Perinatal depression and implementation of the "Thinking Healthy program" support intervention in an impoverished setting of Lima, Peru: Assessment before and during the COVID-19 pandemic.

Socios En Salud (SES) implemented the Thinking Healthy program (THP) to support women with perinatal depression before and during the COVID-19 pandemic in Lima Norte. We carried out an analysis of the in-person (5 modules) and remote (1 module) THP intervention. Depression was detected using PHQ-9, and THP sessions were delivered in women with a score (PHQ-9 ≥ 5). Depression was reassessed and pre- and post-scores were compared. In the pre-pandemic cohort, perinatal depression was 25.4% (47/185), 47 women received THP and 27 were reassessed (57.4%), and the PHQ-9 score median decreased from 8 to 2, p < 0.001. In the pandemic cohort, perinatal depression was 47.5% (117/247), 117 women received THP and 89 were reassessed (76.1%), and the PHQ-9 score median decreased from 7 to 2, p < 0.001. THP's modalities helped to reduce perinatal depression. Pregnant women who received a module remotely also reduced depression.

A mixed methods evaluation of a World Health Organization competency-based training package for foundational helping skills among pre-service and in-service health workers in Nepal, Peru and Uganda.

Health systems globally demand more competent workers but lack competency-based training programs to reach their goals. This study evaluates the effectiveness of a competency-based curriculum (EQUIP-FHS) for trainers and supervisors to teach foundational helping knowledge, attitudes and skills, guided by the WHO/UNICEF EQUIP platform, to improve the competency of in-service and pre-service workers from various health and other service sectors. A mixed-methods, uncontrolled before-and-after trial was conducted in Nepal, Peru, and Uganda from 2020 to 2021. Trainees' (N = 150) competency data were collected during 13 FHS trainings. Paired t-tests assessed pre- to post-change in ENACT competency measures (e.g., harmful, helpful). Qualitative data was analyzed using thematic analysis. EQUIP-FHS trainings, on average, were 20 h in duration. Harmful behaviors significantly decreased, and helpful behaviors significantly increased, across and within sites from pre-to post-training. Qualitatively, trainees and trainers promoted the training and highlighted difficult competencies and areas for scaling the training. A brief competency-based curriculum on foundational helping delivered through pre-service or in-service training can reduce the risk that healthcare workers and other service providers display harmful behaviors. We recommend governmental and nongovernmental organizations implement competency-based approaches to enhance the quality of their existing workforce programming and be one step closer to achieving the goal of quality healthcare around the globe.

Serial 7-Day Electrocardiogram Patch Screening for AF in High-Risk Older Women by the CHARGE-AF Score.

BACKGROUND: Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown. OBJECTIVES: The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score. METHODS: Postmenopausal women with a 5-year predicted risk of new-onset AF ≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Women's Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6 months, and 12 months from study enrollment. RESULTS: On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6 months and 4.9% cumulatively by 12 months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score: 4.2% had AF detected at baseline, 5.9% at 6 months, and 7.2% at 12 months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 [78%]). CONCLUSIONS: Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12 months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Women's Health Initiative Silent Atrial Fibrillation Recording Study [WHISH STAR]; NCT05366803.).

Evidence of influenza infection in dogs and cats in central Chile.

As companion animals, dogs and cats live in close contact with humans, generating the possibility of interspecies pathogen transmission events. Equine origin H3N8 and avian origin H5N1 influenza virus have been reported in dogs and cats respectively since 2004 with outbreaks associated with different strains recorded for both species in Asia and North America. To date, there have been no reports of influenza viruses from companion animals in South America. To fill this gap in knowledge, we performed active epidemiological surveillance in shelters that received abandoned animals, backyard production systems and veterinary clinics between May 2017 and January 2019 to estimate the burden of influenza infection in cats and dogs in the central region of Chile. Blood samples, oropharyngeal swabs or both were collected for influenza A virus detection by RT-qPCR, NP-ELISA, and hemagglutination inhibition assay. Logistic regression models were performed to assess the association between NP-ELISA-positivity and variables including sex and animal origin. The percentage of ELISA-positive samples was 43.5 % (95 % CI: 37.0-50.1) and 23.3 % (95 % CI: 10.6-42.7) for dogs and cats, respectively. No association was found between NP-ELISA results and sex or animal origin for either dogs or cats. Two ELISA positive samples showed hemagglutination inhibition titers against pandemic H1N1 influenza. One dog sample tested positive by RT-qPCR, indicating an overall RT-qPCR positivity in dogs of 1.1 % (95 % CI: 0.05-6.7). None of the tested cat samples were positive by this assay.

