.

Interferon-α and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia.

OBJECTIVE: To investigate whether an elevated interferon-α (IFNα) level early in pregnancy is associated with poor pregnancy outcomes and to examine the relationship of an elevated IFNα level to angiogenic imbalance. METHODS: Women were enrolled in a longitudinal case-control study of pregnant patients with lupus. Serum samples obtained monthly throughout pregnancy were assayed for IFNα and for the antiangiogenic factor soluble Flt-1 and the proangiogenic factor placenta growth factor (PlGF). Each of 28 patients with systemic lupus erythematosus (SLE) with a poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFNα and/or soluble Flt-1 on human endothelial cells and endothelial cell-trophoblast interactions were assessed. RESULTS: Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFNα levels before clinical symptoms. Patients without autoimmune disease who developed preeclampsia did not have increased IFNα levels. In SLE patients with low IFNα levels, marked angiogenic imbalance (higher soluble Flt-1, lower PlGF, and higher soluble Flt-1:PlGF ratios) preceded maternal manifestations of preeclampsia, whereas in SLE patients with high IFNα levels, preeclampsia occurred without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with soluble Flt-1 induced expression of sFLT1 messenger RNA, and IFNα dramatically amplified responses to soluble Flt-1. In a model of spiral artery transformation, only the combination of IFNα and soluble Flt-1 disrupted the ability of trophoblast cells to remodel endothelial tube structures. CONCLUSION: Our findings identify a new mechanism by which IFNα induces an antiangiogenic milieu and increases the sensitivity of endothelial cells to soluble Flt-1, and suggest that elevated IFNα levels may contribute to the pathogenesis of preeclampsia in some pregnant patients with SLE.

Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions.

OBJECTIVE: Antiphospholipid antibodies (aPL) interfere with several physiologic functions of human trophoblasts, including reducing their ability to migrate, decreasing their production of angiogenic factors, and inducing an inflammatory response. This may provide the underlying mechanism by which aPL responses lead to recurrent pregnancy loss or preeclampsia in women with obstetric antiphospholipid syndrome (APS). Although treatment with heparin may reduce the rate of recurrent pregnancy loss, the risk of preeclampsia remains high. Therefore, alternative treatments are needed for the management of pregnant patients with APS. Since aspirin-triggered lipoxins (ATLs) have immune and angiogenic modulatory properties, the objective of this study was to determine the effects of the ATL 15-epi-lipoxin A4 on the function of aPL-altered human trophoblasts in the first trimester of pregnancy. METHODS: A first-trimester human trophoblast cell line (HTR8) was treated with mouse anti-human ß2 -glycoprotein I monoclonal antibodies (aPL) in the presence or absence of the ATL 15-epi-lipoxin A4 . Trophoblast migration and interactions with endometrial endothelial cells were measured using Transwell and coculture assays. Trophoblast secretion of cytokines and angiogenic factors was measured by enzyme-linked immunosorbent assay. RESULTS: Treatment of HTR8 cells with ATL reversed the aPL-induced decrease in trophoblast migration, an effect that appeared to be regulated through restoration of interleukin-6 production. Using a model of spiral artery transformation, aPL and sera from APS patients with pregnancy morbidity disrupted trophoblast-endothelial cell interactions, and treatment with ATL restored the stability of the cocultures. In contrast, ATL treatment did not resolve the proinflammatory and antiangiogenic responses of trophoblasts induced by aPL. CONCLUSION: These findings indicate that ATLs may have some benefits in terms of preventing the effects of aPL on trophoblast function, which raises the possibility of the use of ATLs as an adjuvant therapy in women with aPL.

Placebos, neuropathic pain and gender / Los placebos, el dolor neuropàtico y de género

INTRODUCTION: the placebos' analgesic effect seems to depend on different factors such as socio-cultural, psychological and genetic aspects. The effects of gender on placebos' analgesic response have rarely been documented in clinical studies, even though there have been some reports in experimental studies. OBJETIVE: study the analgesic effect of anticonvulsant and antidepressive drugs in adults suffering from painful diabetic neuropathy and its relationship with gender MATERIAL AND METHODS: a search and systematic selection was made of all clinical trials for analgesic treatment of diabetic neuropathy with anticonvulsant and antidepressive drugs published between January 2000 and February 2011. Randomized, placebo-compared clinical trials were included which had studied the analgesic effect of anticonvulsant and antidepressive drugs in adults suffering from painful diabetic neuropathy, evaluated in such a way that improvement in pain could be objectively classified. The following information was obtained from each article: criteria for diagnosing diabetic neuropathy, medicaments received and improvement of pain in the group being treated and in the placebo group according to patient gender. RESULTS: 12 studies fulfilling the inclusion criteria were found which analyzed latest generation anticonvulsant and antidepressive agents used in managing pain in diabetic neuropathy. Only one study included gender-discriminated results regarding controlling pain in the placebo group. CONCLUSION: the foregoing easily justifies the need for and importance of studying the relationship between gender and placebo response. This association has not been suitably reported to date, except by very few studies.

