LDO proteins and Vac8 form a vacuole-lipid droplet contact site to enable starvation-induced lipophagy in yeast.

Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that directly binds vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy, resulting in impaired caloric restriction-induced longevity. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we identify the tethering machinery of vCLIP and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.

Curcumin Administration Improves Force of mdx Dystrophic Diaphragm by Acting on Fiber-Type Composition, Myosin Nitrotyrosination and SERCA1 Protein Levels.

The vegetal polyphenol curcumin displays beneficial effects against skeletal muscle derangement induced by oxidative stress, disuse or aging. Since oxidative stress and inflammation are involved in the progression of muscle dystrophy, the effects of curcumin administration were investigated in the diaphragm of mdx mice injected intraperitoneally or subcutaneously with curcumin for 4-12-24 weeks. Curcumin treatment independently of the way and duration of administration (i) ameliorated myofiber maturation index without affecting myofiber necrosis, inflammation and degree of fibrosis; (ii) counteracted the decrease in type 2X and 2B fiber percentage; (iii) increased about 30% both twitch and tetanic tensions of diaphragm strips; (iv) reduced myosin nitrotyrosination and tropomyosin oxidation; (v) acted on two opposite nNOS regulators by decreasing active AMP-Kinase and increasing SERCA1 protein levels, the latter effect being detectable also in myotube cultures from mdx satellite cells. Interestingly, increased contractility, decreased myosin nitrotyrosination and SERCA1 upregulation were also detectable in the mdx diaphragm after a 4-week administration of the NOS inhibitor 7-Nitroindazole, and were not improved further by a combined treatment. In conclusion, curcumin has beneficial effects on the dystrophic muscle, mechanistically acting for the containment of a deregulated nNOS activity.

Tailor-Made Bio-Based Non-Isocyanate Polyurethanes (NIPUs).

Non-isocyanate polyurethanes (NIPUs) based on biobased polyamines and polycarbonates are a sustainable alternative to conventional polyurethanes (PU). This article discloses a novel method to control the crosslinking density of fully biobased isocyanate-free polyurethanes, synthesized from triglycerides carbonated previously in scCO2 and different diamines, such as ethylenediamine (EDA), hexamethylenediamine (HMDA) and PriamineTM-1075 (derived from a dimerized fatty acid). As capping substances, water or bioalcohols are used in such a way that the crosslinking density can be adjusted to suit the requirements of the intended application. An optimization of the NIPU synthesis procedure is firstly carried out, establishing the polymerization kinetics and proposing optimal conditions set for the synthesis of the NIPUs. Then, the influence of the partial blocking of the active polymerization sites of the carbonated soybean oil (CSBO), using monofunctional amines, on the physical properties of the NIPUS is explored. Finally, the synthesis of fully biobased NIPUs with a targeted crosslinking density is achieved using hybrid NIPUs, employing partially carbonated oil and H2O or ethanol as blockers to achieve the desired physical properties in a very precise manner.

A myoelectric digital twin for fast and realistic modelling in deep learning.

Muscle electrophysiology has emerged as a powerful tool to drive human machine interfaces, with many new recent applications outside the traditional clinical domains, such as robotics and virtual reality. However, more sophisticated, functional, and robust decoding algorithms are required to meet the fine control requirements of these applications. Deep learning has shown high potential in meeting these demands, but requires a large amount of high-quality annotated data, which is expensive and time-consuming to acquire. Data augmentation using simulations, a strategy applied in other deep learning applications, has never been attempted in electromyography due to the absence of computationally efficient models. We introduce a concept of Myoelectric Digital Twin - highly realistic and fast computational model tailored for the training of deep learning algorithms. It enables simulation of arbitrary large and perfectly annotated datasets of realistic electromyography signals, allowing new approaches to muscular signal decoding, accelerating the development of human-machine interfaces.

