Adipose triglyceride lipase promotes prostaglandin-dependent actin remodeling by regulating substrate release from lipid droplets.

Lipid droplets (LDs), crucial regulators of lipid metabolism, accumulate during oocyte development. However, their roles in fertility remain largely unknown. During Drosophila oogenesis, LD accumulation coincides with the actin remodeling necessary for follicle development. Loss of the LD-associated Adipose Triglyceride Lipase (ATGL) disrupts both actin bundle formation and cortical actin integrity, an unusual phenotype also seen when the prostaglandin (PG) synthase Pxt is missing. Dominant genetic interactions and PG treatment of follicles indicate that ATGL acts upstream of Pxt to regulate actin remodeling. Our data suggest that ATGL releases arachidonic acid (AA) from LDs to serve as the substrate for PG synthesis. Lipidomic analysis detects AA-containing triglycerides in ovaries, and these are increased when ATGL is lost. High levels of exogenous AA block follicle development; this is enhanced by impairing LD formation and suppressed by reducing ATGL. Together, these data support the model that AA stored in LD triglycerides is released by ATGL to drive the production of PGs, which promote the actin remodeling necessary for follicle development. We speculate that this pathway is conserved across organisms to regulate oocyte development and promote fertility.

Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones.

Because both dearth and overabundance of histones result in cellular defects, histone synthesis and demand are typically tightly coupled. In Drosophila embryos, histones H2B, H2A and H2Av accumulate on lipid droplets (LDs), which are cytoplasmic fat storage organelles. Without LD binding, maternally provided H2B, H2A and H2Av are absent; however, how LDs ensure histone storage is unclear. Using quantitative imaging, we uncover when during oogenesis these histones accumulate, and which step of accumulation is LD dependent. LDs originate in nurse cells (NCs) and are transported to the oocyte. Although H2Av accumulates on LDs in NCs, the majority of the final H2Av pool is synthesized in oocytes. LDs promote intercellular transport of the histone anchor Jabba and thus its presence in the ooplasm. Ooplasmic Jabba then prevents H2Av degradation, safeguarding the H2Av stockpile. Our findings provide insight into the mechanism for establishing histone stores during Drosophila oogenesis and shed light on the function of LDs as protein-sequestration sites.

Characterization of Streptomyces nymphaeiformis sp. nov., and its taxonomic relatedness to other polyhydroxybutyrate-degrading streptomycetes.

A polyhydroxybutyrate (PHB)-degrading actinomycete, strain SFB5AT, was identified as a species of Streptomyces based on its membrane fatty acid profile and the presence of ll-diaminopimelic acid in the cell wall. It formed sporulating mycelia on most agar media, but flat or wrinkled, moist colonies on trypticase soy agar. Spores were smooth, cylindrical, and borne on long, straight to flexuous chains. It produced a light brown diffusible pigment, but not melanin. Comparison of genomic digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) values indicated that strain SFB5AT was related to Streptomyces litmocidini JCM 4394T, Streptomyces vietnamensis GIMV4.0001T, Streptomyces nashvillensis JCM 4498T and Streptomyces tanashiensis JCM 4086T, plus 11 other species. However, the dDDH and ANI values were well below the species differentiation thresholds of <70 and <95 %, respectively; also, multilocus sequence analysis distances exceeded the species threshold of 0.007. Moreover, strain SFB5AT differed from the other species in pigmentation and its ability to catabolize arabinose. Strain SFB5AT and 11 of its 15 closest relatives degraded PHB and have genes for extracellular, short-chain-length denatured polyhydroxyalkanoate depolymerases. These enzymes from strain SFB5AT and its closest relatives had a type 1 catalytic domain structure, while those from other relatives had a type 2 structure, which differs from type one in the position of a consensus histidine in the active site. Thus, phenotypic and genotypic differences suggest that strain SFB5AT represents a new species of Streptomyces, for which we propose the name Streptomyces nymphaeiformis sp. nov. The type strain is SFB5AT (=NRRL B-65520T=DSM 112030T).

From Dynamics to Novelty: An Agent-Based Model of the Economic System.