INTRODUCCIÓN: el efecto analgésico del placebo parece depender de diversos factores tales como los aspectos socio-culturales, psicológicos y genéticos. Los efectos del género en la respuesta analgésica del placebo rara vez se documenta en los estudios clínicos, a pesar de que ha habido algunos informes en los estudios experimentales. OBJETIVO: estudiar el efecto de los antiepilépticos y fármacos antidepresivos en la neuropatía diabética en relación con el género MATERIAL Y MÉTODOS: se realizó una búsqueda y selección sistemática de todos los ensayos clínicos para el tratamiento analgésico de la neuropatía diabética con antiepilépticos y fármacos antidepresivos publicados entre enero de 2000 y febrero de 2011. Se incluyeron todos los estudios clínicos aleatorizados, comparados con placebo que estudiaran el efecto analgésico de los antiepilépticos y fármacos antidepresivos en adultos con neuropatía diabética dolorosa, que evaluaran la mejoría en el dolor de manera objetiva. En cada artículo se obtuvo la siguiente información: criterios para el diagnóstico de la neuropatía diabética, medicamentos recibidos y mejoría del dolor en el grupo en tratamiento y en el grupo placebo, según el sexo del paciente. RESULTADOS: 12 estudios cumplían los criterios de inclusión. Sólo un estudio incluyó discriminación de género, los resultados en relación con el control del dolor en el grupo placebo. CONCLUSIONES: los hallazgos de esta investigación justifica la necesidad y la importancia de estudiar la relación entre el género y la respuesta al placebo. Esta asociación no ha sido debidamente reportada hasta la fecha, excepto por muy pocos estudios.

New Generation Antidepressants in Painful Diabetic Neuropathy / Antidepresivos de nueva generation en neuropatia diabetica dolorosa / Antidepressivos de nova geração na neuropatia diabetica dolorosa

The incidence of diabetic neuropathy increases with the duration of diabetes and the degree of hyperglycaemia. Pain is one of the most common and incapacitating symptoms of diabetic neuropathy and its pharmacological control is complex. The effectiveness of antidepressive agents has been described in different types of neuropathic pain, but their effectiveness, when used as analgesics in painful diabetic neuropathy, still remains controversial. Objective: To review the possible role of new-generation antidepressive agents in the treatment of pain in diabetic peripheral neuropathy. This work has thus consisted of a meta-analysis for determining which antidepressive agent had the best analgesic potential in managing pain in patients suffering from painful diabetic neuropathy. Methods: This search covered the Cochrane, MEDLINE, EMBASE and LILACS databases, between January 2000 and August 2007. The following information was obtained from each article: criteria for diagnosing diabetic neuropathy, patients' age average, antidepressant drug received and dose, sample size, duration of the disease and treatment follow-up, outcome measurement, evaluation of pain and rescue medication. Results: A combined RR: 1.67 (95% CI 1.38 - 2.02) was obtained; this result indicated that the antidepressive agent duloxetine, was effective for controlling pain in diabetic neuropathy. The corresponding NNT for Duloxetine was established, according to our interests; NNT = 6 (95% CI 5- 8) for achieving greater than 50% analgesia in patients suffering from painful diabetic neuropathy. Discussion: Antidepressive agents are frequently employed in the specific case of diabetic neuropathy; their analgesic benefit has been demonstrated.

La incidencia de neuropatía diabética aumenta con la duración de la diabetes y el grado de hiperglicemia. El dolor es uno de los síntomas más comunes e incapacitantes de la neuropatía diabética y su control farmacológico es complejo. La efectividad de los antidepresivos ha sido descrita en diferentes tipos de dolor neuropático, pero su verdadera efectividad, al ser usados como analgésicos en el dolor en la neuropatía diabética, aún es controvertida. Objetivo: Realizar una revisión sistemática y meta-análisis para determinar el nivel de evidencia en relación con la potencia analgésica de estos nuevos antidepresivos para el manejo del dolor en el paciente con neuropatía diabética dolorosa. Métodos: La búsqueda cubrió las bases de datos Cochrane, MEDLINE, EMBASE y LILACS entre enero de 2000 y agosto de 2007. De cada artículo se obtuvo la siguiente información: criterios para diagnóstico de neuropatía diabética, edad promedio de los pacientes, antidepresivo recibido y dosis, tamaño de la muestra, duración de la enfermedad, seguimiento del tratamiento, medidas de desenlace, evaluación del dolor y medicación de rescate. Resultados: Se obtuvo un RR combinado de 1,67 (IC 95% 1,38 - 2,02). El NNT correspondiente para la Duloxetina fue de 6 (95% CI 5- 8), para obtener una analgesia superior a 50% en pacientes con dolor por neuropatía diabética. Discusión: Se ha demostrado que los antidepresivos son empleados con frecuencia y efectivos como analgésicos para el dolor por neuropatía diabética.