Peripheral Blood Classical Monocytes and Plasma Interleukin 10 Are Associated to Neoadjuvant Chemotherapy Response in Breast Cancer Patients.

Worldwide, breast cancer (BC) is the leading cause of cancer death among women. For many patients the most effective treatment is a resection surgery that removes the tumor. Within this subset, patients sometimes receive chemotherapy treatment (CT) prior to surgery aiming to reduce tumor size in order to preserve healthy breast tissue. This strategy is commonly called neoadjuvant chemotherapy (NAC). This approach also offers an opportunity to determine treatment sensitivity, especially in aggressive tumors. Post NAC absence of residual disease is associated to long term survival in BC patients and is used to define the need of adjuvant therapy options. Studies suggest that NAC allows the recognition of tumor antigens by immune cells potentiating the eradication of the tumor. However, the dynamic changes in patients' immune cells under NAC remain unclear. Here, we assessed changes in leucocyte and cytokine profiles in order to determine its association to NAC response in BC patients. Peripheral blood patient samples were taken prior to each NAC cycle to assess the abundance of leukocyte subsets and serum cytokines in 20 patients. These immunological features were associated with clinical outcomes including pathological response. We found a positive correlation between plasma Interleukin 10 (IL-10) and classical monocytes in HER2+ BC patients under NAC. We also observed a trend between increased IL-10 and classical monocytes levels and lower rates of pathologic complete response at the end of NAC. These data support the notion that monocyte subsets and IL-10 could be applied as a novel indicator of NAC efficacy in HER2+ BC patients. Finally, we confirm a key role of the immune system in cancer progression and CT response.

The Neutrophil to Lymphocyte Ratio Predicts the Response to Neoadjuvant Chemotherapy in Luminal B Breast Cancer.

Objective: Tumor response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients is a predictor for overall survival. The aim of our study was to determine a relationship between the neutrophil to lymphocyte ratio (NLR) prior to NAC, BC subtypes and the probability of a pathologic complete response (pCR). Materials and Methods: Medical records were collected retrospectively from Centro de Cancer at Red Salud UC-Christus. Clinical data collected included peripheral blood cell counts, BC subtype at diagnosis and the pathology report of surgery after chemotherapy. Results: A total of 88 patients were analyzed. Approximately, a 25% had a pCR, and displayed a significant correlation between BC subtype and pCR (p= 0.0138 Chi2); this was more frequent in epidermal growth factor receptor type 2 (HER2) enriched subtype patients (54%). Luminal B BC patients with a pCR had significantly lower NLR levels (t test, p= 0.0181). Conclusions: HER2-enriched tumors had a higher probability of pCR. In Luminal B tumors, NLR had a statistically significant relationship with the probability of pCR. In this subtype, NLR could be a useful biomarker to predict tumor response to NAC. Further studies including other clinical parameters for systemic inflammation such as platelet counts, intratumoral NLR or body mass index could help identify patients that would get the most benefit from NAC.

Características clínicas y pronóstico de pacientes con cáncer de mama HER2 positivo avanzado, en la era antes y después de terapias anti-HER2 / Survival of patients with advanced HER2+ breast cancer. Analysis of a cancer center database

Background: HER2+ breast cancer (BC) subtype overexpresses the Human Epidermal growth factor Receptor type-2 (HER2) and is characterized by its aggressiveness and its high sensitivity to monoclonal antibody-based HER2-targeted therapies. Aim: To assess the prognosis and evaluate the impact of novel anti-HER2 therapies on advanced HER2+ BC patients treated at our institution over the last decades. Material and Methods: Analysis of the patient database at a cancer center of a university hospital. Information about the subtype of cancer was obtained in 2,149 of 2,724 patients in the database. Eighteen percent of the latter were HER2+. We analyzed data of 83 of these patients with advanced disease. Results: Median overall survival (OS) was 24 months. For patients treated between 1997-2006 median OS was 17 months and for those treated in the period 2007-2017 median OS was 32 months (p = 0.09). Conclusions: A non-significant trend towards better survival in the last decade was observed. HER2+ BC overall survival has improved in our center. This can be probably attributed to the use of novel more effective anti-HER2 therapies.

Can Histological Grade and Mitotic Index Replace Ki67 to Determine Luminal Breast Cancer Subtypes?