Evaluación de la terapia de reproducción médicamente asistida en 9 años: estudio de cohorte retrospectivo / Medically assisted reproductive therapy assessment in 9 years: retrospective cohort study

OBJETIVO: Describir las tasas de recién nacidos vivos (RNV) y embarazo de la terapia de reproducción médicamente asistida de baja complejidad del Centro de Reproducción Humana de la Universidad de Valparaíso, Chile. MÉTODO: Estudio retrospectivo de todos los ciclos de estimulación ovárica controlada con inseminación intrauterina (IIU) completados, entre los años 2011 y 2019. Se evaluaron las características clínicas basales y los resultados en IIU homólogas y heterólogas según el ciclo inseminado, la causa de infertilidad, el rango etario y el índice de masa corporal (IMC). El desenlace principal fue la tasa de RNV por ciclo inseminado. RESULTADOS: Se estudiaron 1415 ciclos en 700 parejas. La tasa acumulativa de RNV fue del 19,6%, un 18,3% en IIU homóloga y un 39,0% en IIU heteróloga. La tasa de RNV fue del 10,0% al primer ciclo, del 5,8% al segundo ciclo y del 3,7% al tercer o más ciclos. Al separar por IIU heteróloga, esta aumenta al 24,4% al primer ciclo y al 14,6% al segundo ciclo. La tasa de RNV es significativamente mejor en pacientes menores de 35 años (23,7%) y con IMC < 29 (20,8%). CONCLUSIONES: El tratamiento de baja complejidad en pacientes infértiles es una opción terapéutica vigente con una aceptable tasa de RNV por ciclo inseminado. Los resultados están influenciados por la edad y por el IMC.

OBJECTIVE: To describe the rates of live newborns (LNB) and pregnancy of the low complexity therapy of the Centre for Human Reproduction of Universidad de Valparaíso, Chile. METHOD: Retrospective study of all cycles of controlled ovarian stimulation with intrauterine insemination (IUI) completed between 2011-2019. The baseline clinical characteristics and results in homologous and heterologous IUI were evaluated according to inseminated cycle, cause of infertility, age range and body mass index (BMI). The main outcome was rate of LNB per inseminated cycle. RESULTS: 1415 cycles were studied in 700 couples. The cumulative rate of LNB was 19.6%, 18.3% in homologous IUI and 39.0% in heterologous IUI. The LNB rate was 10.0% at the first cycle, 5.8% at the second cycle, 3.7% at the third or more cycles. When separating by heterologous IUI, it increases to 24.4% in the first cycle and 14.6% in the second cycle. The LNB rate is significantly better in patients under 35 years of age (23.7%) and with a BMI less than 29 (20.8%). CONCLUSIONS: Treatment of low complexity in selected infertile patients is a current therapeutic option with an acceptable rate of LNB per inseminated cycle. The results are influenced by age and BMI.

Far-field electric potentials provide access to the output from the spinal cord from wrist-mounted sensors.

Objective. Neural interfaces need to become more unobtrusive and socially acceptable to appeal to general consumers outside rehabilitation settings.Approach. We developed a non-invasive neural interface that provides access to spinal motor neuron activities from the wrist, which is the preferred location for a wearable. The interface decodes far-field potentials present at the tendon endings of the forearm muscles using blind source separation. First, we evaluated the reliability of the interface to detect motor neuron firings based on far-field potentials, and thereafter we used the decoded motor neuron activity for the prediction of finger contractions in offline and real-time conditions.Main results. The results showed that motor neuron activity decoded from the far-field potentials at the wrist accurately predicted individual and combined finger commands and therefore allowed for highly accurate real-time task classification.Significance.These findings demonstrate the feasibility of a non-invasive, neural interface at the wrist for precise real-time control based on the output of the spinal cord.

Sterol Metabolism Differentially Contributes to Maintenance and Exit of Quiescence.

Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.

Co-Adaptive Control of Bionic Limbs via Unsupervised Adaptation of Muscle Synergies.

