Uterine peristalsis-induced stresses within the uterine wall may sprout adenomyosis

Adenomyosis is a disease in which ectopic endometrial glands and stromal cells appear in the uterine myometrium. This pathology is common among women of reproductive age, and in addition to chronic pelvic pain and heavy periods it may also cause infertility. The ‘tissue injury and repair’ mechanism in response to increased intrauterine pressures was proposed as the etiology for migration of fragments of basal endometrium into the myometrial wall. In order to investigate this mechanism, a conceptual two-dimensional model of the uterine wall subjected to intrauterine pressures was implemented using ADINA commercial software. The stress field within the uterine wall was examined for a variety of intrauterine sinusoidal pressure waves with varying frequencies. The results revealed that: (1) as the wavelength of the subjected pressure wave decreased, high concentration of stresses developed near the inner uterine cavity; (2) as the pressure wave frequency increased, high gradients of the stresses were obtained; (3) at menstrual phase, the highest stresses obtained at the endometrial–myometrial interface. Therefore, increased uterine activity results in high stresses which may lead to tissue lesions and detachment of endometrial cells.     

Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats

Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.     

ROS Production via P2Y1-PKC-NOX2 Is Triggered by Extracellular ATP after Electrical Stimulation of Skeletal Muscle Cells

During exercise, skeletal muscle produces reactive oxygen species (ROS) via NADPH oxidase (NOX2) while inducing cellular adaptations associated with contractile activity. The signals involved in this mechanism are still a matter of study. ATP is released from skeletal muscle during electrical stimulation and can autocrinely signal through purinergic receptors; we searched for an influence of this signal in ROS production. The aim of this work was to characterize ROS production induced by electrical stimulation and extracellular ATP. ROS production was measured using two alternative probes; chloromethyl-2,7- dichlorodihydrofluorescein diacetate or electroporation to express the hydrogen peroxide-sensitive protein Hyper. Electrical stimulation (ES) triggered a transient ROS increase in muscle fibers which was mimicked by extracellular ATP and was prevented by both carbenoxolone and suramin; antagonists of pannexin channel and purinergic receptors respectively. In addition, transient ROS increase was prevented by apyrase, an ecto-nucleotidase. MRS2365, a P2Y₁ receptor agonist, induced a large signal while UTPyS (P2Y₂ agonist) elicited a much smaller signal, similar to the one seen when using ATP plus MRS2179, an antagonist of P2Y₁. Protein kinase C (PKC) inhibitors also blocked ES-induced ROS production. Our results indicate that physiological levels of electrical stimulation induce ROS production in skeletal muscle cells through release of extracellular ATP and activation of P2Y1 receptors. Use of selective NOX2 and PKC inhibitors suggests that ROS production induced by ES or extracellular ATP is mediated by NOX2 activated by PKC.     

Post-Operative Plasma Osteopontin Predicts Distant Metastasis in Human Colorectal Cancer

BackgroundThe overall prognosis of colorectal cancer (CRC) patients is unsatisfactory due to cancer metastasis after operation. This study aims to investigate the clinical significance of plasma osteopontin (OPN) levels as minimally invasive, predictive, and surrogate biomarkers for prognosis of CRC patients.MethodsThis randomized study design consists of pre-operative and post-operative plasma samples from a total of 79 patients. We determined plasma levels of OPN by ELISA and examined their correlation with the clinicopathological parameters of CRC patients. The effects of endogenous and exogenous OPN on CRC metastasis were investigated by examination of the effect on regulators of epithelial to messenchymal transition and migration assay.ResultsOur findings demonstrated for the first time the clinical correlation of plasma OPN with metastasis of CRC patients. High post-operative plasma OPN level (>153.02 ng/ml) associated with development of metastasis after curative resection (p<0.001). Moreover, post-operative plasma OPN level correlated with disease-free survival of CRC patients (p=0.009) and was an independent factor for predicting development of metastasis in CRC patients after curative resection (p=0.036). Our in vitro model showed that OPN ectopic expression induced DLD1 cell migration through Snail and Twist1 overexpression and E-cadherin repression, and secretory OPN level enhanced cell migration.ConclusionsThe results of the current study suggest that post-operative plasma OPN correlated with post-operative metastasis, suggesting that it is a potential non-invasive biomarker for the development of future metastasis in CRC patients. In addition, OPN was shown to be involved in the metastatic process and thus inhibition of OPN is a potential therapeutic approach to treat CRC patients.     