Introduction: Breast cancer can be classified into subtypes based on immunohistochemical markers, with Ki67 expression levels being used to divide luminal BC tumors in luminal A and B subtypes; however, Ki67 is not routinely determined due to a lack of standardization. Objective: To evaluate histological grade and Eliminate: the mitotic index to determine if they can be used as an alternative method to Ki67 staining for luminal subtype definition. Methods: We evaluated estrogen receptor positive breast cancer tissue samples. Pathological analysis included determination of Ki67. A low level of Ki67 was defined as <14% positive cells. Results: We evaluated 151 breast cancer samples; 24 (15,9%) were classified as I; 74 as HG II (49%), and 53 (35,1%) as HG III. The median value for Ki67 was 13% (range: <1% - 82%) and for MI was 2 (0-12). Histological grade I tumors exhibited Ki67 values significantly lower than HG II and III tumors (Anova, Tamhane test p=0,001). A higher Ki67 value was related to a higher MI (Rho Sperman p=0,336; R2= 0,0273). ROC curve analysis determined that a MI ≥ 3 had a sensibility of 61.9% and specificity of 66.7% in predicting a high Ki67 value (≥14%) (area under the curve: 0,691; p =0,0001). A HG I tumor or HG II-III with MI ≤2, had a high probability of corresponding to a LA tumor (76,3%), as defined using Ki67 expression, while the probability of a LB subtype was higher with HG II-III and a MI ≥3 (57.4%). Global discrimination was 68.1%. Conclusions: For the LA subtype, our predictive model showed a good correlation of HG and MI with the classification based on Ki67<14%. In the LB subtype, the model showed a weak correlation; therefore Ki67 determination seems to be needed for this group of patients.

[Survival of patients with advanced HER2+ breast cancer. Analysis of a cancer center database]. / Características clínicas y pronóstico de pacientes con cáncer de mama HER2 positivo avanzado, en la era antes y después de terapias anti-HER2.

BACKGROUND: HER2+ breast cancer (BC) subtype overexpresses the Human Epidermal growth factor Receptor type-2 (HER2) and is characterized by its aggressiveness and its high sensitivity to monoclonal antibody-based HER2-targeted therapies. AIM: To assess the prognosis and evaluate the impact of novel anti-HER2 therapies on advanced HER2+ BC patients treated at our institution over the last decades. MATERIAL AND METHODS: Analysis of the patient database at a cancer center of a university hospital. Information about the subtype of cancer was obtained in 2,149 of 2,724 patients in the database. Eighteen percent of the latter were HER2+. We analyzed data of 83 of these patients with advanced disease. RESULTS: Median overall survival (OS) was 24 months. For patients treated between 1997-2006 median OS was 17 months and for those treated in the period 2007-2017 median OS was 32 months (p = 0.09). CONCLUSIONS: A non-significant trend towards better survival in the last decade was observed. HER2+ BC overall survival has improved in our center. This can be probably attributed to the use of novel more effective anti-HER2 therapies.

Cáncer de mama avanzado receptor de estrógeno positivo: manejo sistémico actual / Systemic therapy for estrogen receptor positive advanced breast cancer

El cáncer de mama es la primera causa de muerte por cáncer en mujeres chilenas. Mientras la mayoría de las personas logra curarse de esta enfermedad, un 5% de los casos se presenta inicialmente con enfermedad avanzada y hasta un 20-30% de pacientes con enfermedad localizada pueden sufrir recurrencias sistémicas. La mayoría de las neoplasias mamarias son dependientes del estímulo estrogénico, de allí que la deprivación de estrógenos es la principal estrategia terapéutica. Recientemente, el uso de terapias molecularmente dirigidas en combinación con la terapia endocrina ha logrado mejorar los resultados de sobrevida del cáncer de mama avanzado, con menos efectos colaterales que aquellos producidos por la quimioterapia convencional. El conocimiento de los mecanismos de acción de estas nuevas terapias, sus toxicidades, vías de resistencia y selección de pacientes para lograr los mejores beneficios terapéuticos son aspectos relevantes en el manejo de la enfermedad. Presentamos una revisión del estado actual del manejo del cáncer de mama metastásico hormonodependiente con enfásis en el uso de terapias endocrinas combinadas con terapias moleculares.