A incidência de neuropatia diabética aumenta com a duração da diabetes e o grau de hiperglicemia. A dor é um dos sintomas mais comuns e incapacitantes da neuropatia diabética e seu controle farmacológico é complexo. A efetividade dos antidepressivos tem sido descrita em diferentes tipos de dor neuropática, mas sua verdadeira efetividade, quando utilizados como analgésicos na dor na neuropatia diabética, ainda é controvertida. Objetivo: realizar uma revisão sistemática e meta-análise para determinar o nível de evidencia em relação com a potência analgésica destes novos antidepressivos para o manejo da dor no paciente com neuropatia diabética dolorosa. Métodos: A procura cobriu as bases de dados Cochrane, MEDLINE, EMBASE e LILACS entre janeiro de 2000 e agosto de 2007. De cada artigo se obteve a seguinte informação: critérios para diagnóstico de neuropatia diabética, idade em media dos pacientes, antidepressivo recebido e dose, tamanho da amostra, duração da enfermidade, seguimento do tratamento, medidas de desenlace, avaliação da dor e medicação de resgate. Resultados: obteve-se um RR combinado de 1,67 (IC 95% 1,38 - 2,02). O NNT correspondente para a Duloxetina foi de 6 (95% CI 5- 8), para obter uma analgesia superior a 50% em pacientes com dor por neuropatia diabética. Discussão: tem se demonstrado que os antidepressivos são empregados com freqüência e efetivos como analgésicos para a dor por neuropatia diabética.

Antiepileptic drugs in treatment of pain caused by diabetic neuropathy.

Pain is frequent in diabetic neuropathy and is very hard to manage. Antiepileptic drugs have been used in treating pain for several decades. Their effectiveness has been described in different types of neuropathic pain, but when used as analgesics in painful diabetic neuropathy it still remains controversial. To clarify this effectiveness, a meta-analysis was performed to determine which antiepileptic drug had the best analgesic potential for managing pain in patients suffering from painful diabetic neuropathy. The search covered the Cochrane, MEDLINE, EMBASE, and LILACS databases, between January 1966 and September 2005. The following information was obtained from each article: criteria for diagnosing diabetic neuropathy, patients' age average, antiepileptic drug received and dose, sample size, duration of the disease and treatment follow-up, outcome measurement, evaluation of pain, and rescue medication. A combined 2.33 relative risk (95% confidence interval [CI] 1.88-2.88) was obtained; this result indicated that the antiepileptic drugs studied were effective for controlling pain in diabetic neuropathy. The corresponding necessary number to treat (NNT) values were established for evaluating which antiepileptic drug was most effective as an analgesic, according to our interests; pregabalin was shown to be the antiepileptic drug having the lowest NNT (NNT=3.24 and 95% CI 2.12-6.81) for achieving greater than 50% analgesia in patients suffering from painful diabetic neuropathy. Antiepileptic drugs are frequently used in the specific case of diabetic neuropathy; the combined result of this meta-analysis has demonstrated their analgesic benefit.

Manganese and epilepsy: a systematic review of the literature.

Manganese is an essential trace element for the development and function of the central nervous system. Alterations in manganese concentrations, whether excessive or deficient, can be accompanied by convulsions. This article represents a systematic review of available quantitative evidence that might clarify this issue. We searched The Cochrane Library, Medline and LILACS databases from January 1966 through June 2006 and reviewed all resulting English and Spanish language publications, as well as those possibly relevant in other languages based on their abstracts. The final selection included for this review comprises all investigations in humans and animals that compared manganese levels in any tissue of a group with spontaneous or induced convulsions (with or without antiepileptic treatment) and a convulsion-free control group. The literature search identified thirteen publications since then relevant to the issue, four of which failed to meet our criteria for inclusion. Of the remaining nine, six were in humans and three in rodents. At present, there is no satisfactory explanation for the relationship between low manganese levels and the presence of convulsions. There is a documented correlation between low blood manganese levels and the presence of convulsions in both humans and animals. The lack of evidence indicating whether this is a cause or an effect of the convulsions clearly justifies more detailed follow-up investigations in humans.