The modern economy is both a complex self-organizing system and an innovative, evolving one. Contemporary theory, however, treats it essentially as a static equilibrium system. Here we propose a formal framework to capture its complex, evolving nature. We develop an agent-based model of an economic system in which firms interact with each other and with consumers through market transactions. Production functions are represented by a pair of von Neumann technology matrices, and firms implement production plans taking into account current price levels for their inputs and output. Prices are determined by the relation between aggregate demand and supply. In the absence of exogenous perturbations the system fluctuates around its equilibrium state. New firms are introduced when profits are above normal, and are ultimately eliminated when losses persist. The varying number of firms represents a recurrent perturbation. The system thus exhibits dynamics at two levels: the dynamics of prices and output, and the dynamics of system size. The model aims to be realistic in its fundamental structure, but is kept simple in order to be computationally efficient. The ultimate aim is to use it as a platform for modeling the structural evolution of an economic system. Currently the model includes one form of structural evolution, the ability to generate new technologies and new products.

Epidemiology of in-hospital cardiac arrest complicating non-ST-segment elevation myocardial infarction receiving early coronary angiography.

In the period between 2000 and 2014, 584,704 admissions with non-ST-segment elevation myocardial infarction that received early coronary angiography (day zero) were identified from the National Inpatient Sample. In-hospital cardiac arrest was noted in 4349 (0.8%), of which ~47% were from ventricular arrhythmias and ~90% of occurred within ≤4 days. Non-ST-segment elevation myocardial infarction admissions with in-hospital cardiac arrest had higher in-hospital mortality compared to those without (61% vs. 1.6%) with an unchanged temporal trend of in-hospital cardiac arrest rates (adjusted odds ratio 1.29 [95% confidence interval 0.73-2.28]) in 2014 compared to 2000).

Electroencephalography Predicts Poor and Good Outcomes After Cardiac Arrest: A Two-Center Study.

OBJECTIVE: The prognostic role of electroencephalography during and after targeted temperature management in postcardiac arrest patients, relatively to other predictors, is incompletely known. We assessed performances of electroencephalography during and after targeted temperature management toward good and poor outcomes, along with other recognized predictors. DESIGN: Cohort study (April 2009 to March 2016). SETTING: Two academic hospitals (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Mayo Clinic, Rochester, MN). PATIENTS: Consecutive comatose adults admitted after cardiac arrest, identified through prospective registries. INTERVENTIONS: All patients were managed with targeted temperature management, receiving prespecified standardized clinical, neurophysiologic (particularly, electroencephalography during and after targeted temperature management), and biochemical evaluations. MEASUREMENTS AND MAIN RESULTS: We assessed electroencephalography variables (reactivity, continuity, epileptiform features, and prespecified "benign" or "highly malignant" patterns based on the American Clinical Neurophysiology Society nomenclature) and other clinical, neurophysiologic (somatosensory-evoked potential), and biochemical prognosticators. Good outcome (Cerebral Performance Categories 1 and 2) and mortality predictions at 3 months were calculated. Among 357 patients, early electroencephalography reactivity and continuity and flexor or better motor reaction had greater than 70% positive predictive value for good outcome; reactivity (80.4%; 95% CI, 75.9-84.4%) and motor response (80.1%; 95% CI, 75.6-84.1%) had highest accuracy. Early benign electroencephalography heralded good outcome in 86.2% (95% CI, 79.8-91.1%). False positive rates for mortality were less than 5% for epileptiform or nonreactive early electroencephalography, nonreactive late electroencephalography, absent somatosensory-evoked potential, absent pupillary or corneal reflexes, presence of myoclonus, and neuron-specific enolase greater than 75 µg/L; accuracy was highest for early electroencephalography reactivity (86.6%; 95% CI, 82.6-90.0). Early highly malignant electroencephalography had an false positive rate of 1.5% with accuracy of 85.7% (95% CI, 81.7-89.2%). CONCLUSIONS: This study provides class III evidence that electroencephalography reactivity predicts both poor and good outcomes, and motor reaction good outcome after cardiac arrest. Electroencephalography reactivity seems to be the best discriminator between good and poor outcomes. Standardized electroencephalography interpretation seems to predict both conditions during and after targeted temperature management.

Improving Survival From Cardiac Arrest: A Review of Contemporary Practice and Challenges.