Breast cancer is the leading cause of cancer death in Chilean women. While most patientes are cured, five percent of cases present with advanced disease initially and up to 20-30% of patients with localized disease may suffer systemic recurrences. The majority of breast neoplasms are dependent on the estrogenic stimulus, hence the deprivation of estrogen is the main therapeutic strategy. Recently, the use of molecular targeted therapies in combination with endocrine therapy has been successful in improving the survival outcomes of advanced breast cancer, with fewer side effects than those produced by conventional chemotherapy. Knowledge of the mechanisms of action of these new therapies, their toxicities, resistance pathways and patient selection to achieve the best therapeutic benefits are relevant aspects in the management of the disease. We present a review of the current state of management of hormone-dependent metastatic breast cancer with emphasis on the use of endocrine therapies combined with molecular therapies.

[Detection of the mecA gene in coagulase positive Staphylococcus isolated from cats]. / Detección del gen mecA en cepas de Staphylococcus coagulasa positiva aisladas desde gatos.

INTRODUCTION: Bacterial resistance is a global concern for public health. Reports of antimicrobial resistance, including that against methicillin, have increased in strains of coagulase positive Staphylococcus (CPS) isolated from pets, however in Chile this information is limited. OBJECTIVES: To determine the antimicrobial susceptibility profiles and to detect the mecA gene in CPS strains isolated from cats in Chile. MATERIALS AND METHODS: 134 samples were obtained from healthy cats and cats with skin lesions. These strains were characterized in their coagulase production and identified by BBL Crystal kit. The antimicrobial susceptibility was determined by Kirby Bauer method against 12 antimicrobials, including oxacillin. All strains were subjected to PCR to detect the mecA gene. RESULTS: 72 CPS strains were isolated, including S. aureus and S. intermedius. Antimicrobial resistance against at least one drug was detected in strains from both healthy cats (75%) and from cats with skin lesions (87.5%). The mecA gene was detected in eight methicillin-resistant strains and also in three sensitive strains, being in general multi-resistant. DISCUSSION: These results highlight the role of pets as reservoirs of bacterial resistance, and their potential impact on national public health.

Detección del gen mecA en cepas de Staphylococcus coagulasa positiva aisladas desde gatos / Detection of the mecA gene in coagulase positive Staphylococcus isolated from cats

Introduction: Bacterial resistance is a global concern for public health. Reports of antimicrobial resistance, including that against methicillin, have increased in strains of coagulase positive Staphylococcus (CPS) isolated from pets, however in Chile this information is limited. Objectives: To determine the antimicrobial susceptibility profiles and to detect the mecA gene in CPS strains isolated from cats in Chile. Materials and Methods : 134 samples were obtained from healthy cats and cats with skin lesions. These strains were characterized in their coagulase production and identified by BBL Crystal kit. The antimicrobial susceptibility was determined by Kirby Bauer method against 12 antimicrobials, including oxacillin. All strains were subjected to PCR to detect the mecA gene. Results: 72 CPS strains were isolated, including S. aureus and S. intermedius. Antimicrobial resistance against at least one drug was detected in strains from both healthy cats (75%) and from cats with skin lesions (87.5%). The mecA gene was detected in eight methicillin-resistant strains and also in three sensitive strains, being in general multi-resistant. Discussion: These results highlight the role of pets as reservoirs of bacterial resistance, and their potential impact on national public health.

Introducción: La resistencia bacteriana constituye un tema de preocupación para la salud pública mundial. Últimamente han aumentado los reportes de resistencia a antimicrobianos, incluida meticilina, en cepas de Staphylococcus coagulasa positiva (SCP) aisladas desde mascotas. Sin embargo, en Chile esta información es escasa. Objetivos: Determinar el perfil de susceptibilidad antimicrobiana y detectar el gen mecA en cepas de SCP aisladas desde gatos en Chile. Materiales y Métodos: Se obtuvieron 134 muestras desde gatos sanos y con lesiones dermatológicas. Las cepas fueron caracterizadas en su producción de coagulasa e identificadas mediante kit BBL Crystal. La susceptibilidad antimicrobiana se determinó mediante el método de Kirby Bauer ante 12 antimicrobianos, incluida oxacilina. Todas las cepas fueron sometidas a RPC para la detección del gen mecA. Resultados: 72 cepas de SCP fueron aisladas, incluyendo S. aureus y S. intermedius. Se detectó resistencia antimicrobiana a al menos un antimicrobiano en cepas de gatos sanos (75%) y de gatos con lesiones cutáneas (87,5%). El gen mecA fue detectado en ocho cepas resistentes a meticilina y en tres cepas sensibles, siendo en general multi-resistentes. Discusión: Estos resultados destacan el rol de las mascotas como reservorios de resistencia bacteriana y su potencial impacto en la salud pública.