Neurite growth acceleration of adult Dorsal Root Ganglion neurons illuminated by low‐level Light Emitting Diode light at 645 nm

The effect of a 645 nm Light Emitting Diode (LED) light irradiation on the neurite growth velocity of adult Dorsal Root Ganglion (DRG) neurons with peripheral axon injury 4–10 days before plating and without previous injury was investigated. The real amount of light reaching the neurons was calculated by taking into account the optical characteristics of the light source and of media in the light path. The knowledge of these parameters is essential to be able to compare results of the literature and a way to reduce inconsistencies. We found that 4 min irradiation of a mean irradiance of 11.3 mW/cm² (corresponding to an actual irradiance reaching the neurons of 83 mW/cm²) induced a 1.6‐fold neurite growth acceleration on non‐injured neurons and on axotomized neurons. Although the axotomized neurons were naturally already in a rapid regeneration process, an enhancement was found to occur while irradiating with the LED light, which may be promising for therapy applications.

Dorsal Root Ganglion neurons ( A ) without previous injury and ( B ) subjected to a conditioning injury.     

Maternal Serum Meteorin Levels and the Risk of Preeclampsia

Background

Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker.

Methods and Findings

Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included.

Conclusions

The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia.     

Inequality as a Powerful Predictor of Infant and Maternal Mortality around the World

Background

Maternal and infant mortality are highly devastating, yet, in many cases, preventable events for a community. The human development of a country is a strong predictor of maternal and infant mortality, reflecting the importance of socioeconomic factors in determinants of health. Previous research has shown that the Human Development Index (HDI) predicts infant mortality rate (IMR) and the maternal mortality ratio (MMR). Inequality has also been shown to be associated with worse health in certain populations. The main purpose of the present study was to determine the correlation and predictive power of the Inequality Adjusted Human Development Index (IHDI) as a measure of inequality with the Infant Mortality Rate (IMR), Maternal Mortality Rate (MMR), Early Neonatal Mortality Rate (ENMR), Late Neonatal Mortality Rate (LNMR), and the Post Neonatal Mortality Rate (PNMR).

Methods and Findings

Data for the present study were downloaded from two sources: infant and maternal mortality data were downloaded from the Global Burden of Disease 2013 Cause of Death Database and the Human Development Index (HDI) and Inequality-Adjusted Human Development Index (IHDI) data were downloaded from the United Nations Development Program (UNDP). Pearson correlation coefficients were estimated, following logarithmic transformations to the data, to examine the relationship between HDI and IHDI with MMR, IMR, ENMR, LNMR, and PNMR. Steiger’s Z test for the equality of two dependent correlations was utilized in order to determine whether the HDI or IHDI was more strongly associated with the outcome variables. Lastly, we constructed OLS regression models in order to determine the predictive power of the HDI and IHDI in terms of the MMR, IMR, ENMR, LNMR, and PNMR.Maternal and infant mortality were both strongly and negatively correlated with both HDI and IHDI; however, Steiger’s Z test for the equality of two dependent correlations revealed that IHDI was more strongly correlated than HDI with MMR (Z = 4.897, p < 0.001), IMR (Z = 2.524, p = 0.012), ENMR (Z = 2.936, p = 0.003), LNMR (Z = 2.272, p = 0.023), and PNMR (Z = 2.277, p = 0.023). Furthermore, side-by-side OLS regression models revealed that, when IHDI was used as the predictor variable instead of HDI, the R ² value was 0.053 higher for MMR, 0.025 higher for IMR, 0.038 higher for ENMR, 0.029 higher for LNMR, and 0.026 higher for PNMR.

Conclusions

Even when both the HDI and the IHDI correlate with the infant and maternal mortality rates, the IHDI is a better predictor for these two health indicators. Therefore, these results add more evidence that inequality is playing an important role in determining the health status of various populations in the world and more efforts should be put into programs to fight inequality.     

Sleep/Wake Dynamics Changes during Maturation in Rats

Objectives

Conventional scoring of sleep provides little information about the process of transitioning between vigilance states. We applied the state space technique (SST) using frequency band ratios to follow normal maturation of different sleep/wake states, velocities of movements, and transitions between states of juvenile (postnatal day 34, P34) and young adult rats (P71).

Design

24-h sleep recordings of eight P34 and nine P71 were analyzed using conventional scoring criteria and SST one week following implantation of telemetric transmitter. SST is a non-categorical approach that allows novel quantitative and unbiased examination of vigilance-states dynamics and state transitions. In this approach, behavioral changes are described in a 2-dimensional state space that is derived from spectral characteristics of the electroencephalography.

Measurements and Results

With maturation sleep intensity declines, the duration of deep slow wave sleep (DSWS) and light slow wave sleep (LSWS) decreases and increases, respectively. Vigilance state determination, as a function of frequency, is not constant; there is a substantial shift to higher ratio 1 in all vigilance states except DSWS. Deep slow wave sleep decreases in adult relative to juvenile animals at all frequencies. P71 animals have 400% more trajectories from Wake to LSWS (p = 0.005) and vice versa (p = 0.005), and 100% more micro-arousals (p = 0.021), while trajectories from LSWS to DSWS (p = 0.047) and vice versa (p = 0.033) were reduced by 60%. In both juvenile and adult animals, no significant changes were found in sleep velocity at all regions of the 2-dimensional state space plot; suggesting that maturation has a partial effect on sleep stability.

Conclusions

Here, we present novel and original evidence that SST enables visualization of vigilance-state intensity, transitions, and velocities that were not evident by traditional scoring methods. These observations provide new perspectives in sleep state dynamics and highlight the usefulness of this technique in exploring the development of sleep-wake activity.     

Responses and adaptation by Nephotettix virescens to monogenic and pyramided rice lines with Grh‐resistance genes

The green leafhopper, Nephotettix virescens (Distant) (Hemiptera: Cicadellidae), occasionally damages rice in Asia either directly, by feeding on the host phloem, or indirectly by transmitting tungro virus. We assessed the nature of resistance against the leafhopper in monogenic and pyramided near‐isogenic rice lines containing the resistance genes Grh2 and Grh4. Only the pyramided line was resistant to leafhopper damage. Leafhopper nymphs and adults had high mortality and low weight gain when feeding on the pyramided line and adults laid few eggs. In contrast, although there was some minor resistance in 45‐day‐old plants that possessed either Grh2 or Grh4 genes, the monogenic lines were generally as susceptible to the leafhopper as the recurrent parent line Taichung65 (T65). Resistance in the pyramided line was stable as the plant aged and under high nitrogen, and affected each of five Philippine leafhopper populations equally. Furthermore, in a selection study, leafhoppers failed to adapt fully to the pyramided resistant line: nymph and adult survival did improve during the first five generations of selection and attained similar levels as on T65, but egg‐laying failed to improve over 10 generations. Our preliminary results suggested that resistance was associated with physiological costs to the plants in some experiments. The results of this study demonstrate the success of pyramiding resistance genes through marker‐assisted breeding, to achieve a strong and potentially durable resistance. We discuss the utility of gene pyramiding and the development of near‐isogenic lines for leafhopper management.