Cardiac arrest is a common and lethal condition frequently encountered by emergency medicine providers. Resuscitation of persons after cardiac arrest remains challenging, and outcomes remain poor overall. Successful resuscitation hinges on timely, high-quality cardiopulmonary resuscitation. The optimal method of providing chest compressions and ventilator support during cardiac arrest remains uncertain. Prompt and effective defibrillation of ventricular arrhythmias is one of the few effective therapies available for treatment of cardiac arrest. Despite numerous studies during several decades, no specific drug delivered during cardiac arrest has been shown to improve neurologically intact survival after cardiac arrest. Extracorporeal circulation can rescue a minority of highly selected patients with refractory cardiac arrest. Current management of pulseless electrical activity is associated with poor outcomes, but it is hoped that a more targeted diagnostic approach based on electrocardiography and bedside cardiac ultrasonography may improve survival. The evolution of postresuscitation care appears to have improved cardiac arrest outcomes in patients who are successfully resuscitated. The initial approach to early stabilization includes standard measures, such as support of pulmonary function, hemodynamic stabilization, and rapid diagnostic assessment. Coronary angiography is often indicated because of the high frequency of unstable coronary artery disease in comatose survivors of cardiac arrest and should be performed early after resuscitation. Optimizing and standardizing our current approach to cardiac arrest resuscitation and postresuscitation care will be essential for developing strategies for improving survival after cardiac arrest.

Nanomolar concentrations of the photodynamic compound TLD-1433 effectively inactivate numerous human pathogenic viruses.

The anti-viral properties of a small (≈1 kDa), novel Ru(II) photo dynamic compound (PDC), referred to as TLD-1433 (Ruvidar™), are presented. TLD-1433 had previously been demonstrated to exert strong anti-bacterial and anti-cancer properties. We evaluated the capacity of TLD-1433 to inactivate several human pathogenic viruses. TLD-1433 that was not photo-activated was capable of effectively inactivating 50 % of influenza H1N1 virus (ID50) at a concentration of 117 nM. After photo-activation, the ID50 was reduced to <10 nM. The dose of photo-activated TLD-1433 needed to reduce H1N1 infectivity >99 % (ID99) was approximately 170 nM. Similarly, the ID99 of photo-activated TLD-1433 was determined to range from about 20 to 120 nM for other tested enveloped viruses; specifically, a human coronavirus, herpes simplex virus, the poxvirus Vaccinia virus, and Zika virus. TLD-1433 also inactivated two tested non-enveloped viruses; specifically, adenovirus type 5 and mammalian orthoreovirus, but at considerably higher concentrations. Analyses of TLD-1433-treated membranes suggested that lipid peroxidation was a major contributor to enveloped virus inactivation. TLD-1433-mediated virus inactivation was temperature-dependent, with approximately 10-fold more efficient virucidal activity when viruses were treated at 37 °C than when treated at room temperature (∼22 °C). The presence of fetal bovine serum and virus solution turbidity reduced TLD-1433-mediated virucidal efficiency. Immunoblots of TLD-1433-treated human coronavirus indicated the treated spike protein remained particle-associated.

Post-cardiac arrest mortality is declining: a study of the US National Inpatient Sample 2001 to 2009.

BACKGROUND: Despite several advances in postresuscitation care over the past decade, population-based mortality rates for patients hospitalized with cardiac arrest in the United States have not been studied over this time period. The aim of this study was to determine the annual in-hospital mortality rates of patients with cardiac arrest from 2001 to 2009. METHODS AND RESULTS: The US mortality rates for hospitalized patients with cardiac arrest were determined using the 2001 to 2009 US National Inpatient Sample, a national hospital discharge database. Using the International Classification of Diseases, 9(th) Edition, code 427.5, we identified patients hospitalized in the United States with cardiac arrest from 2001 to 2009. The main outcome measure was in-hospital mortality. A total of 1 190 860 patients were hospitalized with a diagnosis of cardiac arrest in the United States from 2001 to 2009. The in-hospital mortality rate decreased each year from 69.6% in 2001 to 57.8% in 2009. In multivariable analysis, when controlling for age, sex, race, and comorbidities, earlier year was a strong independent predictor of in-hospital death. The mortality rate declined across all analyzed subgroups, including sex, age, race, and stratification by comorbidity. CONCLUSIONS: The in-hospital mortality rate of patients hospitalized with cardiac arrest in the United States decreased by 11.8% from 2001 to 2009.

Therapeutic hypothermia for out-of-hospital ventricular fibrillation survivors: a feasibility study comparing time to achieve target core temperature using conventional conductive cooling versus combined conductive plus pericranial convective cooling.