OBJECTIVE: In this work, we present a myoelectric interface that extracts natural motor synergies from multi-muscle signals and adapts in real-time with new user inputs. With this unsupervised adaptive myocontrol (UAM) system, optimal synergies for control are continuously co-adapted with changes in user motor control, or as a function of perturbed conditions via online non-negative matrix factorization guided by physiologically informed sparseness constraints in lieu of explicit data labelling. METHODS: UAM was tested in a set of virtual target reaching tasks completed by able-bodied and amputee subjects. Tests were conducted under normative and electrode perturbed conditions to gauge control robustness with comparisons to non-adaptive and supervised adaptive myocontrol schemes. Furthermore, UAM was used to interface an amputee with a multi-functional powered hand prosthesis during standardized Clothespin Relocation Tests, also conducted in normative and perturbed conditions. RESULTS: In virtual tests, UAM effectively mitigated performance degradation caused by electrode displacement, affording greater resilience over an existing supervised adaptive system for amputee subjects. Induced electrode shifts also had negligible effect on the real world control performance of UAM with consistent completion times (23.91 ±1.33 s) achieved across Clothespin Relocation Tests in the normative and electrode perturbed conditions. CONCLUSION: UAM affords comparable robustness improvements to existing supervised adaptive myocontrol interfaces whilst providing additional practical advantages for clinical deployment. SIGNIFICANCE: The proposed system uniquely incorporates neuromuscular control principles with unsupervised online learning methods and presents a working example of a freely co-adaptive bionic interface.

Chronic Systemic Curcumin Administration Antagonizes Murine Sarcopenia and Presarcopenia.

Curcumin administration attenuates muscle disuse atrophy, but its effectiveness against aging-induced, selective loss of mass or force (presarcopenia or asthenia/dynopenia), or combined loss (sarcopenia), remains controversial. A new systemic curcumin treatment was developed and tested in 18-month-old C57BL6J and C57BL10ScSn male mice. The effects on survival, liver toxicity, loss of muscle mass and force, and satellite cell responsivity and commitment were evaluated after 6-month treatment. Although only 24-month-old C57BL10ScSn mice displayed age-related muscle impairment, curcumin significantly increased survival of both strains (+20-35%), without signs of liver toxicity. Treatment prevented sarcopenia in soleus and presarcopenia in EDL of C57BL10ScSn mice, whereas it did not affect healthy-aged muscles of C57BL6J. Curcumin-treated old C57BL10ScSn soleus preserved type-1 myofiber size and increased type-2A one, whereas EDL maintained adult values of total myofiber number and fiber-type composition. Mechanistically, curcumin only partially prevented the age-related changes in protein level and subcellular distribution of major costamere components and regulators. Conversely, it affected satellite cells, by maintaining adult levels of myofiber maturation in old regenerating soleus and increasing percentage of isolated, MyoD-positive satellite cells from old hindlimb muscles. Therefore, curcumin treatment successfully prevents presarcopenia and sarcopenia development by improving satellite cell commitment and recruitment.

Glucosinolate Bioactivation by Apis mellifera Workers and Its Impact on Nosema ceranae Infection at the Colony Level.

The microsporidian fungus Nosema ceranae represents one of the primary bee infection threats worldwide and the antibiotic fumagillin is the only registered product for nosemosis disease control, while few alternatives are, at present, available. Natural bioactive compounds deriving from the glucosinolate-myrosinase system (GSL-MYR) in Brassicaceae plants, mainly isothiocyanates (ITCs), are known for their antimicrobial activity against numerous pathogens and for their health-protective effects in humans. This work explored the use of Brassica nigra and Eruca sativa defatted seed meal (DSM) GSL-containing diets against natural Nosema infection in Apis mellifera colonies. DSM patties from each plant species were obtained by adding DSMs to sugar candy at the concentration of 4% (w/w). The feeding was administered in May to mildly N. ceranae-infected honey bee colonies for four weeks at the dose of 250 g/week. In the treated groups, no significant effects on colony development and bee mortality were observed compared to the negative controls. The N. ceranae abundance showed a slight but significant decrease. Furthermore, the GSL metabolism in bees was investigated, and MYR hydrolytic activity was qualitatively searched in isolated bee midgut and hindgut. Interestingly, MYR activity was detected both in the bees fed DSMs and in the control group where the bees did not receive DSMs. In parallel, ITCs were found in gut tissues from the bees treated with DSMs, corroborating the presence of a MYR-like enzyme capable of hydrolyzing ingested GSLs. On the other hand, GSLs and other GSL hydrolysis products other than ITCs, such as nitriles, were found in honey produced by the treated bees, potentially increasing the health value of the final product for human consumption. The results are indicative of a specific effect on the N. ceranae infection in managed honey bee colonies depending on the GSL activation within the target organ.

Alteraciones de Número en Dentición de Pacientes entre 2 y 12 Años de Edad con Disrafias Labio Alvéolo Palatina Atendidos en la Unidad de Odontopediatría del Hospital Regional Antofagasta, Chile / Dentition Number Alterations in Patients between 2 and 12 Years of Age with Cleft Alveolus Palate Examined at the Pediatric Dental Unit of the Regional Hospital Antofagasta, Chile

Se realizó un estudio de las alteraciones de número dientes en 71 pacientes entre 2 y 12 años de edad, portadores de Fisura Labio Alvéolo Palatina del Hospital Regional de Antofagasta, atendidos entre Abril del 2004 y Julio del 2010, utilizando las fichas clínicas, radiografías panorámicas, oclusales o periapicales. Se encontró una prevalencia de agenesias dentarias en un 57,75%, de dientes supernumerarios en un 23,95%. Sólo el 18,4% de los niños no presentó alteraciones de número. En la distribución por sexo, en los niños la fisura labial y fisura labio alvéolo palatina bilateral presentó una mayor frecuencia, mientras que en las niñas las fisuras palatinas y fisuras labio alvéolo palatinas unilaterales fueron más frecuentes. Según el tipo de fisura, la más frecuente fue la fisura labio alvéolo palatina unilateral con un 64,79%. La frecuencia de agenesias en el lado de la fisura fue de un 89,3%. El diente más afectado en las agenesias fue el incisivo lateral con un 78,6% en los niños entre 2 a 6 años, y con un 100% en los niños entre 7 y 12 años. Se observó que el 61,5% de los niños con agenesia tenían 1 diente afectado, el 30,8% mostraron 2 dientes afectados y solo el 7,7% presentó 3 o más dientes afectados.

The present study was carried out to research alterations of teeth in 71 patients, whose ages were between two and twelve years old and who exhibited alveolus cleft lip palate. These patients were treated at The Regional Hospital in Antofagasta around April 2004 and July 2010, therefore, we used the tabs clinics, panoramic radiograph, occlusal and periapical radiographs. A prevalence of tooth agenesis in 57.75% of supernumerary teeth in 23.95% was found and 18.4% of children did not show any modification of number. In connection with the distribution by sex of the cleft lip and cleft lip bilateral alveolar palatine presented a high frequency in boys , and the palate clefts with fissure unilateral alveolus cleft lip were frequently observed in girls. Regarding to the types of cleft lip, the most frequent found was the alveolar cleft lip palate unilateral with 64.70% over the total of the fissures. On the other hand, the frequency of agenesis, related to fissure was 89.3%. The most affected tooth in agenesis was the lateral incisor with 78.6% in children whose ages were from 2 to 6 years old, and 100% in children from 7 to 12.It was also observed that 61.5% of children with agenesis had one affected tooth, 30.8 % had two affected teeth and only 7.7% had three or more affected teeth.

Genotipo y fenotipo de la enzima tiopurina metiltransferasa en población chilena / Phenotype and genotype of thiopurine methyltransferase in Chilean individuals

Background: Thiopurines (azathioprine and 6-mercaptopurine) are highly effective medications but with potential adverse effects. Thiopurine methyltransferase (TMPT) is the key enzyme in their pharmacokinetics and is genetically regulated. A low activity of TPMT is associated with myelotoxicity. The genotype and enzyme activity can vary by ethnicity. Aim: To study the activity and genotype of TPMT in a group of Chilean subjects. Material and Methods: In 200 healthy adult blood donors, TPMT activity was determined by high performance liquid chromatography (HPLC). Deficient, low, normal or high levels were defined when enzymatic activity was < 5, 6-24,25-55 and > 56 nmol/grHb/h, respectively. Genotyping of TPMT (*1, *2, *3A, *3B, *3C) was performed by PCR. Results: Seventy seven women (38.5%) and 123 men (61.5%), with an average age of 34.9 years were studied. Eighteen subjects (9%) had a low enzymatic activity, 178 (89%) had normal activity, 4 (2%) had high activity and no genotype deficient subjects were identified. The wild type genotype (*1) was found in 184 (92%) individuals and 16 (8%) were heterozygous for the variants: *2 (n = 2), *3A (n = 13) and *3C (n = 1). No homozygous subjects for these variants were identified. Wild type genotype had an increased enzymatic activity (40.8 ± 7.2 nmol/gHb/h) compared to heterozygous group (21.2 ± 3 nmol/ gHb/h; p < 0.001). Conclusions: Less than 10% of a Chilean population sample has a low enzymatic activity or allelic variants in the TPMT gene, supporting the use of thiopurines according to international recommendations.

[Phenotype and genotype of thiopurine methyltransferase in Chilean individuals]. / Genotipo y fenotipo de la enzima tiopurina metiltransferasa en población chilena.

BACKGROUND: Thiopurines (azathioprine and 6-mercaptopurine) are highly effective medications but with potential adverse effects. Thiopurine methyltransferase (TMPT) is the key enzyme in their pharmacokinetics and is genetically regulated. A low activity of TPMT is associated with myelotoxicity. The genotype and enzyme activity can vary by ethnicity. AIM: To study the activity and genotype of TPMT in a group of Chilean subjects. MATERIAL AND METHODS: In 200 healthy adult blood donors, TPMT activity was determined by high performance liquid chromatography (HPLC). Deficient, low, normal or high levels were defined when enzymatic activity was < 5, 6-24,25-55 and > 56 nmol/grHb/h, respectively. Genotyping of TPMT (*1, *2, *3A, *3B, *3C) was performed by PCR. RESULTS: Seventy seven women (38.5%) and 123 men (61.5%), with an average age of 34.9 years were studied. Eighteen subjects (9%) had a low enzymatic activity, 178 (89%) had normal activity, 4 (2%) had high activity and no genotype deficient subjects were identified. The wild type genotype (*1) was found in 184 (92%) individuals and 16 (8%) were heterozygous for the variants: *2 (n = 2), *3A (n = 13) and *3C (n = 1). No homozygous subjects for these variants were identified. Wild type genotype had an increased enzymatic activity (40.8 ± 7.2 nmol/gHb/h) compared to heterozygous group (21.2 ± 3 nmol/ gHb/h; p < 0.001). CONCLUSIONS: Less than 10% of a Chilean population sample has a low enzymatic activity or allelic variants in the TPMT gene, supporting the use of thiopurines according to international recommendations.

Hallux límitus post-quirúrgico. A propósito de un caso / Post surgical hallux limitus. A clinical case

En el presente trabajo se expone un caso clínico de una mujer de 53 años que acude a la Clínica Podológica por presentar artralgia de la Primera Articulación Metatarsofalángica durante la fase propulsiva, de 4 años de evolución. Tras exploración podológica se diagnosticó de Hallux Límitus Funcional caracterizado por una alteración biomecánica de la 1ª AMTF con disminución de la flexión dorsal del Hallux por debajo de los 65º en dinámica con probable etiología quirúrgica por descenso plantar de la primera cabeza metatarsiana. Dicha alteración biomecánica comporta una serie de mecanismos compensatorios al resto del antepié y retropié causados por la insuficiencia estructural y funcional del primer radio. A nivel podológico, se pueden realizar una amplia variedad de tratamientos pero sin lugar a dudas y en cualquier caso, es de relevancia una minuciosa y planificada exploración y valoración del pie junto a toda la Extremidad Inferior del paciente. El objetivo del trabajo es justificar si existe una relación entre Hallux Límitus Funcional y el descenso plantar de la primera cabeza metatarsiana o se contemplan como entidades patológicas independientes y analizar qué tratamientos serían los más indicados. Para ello, se analizó la exploración la patomecánica, el tratamiento del caso clínico estudiado, y se realizó una revisión bibliográfica de la documentación científica relacionada con dichas alteraciones. Tras exhaustivos análisis se concluye que dichas patologías pueden presentar una relación etiológica si durante la fase propulsiva se produce un momento dorsiflexor de la 1ª cabeza metatarsiana como respuesta a las Fuerzas Reactivas del Suelo, limitándose así la flexión dorsal y la activación del Mecanismo Windlass para convertir el pie en una palanca rígida y producir un despegue del primer radio eficiente. Tanto la exploración como la patomecánica del primer radio, son determinantes para el diagnóstico y tratamiento de dichas patalogías, así como conocer las consecuencias que pueden desencadenar en el resto del pie y extremidad inferior, ya que variarán el tratamiento ortopodológico, quirúrgico y físico. En el paciente, las patologías expuestas se atribuyen a una corrección quirúrgica de Hallux Abductus Valgus que ha provocado un descenso plantar de la cabeza metatarsiana (AU)

In this paper, we present a clinical case of a 53 years old woman who comes to the podiatry clinic, suffering from an arthralgia of the 1st metatarsophalangeal joint, during the propulsive stage of gait, for 4 years. After the clinic examination, she was diagnosed as a functional hallux limitus, characterized by a biomechanical alteration of the 1st metatarsophalangeal with a disminution of the dorsal flexion of the hallux below 65º in the dynamic with a probable surgery etiology, because of the descending of the 1st metatarsal head. This biomechanical alteration involves a series of compensatory mechanism for the rest of the forefoot and hindfoot caused by structural and functional failure of the first radio. At a podiatric level, we can executive a wide variety of treatments but, in all cases, we need a planned and through examination and assesment of the foot and lower extremities of the patient. The aim of this paper is to justify whether there is a relationship between Functional Hallux Limitus and the descent of the first metatarsal head, or if they are independent pathological identities and to analyze what kind of treatments are the most suitable. For this purpose, we analyzed the examination, the patomechanics, the treatment and we carried out a bibliographic revision of the scientific documentation related to those alterations. After exhaustive analysis, we conclude that these conditions may have an etiological relationship if during the propulsive phase there is a dorsiflexor moment of the 1st metatarsal head in response to the reactive forces on the ground, thus limiting the dorsal flexion and activating the Windlass Mechanism in order to convert the foot into a rigid lever and produce an efficient launch of the first radio. Both exploration and patomechanics of the first radio are crucial for the diagnosis and treatment for these pathologies, as well as knowing the consequences that can be generated on the rest of the foot and lower limb, as several orthopedic, surgical and physical treatments. The conditions of our patient are attributed to a surgical correction of hallux valgus abductus which led to a lowering of the metatarsal head (AU)

Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events?

We tested the hypothesis that endothelial dysfunction could cause placentation-related defects, persist after the complicated pregnancy, and probably cause cardiovascular disease later in life. Brachial arterial reactivity and factors related to endothelial dysfunction, such as circulating cholesterol, uric acid, nitrites, l-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1, in women with previous healthy pregnancies (n=22), patients with severe preeclampsia (n=25), or patients with recurrent pregnancy loss (n=29), at day 10 of the luteal phase of an ovulatory cycle an average of 11 to 27 months after pregnancy were evaluated. Both groups with placentation defects had a significant decrease in endothelium-dependent dilatation, a higher rate of endothelial dysfunction, lower serum nitrites, and higher cholesterol as compared with control subjects; subjects with previous preeclampsia additionally had higher normal blood pressures and a greater parental prevalence of cardiovascular disease. Patients with recurrent pregnancy loss also demonstrated a significantly lower endothelium-independent vasodilatation. A trend to an inverse correlation was found between serum cholesterol serum and endothelial-mediated vasodilatation in the whole study population. Uric acid, l-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1 were similar in all of the groups. We postulate that endothelial dysfunction may represent a link between preeclampsia and increased cardiovascular disease latter in life and propose that women with unexplained recurrent miscarriages are also at increased cardiovascular risk. The identification and correction of endothelial dysfunction detected during the reproductive stage on obstetric outcome and on cardiovascular diseases needs to be elucidated.