High prevalence of vitamin D deficiency in women with breast cancer: The first Chilean study.

BACKGROUND: Breast cancer (BC) is the leading cause of female death from malignancy worldwide. One factor that has been associated to a higher incidence and poor prognosis is a Vitamin D deficiency (measured as 25-Hydroxi-Vitamin D (25OHD)). Our aim was to determine 25OHD levels in serum samples of Chilean BC patients before endocrine therapy and its association to clinical parameters at the time of diagnosis. METHODS: We analyzed clinical records of 105 women, evaluated at the Cancer Center of the Pontificia Universidad Católica de Chile. Serum levels of 25OHD were determined using a chemiluminescent microparticle immunoassay. RESULTS: The prevalence of vitamin D deficiency before endocrine therapy was of 70.5%. Only 7% of our patients showed sufficient vitamin D levels at the beginning of the endocrine treatment. There was a significant correlation found between age and 25OHD levels, and also between body fat percentage and 25OHD levels (r(2) = 0.04; p = 0.021; r(2) = 0.028; p = 0.0432, respectively). Summer 25OHD levels were significantly higher than winter levels (p = 0.0322). CONCLUSION: Vitamin D deficiency is highly prevalent in Chilean BC women before endocrine therapy and 25OHD levels are inversely correlated to the age and body fat percentage of patients. Further studies are needed to determine causal relationship between vitamin D levels and BC development and outcome.

Clinico-Pathologic Subtypes of Breast Cancer Primary Tumors Are Related to Prognosis after Recurrence

Background: Pathological factors, based mainly on immunohistochemistry (IHC) and histological differentiation, are mostly used to differentiate breast cancer (BC) subtypes. Our present aim was to describe the characteristics and survival of a relapsing BC patient cohort based on clinico-pathologic subtypes determined for the primary tumors. Methods: We used a clinico- pathological definition of BC subtypes based on histological grade (HG), estrogen receptor (ER), progesterone receptor (PgR),and epidermal growth factor receptor type 2 (HER2) expression assessed by IHC. We determined variables associated with loco-regional recurrence (LRR), second primaries (SP), systemic recurrence (SR) and post-recurrence survival (PRS). Results: Out of 1,702 patients, 240 (14%) had an event defined as recurrence. Those with recurrent disease were significantly younger than those without,and were initially diagnosed at more advanced stages, with larger tumors, greater lymph nodal involvement and higher HG. With a median follow up of 61 months (1-250), 4.6% of patients without recurrence and 56.6% of patients with an event defined as recurrence had died. The median PRS for the LRR group was 77 months; 75 months for those who developed a SP and 22 months for patients with an SR (p <0.0001). In SR cases, the median PRS was shorter for ER- tumors than for ER+ tumors (15 vs. 26 months, respectively; p = 0.0019, HR 0.44; CI: 0.25-0.44). Conclusions: Subtype, defined through classic histopathologic parameters determined for primary tumors, was found to eb related to type of recurrence and also to prognosis after relapse.

Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia.

INTRODUCTION: Preeclampsia is a maternal hypertensive disorder with uncertain etiology and a leading cause of maternal and fetal mortality worldwide, causing nearly 40% of premature births delivered before 35 weeks of gestation. The first stage of preeclampsia is characterized by reduction of utero-placental blood flow which is reflected in high blood pressure and proteinuria during the second half of pregnancy. In human placenta androgens derived from the maternal and fetal adrenal glands are converted into estrogens by the enzymatic action of placental aromatase. This implies that alterations in placental steroidogenesis and, subsequently, in the functionality or bioavailability of placental aromatase may be mechanistically involved in the pathophysiology of PE. METHODS: Serum samples were collected at 32-36 weeks of gestation and placenta biopsies were collected at time of delivery from PE patients (n = 16) and pregnant controls (n = 32). The effect of oxygen tension on placental cells was assessed by incubation JEG-3 cells under 1% and 8% O2 for different time periods, Timed-mated, pregnant New Zealand white rabbits (n = 6) were used to establish an in vivo model of placental ischemia (achieved by ligature of uteroplacental vessels). Aromatase content and estrogens and androgens concentrations were measured. RESULTS: The protein and mRNA content of placental aromatase significantly diminished in placentae obtained from preeclamptic patients compared to controls. Similarly, the circulating concentrations of 17-ß-estradiol/testosterone and estrone/androstenedione were reduced in preeclamptic patients vs. controls. These data are consistent with a concomitant decrease in aromatase activity. Aromatase content was reduced in response to low oxygen tension in the choriocarcinoma JEG-3 cell line and in rabbit placentae in response to partial ligation of uterine spiral arteries, suggesting that reduced placental aromatase activity in preeclamptic patients may be associated with chronic placental ischemia and hypoxia later in gestation. CONCLUSIONS: Placental aromatase expression and functionality are diminished in pregnancies complicated by preeclampsia in comparison with healthy pregnant controls.