OBJECTIVE: Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurologic outcome, as well as to reduce healthcare costs in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation. Accordingly, the American Heart Association has categorized this as a Class IB intervention. The therapeutic window for initiating TH is narrow, and thus, achieving target temperature expeditiously is of paramount importance to improve postresuscitative neurologic outcome. The present investigation is a feasibility study designed to assess the practicality and efficacy of including pericranial cooling in our postresuscitative TH protocol. Specifically, we compared time required to achieve target temperature (33°C) using our present standard of TH care (ie, conductive body cooling, conventional TH group) versus combined conductive body cooling plus convective (forced-air) head and neck cooling (combined TH group). DESIGN: Adult patients who experienced OHCA were included in the study provided TH could be initiated within 4 hours of resuscitation from ventricular fibrillation. Patients enrolled in both groups were cooled using the servo-controlled Arctic Sun conductive cooling system (Medivance, Inc, Louisville, CO). However, patients enrolled in the combined TH group also received forced-air pericranial cooling with an ambient temperature of approximately 13°C. In all cases, the target core (bladder) temperature was 33°C. The primary endpoint (ie, time required to achieve a core temperature of 33°C) was analyzed as a continuous variable and compared between groups using the rank sum test, whereas categorical variables were compared between groups using the chi-square test. SETTING: Cardiac intensive care unit at a major tertiary care teaching center in Rochester, MN. PARTICIPANTS: Adult patients who experienced OHCA were included in the study. INTERVENTIONS: Patients enrolled in both groups were cooled using the servo-controlled Arctic Sun conductive cooling system (Medivance, Inc, Louisville, CO). However, patients enrolled in the combined TH group also received forced-air pericranial cooling with an ambient temperature of approximately 13°C. MEASUREMENTS: Only patients admitted after January 1, 2008, were included in the analysis (28 combined TH group patients v 55 conventional TH group patients). Demographic data were similar between groups. When compared with the conventional TH group, time to achieve 33°C was significantly shorter in the combined TH group: 207 minutes (173 and 286 min) [median (25th, 75th percentile)] v 181 minutes (63 and 247 min). The magnitude and frequency of hypothermia-mediated physiologic perturbations (eg, hypokalemia) were similar for both groups. CONCLUSIONS: Both TH cooling paradigms effectively achieved 33°C; however, the combined TH technique significantly decreased the time required to achieve the target temperature. Although not evaluated in this study, such an effect may further improve postresuscitative neurologic outcomes beyond that previously described using conventional TH. Although a positive result (ie, abbreviated time taken to achieve target temperature) was observed, we maintain guarded enthusiasm for this evolving adjunctive technique until corroborative outcome-based evidence is available.

Visualizing Lipid Droplets in Drosophila Oogenesis.

Lipid droplets (LDs) are fat storage organelles highly abundant in oocytes and eggs of many vertebrates and invertebrates. They have roles both during oogenesis and in provisioning the developing embryo. In Drosophila, large numbers of LDs are generated in nurse cells during mid-oogenesis and then transferred to oocytes. Their number and spatial distribution changes developmentally and in response to various experimental manipulations. This chapter demonstrates how to visualize LDs in Drosophila follicles, both in fixed tissues and living samples. For fixed samples, the protocol explains how to prepare female flies, dissect ovaries, isolate follicles, fix, apply stains, mount the tissue, and perform imaging. For live samples, the protocol shows how to dissect ovaries, apply a fluorescent LD dye, and culture follicles such that they remain alive and healthy during imaging. Finally, a method is provided that employs in vivo centrifugation to assess colocalization of markers with LDs.

Absence of significant myocardial injury following elective direct current cardioversion for atrial fibrillation.

Background: Direct current (DC) cardioversion is used to terminate cardiac arrhythmias. Current guidelines list cardioversion as a cause of myocardial injury. Objective: This study determined whether external DC cardioversion results in myocardial injury measured by serial changes in high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI). Methods: This was a prospective study of patients undergoing elective external DC cardioversion for atrial fibrillation. hs-cTnT and hs-cTnI were measured precardioversion and at least 6 hours postcardioversion. Myocardial injury was present when there were significant changes in both hs-cTnT and hs-cTnI. Results: Ninety-eight subjects were analyzed. Median cumulative energy delivered was 121.9 (interquartile range [IQR] 102.2-302.7) J. Multiple cases 23 (23.5%) required 300 J or more. Maximum cumulative energy delivered was 2455.1 J. There were small significant changes in both hs-cTnT (median precardioversion 12 [IQR 7-19) ng/L], median postcardioversion 13 [IQR 8-21] ng/L; P < .001) and hs-cTnI (median precardioversion 5 [IQR 3-10) ng/L], median postcardioversion 7 [IQR 3.6-11) ng/L; P < .001). Results were similar in patients with high-energy shocks and did not vary based on precardioversion values. Only 2 (2%) cases met criteria for myocardial injury. Conclusion: DC cardioversion resulted in a small but statistically significant changes in hs-cTnT and hs-cTnI in 2% of patients studied irrespective of shock energy. Patients with marked troponin elevations after elective cardioversion should be assessed for other causes of myocardial injury. It should not be assumed the myocardial injury was from the cardioversion.

