Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Pre-gestational vs gestational exposure to maternal obesity differentially programs the offspring in mice.

AIMS/HYPOTHESIS: Maternal obesity is associated with an increased risk of obesity and impaired glucose homeostasis in offspring. However, it is not known whether a gestational or pre-gestational exposure confers similar risks, and if so, what the underlying mechanisms are. METHODS: We used reciprocal two-cell embryo transfers between mice fed either a control or high-fat diet (HFD) starting at the time of weaning. Gene expression in placenta was assessed by microarray analyses. RESULTS: A pre-gestational exposure to a maternal HFD (HFD/control) impaired fetal and placental growth despite a normal gestational milieu. Expression of imprinted genes and genes regulating vasculogenesis and lipid metabolism was markedly altered in placenta of HFD/control. An exposure to an HFD (control/HFD) only during gestation also resulted in fetal growth restriction and decreased placental weight. Interestingly, only a gestational exposure to an HFD (control/HFD) resulted in obesity and impaired glucose tolerance in adulthood. CONCLUSIONS/INTERPRETATION: An HFD during pregnancy has profound consequences for the offspring later in life. Our data demonstrate that the mechanism underlying this phenomenon is not related to placental dysfunction, intrauterine growth restriction or postnatal weight gain, but rather an inability of the progeny to adapt to the abnormal gestational milieu of an HFD. Thus, the ability to adapt to an adverse intrauterine environment is conferred prior to pregnancy and it is possible that the effects of a maternal HFD may be transmitted to subsequent generations.

Obesity at conception programs the opioid system in the offspring brain.

Maternal obesity during pregnancy increases the risk for offspring obesity, in part through effects on the developing brain. Previous research has shown that perinatal consumption of highly palatable foods by the mother can influence the development of offspring taste preferences and alter gene expression within the central nervous system (CNS) reward system. Opioids stimulate consumption of both fats and carbohydrates, and overconsumption of these energy dense foods increases the risk for obesity. What has remained unclear is whether this risk can be transmitted to the offspring before gestation or if it is wholly the gestational exposure that affects offspring brain development. Utilizing an embryo transfer experimental design, 2-cell embryos were obtained from obese or control dams, and transferred to obese or control gestational carriers. Expression of the mu-opioid receptor (MOR), preproenkephalin (PENK), and the dopamine transporter was evaluated in the hypothalamus and reward circuitry (ventral tegmental area, prefrontal cortex, and nucleus accumbens) in adult and late embryonic brains. Obesity before pregnancy altered expression levels of both MOR and PENK, with males relatively more affected than females. These data are the first to demonstrate that obesity at conception, in addition to during gestation, can program the brain reward system.

Does intracytoplasmic sperm injection improve the fertilization rate and decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and meta-analysis.

OBJECTIVE: To determine if intracytoplasmic sperm injection (ICSI), compared with conventional insemination, improves fertilization rates and prevents total failed fertilization (TFF) in couples with unexplained infertility. DESIGN: Systematic review and meta-analysis. SETTING: IVF centers. PATIENT(S): Couples with well-defined unexplained infertility undergoing IVF. INTERVENTION(S): A systematic review was performed by searching Medline and Embase for 1992-2012. Studies in which sibling oocytes were randomly split between conventional insemination and ICSI were included. A random effects model was utilized for the meta-analysis. Meta-analysis of Observational Studies in Epidemiology guidelines were applied. MAIN OUTCOME MEASURE(S): Fertilization rate and TFF rate by insemination method. RESULT(S): Eleven studies with a total of 901 couples (female age range 30-35 years) with 11,767 sibling oocytes were included in the meta-analysis. The pooled relative risk (RR) of a mature oocyte fertilizing was higher with ICSI than with conventional insemination (RR 1.49, 95% confidence interval [CI] 1.35-1.65.) The pooled RR of fertilization per allocated oocyte (before randomization) was higher with ICSI than with conventional insemination (RR 1.27, 95% CI 1.02-1.58; n = 5 studies.) The pooled RR of TFF was significantly higher with conventional insemination than with ICSI (RR 8.22, 95% CI 4.44-15.23). The number of subjects needed to treat with ICSI to prevent one case of TFF was five. CONCLUSION(S): This meta-analysis favors the use of ICSI to increase fertilization rates and decrease the risk of TFF in couples with well-defined unexplained infertility. Further studies are needed to determine the impact on clinical pregnancy and live birth rate.

Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling.

An abnormally decreased placental weight has been linked to increased perinatal complications, including intrauterine fetal demise (IUFD) and fetal growth restriction (IUGR). Despite its promise, determining placental weight prenatally using three-dimensional systems is time-consuming and requires expensive technology and expertise. We propose a novel method using two-dimensional sonography that provides an immediate estimation of placental volume. Placental volume was calculated in 29 third-trimester pregnancies using linear measurements of placental width, height, and thickness to calculate the convex-concave shell volume within 24 hours of birth. Data were analyzed to calculate Spearman's rho (r (s)) and significance. There was a significant correlation between estimated placental volume (EPV) and actual placental weight (r (s) = 0.80, P < 0.001). Subgroup analysis of preterm gestations ( N = 14) revealed an even more significant correlation of EPV to actual placental weight (r (s) = 0.89, P < 0.001). Placental weight can be accurately predicted by two-dimensional ultrasound with volumetric calculations. This method is simple, rapid, and accurate, making it practical for routine prenatal care, as well as for high-risk cases with decreased fetal movement and IUGR. Routine EPV surveillance may decrease the rates of perinatal complications and unexpected IUFD.

Aromatase inhibitor for treatment of a recurrent abdominal wall endometrioma in a postmenopausal woman.

OBJECTIVE: Treat an abdominal wall endometrioma in a post-menopausal patient. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): A post-menopausal women with a large recurrent abdominal wall endometrioma. INTERVENTION(S): The patient was managed with the combination of an aromatase inhibitor, a progestin, and serial cyst aspiration. MAIN OUTCOME MEASURE(S): Serum and cyst estradiol levels as well as sonographic demonstration of resolution. RESULT(S): Serum and cyst estradiol levels were significantly diminished and the cyst diminished in size. CONCLUSION(S): Taken together, this case demonstrates a novel approach for managing and monitoring medical therapy for unusual clinical presentations of endometriosis. Furthermore, it illustrates that endometriotic implants can be a source of circulating estrogen in postmenopausal women, and that this source of estrogen is generated by increased aromatase activity.

Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia.

OBJECTIVE: The cause of preeclampsia remains unknown and the diagnosis can be uncertain. We used proteomic-based analysis of urine to improve disease classification and extend the pathophysiologic understanding of preeclampsia. STUDY DESIGN: Urine samples from 284 women were analyzed by surface-enhanced laser desorption/ionization. In the exploratory phase, 59 samples were used to extract the proteomic fingerprint characteristic of severe preeclampsia requiring mandated delivery and to develop a diagnostic algorithm. In the challenge phase, we sought to prospectively validate the algorithm in 225 women screened for a variety of high- and low-risk conditions, including preeclampsia. Of these, 19 women were followed longitudinally throughout pregnancy. The presence of biomarkers was interpreted relative to clinical classification, need for delivery, and other urine laboratory measures (ratios of protein to creatinine and soluble fms-like tyrosine kinase-1 to placental growth factor). In the translational phase, biomarker identification by tandem mass spectrometry and validation experiments in urine, serum, and placenta were used to identify, quantify, and localize the biomarkers or related proteins. RESULTS: We report that women with preeclampsia appear to present a unique urine proteomic fingerprint that predicts preeclampsia in need of mandated delivery with highest accuracy. This characteristic proteomic profile also has the ability to distinguish preeclampsia from other hypertensive or proteinuric disorders in pregnancy. Pregnant women followed longitudinally who developed preeclampsia displayed abnormal urinary profiles more than 10 weeks before clinical manifestation. Tandem mass spectrometry and de novo sequencing identified the biomarkers as nonrandom cleavage products of SERPINA1 and albumin. Of these, the 21 amino acid C-terminus fragment of SERPINA1 was highly associated with severe forms of preeclampsia requiring early delivery. In preeclampsia, increased and aberrant SERPINA1 immunoreactivity was found in urine, serum, and placenta, in which it localized predominantly to placental villi and placental vascular spaces adherent to the endothelium. In addition, significant perivascular deposits of misfolded SERPINA1 aggregates were exclusively identified in preeclamptic placentae. CONCLUSION: Proteomics-based characterization of urine in preeclampsia identified a proteomic fingerprint composed of SERPINA1 and albumin fragments, which can accurately diagnose preeclampsia and shows promise to discriminate it from other hypertensive proteinuric diseases. These findings provide insight into a novel pathophysiological mechanism of preeclampsia related to SERPINA1 misfolding, which may offer new therapeutic opportunities in the future.