Applying SWATH Mass Spectrometry to Investigate Human Cervicovaginal Fluid During the Menstrual Cycle.

Inherent interindividual and intraindividual variation in the length of the menstrual cycle limits the accuracy of predicting days of peak fertility. To improve detection of days of peak fertility, a more detailed understanding of longitudinal changes in cervicovaginal fluid (CVF) biomarkers during the normal menstrual cycle is needed. The aim of this study, therefore, was to characterize longitudinal changes in CVF proteins during the menstrual cycle using a quantitative, data-independent acquisition mass spectrometry approach. Six serial samples were collected from women (n = 10) during the menstrual cycle. Samples were obtained at two time points for each phase of the cycle: early and late preovulatory, ovulatory, and postovulatory. Information-dependent acquisition (IDA) of mass spectra from all individual CVF samples was initially performed and identified 278 total proteins. Samples were then pooled by time of collection (n = 6 pools) and analyzed using IDA and information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]). The IDA library generated contained 176 statistically significant protein identifications (P < 0.000158). The variation in the relative abundance of CVF proteins across the menstrual cycle was established by comparison with the SWATH profile against the IDA library. Using time-series, pooled samples obtained from 10 women, quantitative data were obtained by SWATH analysis for 43 CVF proteins. Of these proteins, 28 displayed significant variation in relative abundance during the menstrual cycle (assessed by ANOVA). Statistical significant changes in the relative expression of CVF proteins during preovulatory, ovulatory, and postovulatory phases of menstrual cycle were identified. The data obtained may be of utility not only in elucidating underlying physiological mechanisms but also as clinically useful biomarkers of fertility status.

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.

During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.

Innate immune system and preeclampsia.

Normal pregnancy is considered as a Th2 type immunological state that favors an immune-tolerance environment in order to prevent fetal rejection. Preeclampsia (PE) has been classically described as a Th1/Th2 imbalance; however, the Th1/Th2 paradigm has proven insufficient to fully explain the functional and molecular changes observed during normal/pathological pregnancies. Recent studies have expanded the Th1/Th2 into a Th1/Th2/Th17 and regulatory T-cells paradigm and where dendritic cells could have a crucial role. Recently, some evidence has emerged supporting the idea that mesenchymal stem cells might be part of the feto-maternal tolerance environment. This review will discuss the involvement of the innate immune system in the establishment of a physiological environment that favors pregnancy and possible alterations related to the development of PE.

Preterm labour: association between labour physiology, tocolysis and prevention.

INTRODUCTION: In developed countries, preterm birth is the major cause of perinatal morbidity, mortality and the most important public health problem in the obstetric field. In the past decades, an increasing trend has been observed regardless of the great efforts focussed on the improvement of our understanding of the physiopathological mechanisms behind preterm labour (PTL) and the improvement in the use of tocolytic drugs. AREAS COVERED: In this review, the authors focus on some points of the physiopathology of labour in order to understand the rationality behind the different management approaches developed for the PTL syndrome. EXPERT OPINION: There is a need to develop new tools for the treatment of patients with PTL. Research focussed on improving tocolysis, the physiology of labour and pathological processes involved in PTL would afford new approaches for the treatment of PTL, allowing clinicians to provide integrative solutions for this multifactorial disease. Recently, the prophylactic use of progesterone pessary and cerclage in women with high risk of premature labour has been reported to reduce the incidence of premature births and improve neonatal outcomes. These results highlight the importance of prediction models in order to establish preventative strategies early in pregnancy.

Levels of key enzymes of methionine-homocysteine metabolism in preeclampsia.

OBJECTIVE: To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE). METHODS: Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. RESULTS: RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. CONCLUSION: The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease.