Adaptive Potential of Epigenetic Switching During Adaptation to Fluctuating Environments.

Epigenetic regulation of gene expression allows for the emergence of distinct phenotypic states within the clonal population. Due to the instability of epigenetic inheritance, these phenotypes can intergenerationally switch between states in a stochastic manner. Theoretical studies of evolutionary dynamics predict that the phenotypic heterogeneity enabled by this rapid epigenetic switching between gene expression states would be favored under fluctuating environmental conditions, whereas genetic mutations, as a form of stable inheritance system, would be favored under a stable environment. To test this prediction, we engineered switcher and non-switcher yeast strains, in which the uracil biosynthesis gene URA3 is either continually expressed or switched on and off at two different rates (slow and fast switchers). Competitions between clones with an epigenetically controlled URA3 and clones without switching ability (SIR3 knockout) show that the switchers are favored in fluctuating environments. This occurs in conditions where the environments fluctuate at similar rates to the rate of switching. However, in stable environments, but also in environments with fluctuation frequency higher than the rate of switching, we observed that genetic changes dominated. Remarkably, epigenetic clones with a high, but not with a low, rate of switching can coexist with non-switchers even in a constant environment. Our study offers an experimental proof of concept that helps defining conditions of environmental fluctuation under which epigenetic switching provides an advantage.

Manifestation of an undifferentiated uterine sarcoma in a 51 years old patient and its prognosis: A case report.

INTRODUCTION: Undifferentiated uterine sarcoma is a rare histological subtype of uterine sarcoma. This study aimed to summarize the clinical and pathological presentation of this case. CASE REPORT: A 51-years-old patient was admitted to the clinic because of severe pain in the lower abdomen, and scanty bleeding from the genitals. Gynecological examination revealed an enlarged uterus. Conventional and Doppler transvaginal sonography detected a tumorously altered uterus with a maximum diameter of 20 cm a tumefaction with unclear borders and a diameter of 10 cm, with hyperechoic and hypoechoic fields within the tumefaction, presenting pathological vascularization and reduced values of the (Pulsatile index  ≤ 1) and (Resistance index  ≤ 0.40). Preoperatively, the chest, abdomen, and pelvis were examined. The patient underwent surgery and total abdominal hysterectomy with bilateral salpingo-oophorectomy, and partial omentectomy, with complete removal of the tumor. A pathohistological diagnosis, of undifferentiated uterine sarcoma, was made by excluding other types of uterine sarcomas. At the control examination after completion of chemotherapy, recurrence was ascertained. CONCLUSION: undifferentiated uterine sarcoma is an aggressive malignant tumor that in most cases shows rapid progression of the disease after complete resection of the tumor, with a poor prognosis.

The effect of continuous positive airway pressure treatment on hypertensive disorder in pregnant women with obstructive sleep apnea.

PURPOSE: Our study aimed to determine the effect of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) on the incidence and severity of hypertensive syndrome in pregnancy. METHODS: The study included women with high-risk pregnancies and the Epworth Sleepiness Scale score ≥ of 10. Polygraphic testing was done between 18 and 20 weeks. Participants were divided into three groups: pregnant women with OSA starting treatment with CPAP for 4 weeks between 24 and 28 gestational weeks, women with OSA treated conservatively, and women without OSA as the control group. Participants were followed up regularly for 4 weeks until the delivery and 1 week after for the occurrence of hypertensive syndrome and other maternal complications. RESULTS: Among the 110 women enrolled in the study, the prevalence of hypertensive syndrome in 41 pregnant women with OSA treated conservatively was 39%, 50 women with OSA treated with CPAP 26%, and 19 women in the control group 21%, p = 0.1. The group treated with CPAP when compared with the conservatively treated group had a significantly lower incidence of severe forms of hypertensive syndrome (8% vs. 24%, p = 0.02.), and after 1 month of treatment had higher night oxygen saturation (92%, vs. 87%, p = 0.003) and lower Epworth Sleepiness Scale score (respectively, 4.2 ± 2.3 vs. 9.4 ± 4.1, p < 0001). The respiratory event index was significantly associated with hypertension severity (patients with preeclampsia 9.5 ± 4.9 vs. without hypertension 6.9 ± 4.5, p = 0.04). CONCLUSION: CPAP therapy significantly reduced the incidence of severe forms of hypertensive syndrome in pregnant women with OSA.

Effects of Metformin-Single Therapy on the Level of Inflammatory Markers in Serum of Non-Obese T2DM Patients with NAFLD.

BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. METHODS: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests), serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide) and FLI/- FIB-4 were calculated. RESULTS: FLI score and ultrasound NAFLD grades were found to correlate (p<0.05). We observed a significant correlation between the levels of ferritin and C-reactive protein (CRP) (p<0.05), and the FLI (p<0.05). Body weight (BW) (p<0.05), waist circumference (WC) (p<0.05), the levels of HbA1c (p<0.05), transferrin (p<0.05), insulin (p<0.05), and FLI score (p<0.05) significantly differed between groups as defined by the severity of NAFLD. CONCLUSION: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.

Empirical evidence for epigenetic inheritance driving evolutionary adaptation.

The cellular machinery that regulates gene expression can be self-propagated across cell division cycles and even generations. This renders gene expression states and their associated phenotypes heritable, independently of genetic changes. These phenotypic states, in turn, can be subject to selection and may influence evolutionary adaptation. In this review, we will discuss the molecular basis of epigenetic inheritance, the extent of its transmission and mechanisms of evolutionary adaptation. The current work shows that heritable gene expression can facilitate the process of adaptation through the increase of survival in a novel environment and by enlarging the size of beneficial mutational targets. Moreover, epigenetic control of gene expression enables stochastic switching between different phenotypes in populations that can potentially facilitate adaptation in rapidly fluctuating environments. Ecological studies of the variation of epigenetic markers (e.g. DNA methylation patterns) in wild populations show a potential contribution of this mode of inheritance to local adaptation in nature. However, the extent of the adaptive contribution of the naturally occurring variation in epi-alleles compared to genetic variation remains unclear. This article is part of the theme issue 'How does epigenetics influence the course of evolution?'

Epigenetic gene silencing alters the mechanisms and rate of evolutionary adaptation.

Epigenetic, non-DNA sequence-based inheritance can potentially contribute to adaptation but, due to its transient nature and the difficulty involved in uncoupling it from genetic variation, it is unclear whether it has any effect on long-term evolution. However, short-term epigenetic inheritance may interact with genetic change by modifying the rate and type of adaptive mutations. Here, we test this notion in an experimental evolution set-up in yeast. We tune low, intermediate and high levels of heritable silencing of a URA3 reporter under selection by insertion at different positions within silent subtelomeric chromatin in otherwise isogenic Saccharomyces cerevisiae. Heritable silencing does not impact mutation rate but drives population size expansion and rapid epigenetic adaptation. This eventually leads to genetic assimilation of the silent phenotype by mutations that reduce or abolish URA3 expression. Moreover, at intermediate or low levels of heritable silencing we find that populations evolve more rapidly by accumulation of adaptive mutations, in part through acquisition of novel alleles that enhance gene silencing, aiding accelerated adaptation. We provide an experimental proof of concept that defines the impact and mechanisms of how short-term epigenetic inheritance can shape adaptive evolution.

[Effect of hysteroscopic examination on the outcome of in vitro fertilization].

BACKGROUND/AIM: Implantation failure after embryo transfer is one of the main problems of in vitro fertilization (IVF) and intrauterine pathologies can lead to unsuccessful outcome. The aim of this study was to determine if hysteroscopic examination of uterine cavity and consequent treatment of intrauterine lesions prior to IVF could improve the pregnancy rate in women under 38. METHODS: This study included 480 patients under 38, who had undergone IVF or IVF\ICSI--embryo transfer cycles, in which one or more good quality embryos were transferred. By transvaginal sonography performed within the past 2 months, the uterus was found normal in all the patients enrolled in our IVF unit. The patients were divided into three groups: group A--with no hysteroscopic evaluation and no pathology, group B --with hysteroscopy but no pathology, and group C--with abnormal hysteroscopy finding and corresponding treatment. RESULTS: The obtained results revaled no difference in the mean age, duration of infertility, number of mature oocytes in either group (p > 0.05). Clinical pregnancy rates in the groups A, B and C were 36.9%, 58.75% and 32.7%, respectively, and delivery rates were 27.5%, 48.7% and 25.7%, respectively. There was a statistically significant difference among the groups concerning pregnancy and delivery rates. CONCLUSION: Considering the results of this study we could conclude that hysteroscopy, as a routine examination, should be performed before the first IVF-ET cycle in all patients thereby reducing the failures and then the costs of IVF-ET.

[Course and outcome of adolescent deliveries--a comparative analysis for 1992 and 2002].

INTRODUCTION: Adolescent pregnancy is considered to be risky, with potential psychosocial and health risks. From a medical point of view, adolescent pregnancy and delivery are risky and mortality of mothers and newborns is higher than in women aged 20-30. MATERIAL AND METHODS: The analysis included all adolescent deliveries at the Department of Gynecology and Obstetrics in Novi Sad in 1992 and 2002. These data were compared with those observed in women aged 19 and older, for the same years. RESULTS: In respect to the number of adolescent deliveries, a decreasing tendency is observed. Also, there is an increasing trend in the number of cesarean sections in adolescents, which follows the trend of higher rates of cesarean deliveries in general. Episiotomy is more often performed in adolescents than in older women, but a decreasing trend is also observed in this population, which was also the case in women over 19. Vacuum extraction is less frequent in cases of adolescent deliveries. A very small percentage of malformed and stillborn newborns is registered in adolescents, whereas the percentage of premature births is similar in both groups. CONCLUSION: Although adolescent pregnancy and delivery are risky, good obstetrical care and efficient control during delivery provide optimal conditions for successful deliveries among adolescents.