Different isoforms of the C. elegans FGF receptor are required for attraction and repulsion of the migrating sex myoblasts.

The Caenorhabditis elegans FGF receptor, EGL-15, is alternatively-spliced to yield two major isoforms that differ in their extracellular domains. The EGL-15(5A) isoform is necessary for the gonadal chemoattraction of the migrating sex myoblasts (SMs), while the EGL-15(5B) isoform is required for viability. Here we show that 5A is predominantly expressed in the M lineage, which gives rise to the migrating SMs and their sex muscle descendants, while 5B is predominantly expressed in the hypodermis. Tissue-specific expression, however, explains only part of the functional differences between these two receptor isoforms. 5A can carry out the reciprocal essential function of 5B when expressed in the hypodermis, but 5B is incapable of carrying out SM chemoattraction. Our data, therefore, indicate that the structural differences in these two isoforms contribute to their functional differences. Two lines of evidence indicate that the 5B isoform also plays a role in SM migration, implicating it in the repulsion that is observed when the chemoattraction is compromised. Thus, structural differences in the extracellular domains of these two isoforms can specify either attraction to or repulsion from the gonad.

Stem cells and the pathogenesis of endometriosis.

Endometriosis is a common gynecological disorder that is defined by the presence of endometrial tissue outside the uterine cavity. This disease often results in extensive morbidity, including chronic pelvic pain and infertility. The pathogenesis of endometriosis is likely multifactorial, and extensive investigation has explored the role of genetics, environmental factors, and the immune system in predisposing patients to developing endometriosis. A series of recent publications have described the identification of endometrial stem/progenitor cells. Such cells have long been speculated to function in the cyclic regeneration of the endometrium during the menstrual cycle and in the pathogenesis of several gynecological disorders. This narrative review will (i) examine the evidence for endometrial stem cells, (ii) examine their potential role in the pathogenesis of endometriosis, and (iii) identify important unanswered questions with suggestions for future investigation.

FGF and PI3 kinase signaling pathways antagonistically modulate sex muscle differentiation in C. elegans.

Myogenesis in vertebrate myocytes is promoted by activation of the phosphatidyl-inositol 3'-kinase (PI3 kinase) pathway and inhibited by fibroblast growth factor (FGF) signaling. We show that hyperactivation of the Caenorhabditis elegans FGF receptor, EGL-15, similarly inhibits the differentiation of the hermaphrodite sex muscles. Activation of the PI3 kinase signaling pathway can partially suppress this differentiation defect, mimicking the antagonistic relationship between these two pathways known to influence vertebrate myogenesis. When ectopically expressed in body wall muscle precursor cells, hyperactivated EGL-15 can also interfere with the proper development of the body wall musculature. Hyperactivation of EGL-15 has also revealed additional effects on a number of fundamental processes within the postembryonic muscle lineage, such as cell division polarity. These studies provide important in vivo insights into the contribution of FGF signaling events to myogenesis.