The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle.

Nuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fatty-acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.

A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients with Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer.

Background: A phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design setting and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

The recommendations for electrical therapies described in this section are designed to improve survival from SCA and life-threatening arrhythmias. Whenever defibrillation is attempted, rescuers must coordinate high-quality CPR with defibrillation to minimize interruptions in chest compressions and to ensure immediate resumption of chest compressions after shock delivery. The high first-shock efficacy of newer biphasic defibrillators led to the recommendation of single shocks plus immediate CPR instead of 3-shock sequences that were recommended prior to 2005 to treat VF. Further data are needed to refine recommendations for energy levels for defibrillation and cardioversion using biphasic waveforms.

Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

The goal of therapy for bradycardia or tachycardia is to rapidly identify and treat patients who are hemodynamically unstable or symptomatic due to the arrhythmia. Drugs or, when appropriate, pacing may be used to control unstable or symptomatic bradycardia. Cardioversion or drugs or both may be used to control unstable or symptomatic tachycardia. ACLS providers should closely monitor stable patients pending expert consultation and should be prepared to aggressively treat those with evidence of decompensation.

RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes.

Nuclear receptors control the function of cells by regulating transcription from specific gene networks. The establishment and maintenance of epigenetic gene marks is fundamental to the regulation of gene transcription and the control of cell function. RIP140 is a corepressor for nuclear receptors that suppresses transcription from a broad programme of metabolic genes and thereby controls energy homoeostasis in vivo. Here we show by analysis of Ucp1, a gene which is typically expressed in brown but not white adipocytes, that RIP140 is essential for both DNA and histone methylation to maintain gene repression. RIP140 expression promotes the assembly of DNA and histone methyltransferases (HMTs) on the Ucp1 enhancer and leads to methylation of specific CpG residues and histones as judged by bisulphite genomic sequencing and chromatin immunoprecipitation assays. Our results suggest that RIP140 serves as a scaffold for both DNA and HMT activities to inhibit gene transcription by two key epigenetic repression systems.

Home use of automated external defibrillators for sudden cardiac arrest.

BACKGROUND: The most common location of out-of-hospital sudden cardiac arrest is the home, a situation in which emergency medical services are challenged to provide timely care. Consequently, home use of an automated external defibrillator (AED) might offer an opportunity to improve survival for patients at risk. METHODS: We randomly assigned 7001 patients with previous anterior-wall myocardial infarction who were not candidates for an implantable cardioverter-defibrillator to receive one of two responses to sudden cardiac arrest occurring at home: either the control response (calling emergency medical services and performing cardiopulmonary resuscitation [CPR]) or the use of an AED, followed by calling emergency medical services and performing CPR. The primary outcome was death from any cause. RESULTS: The median age of the patients was 62 years; 17% were women. The median follow-up was 37.3 months. Overall, 450 patients died: 228 of 3506 patients (6.5%) in the control group and 222 of 3495 patients (6.4%) in the AED group (hazard ratio, 0.97; 95% confidence interval, 0.81 to 1.17; P=0.77). Mortality did not differ significantly in major prespecified subgroups. Only 160 deaths (35.6%) were considered to be from sudden cardiac arrest from tachyarrhythmia. Of these deaths, 117 occurred at home; 58 at-home events were witnessed. AEDs were used in 32 patients. Of these patients, 14 received an appropriate shock, and 4 survived to hospital discharge. There were no documented inappropriate shocks. CONCLUSIONS: For survivors of anterior-wall myocardial infarction who were not candidates for implantation of a cardioverter-defibrillator, access to a home AED did not significantly improve overall survival, as compared with reliance on conventional resuscitation methods. (ClinicalTrials.gov number, NCT00047411 [ClinicalTrials.gov].).

Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function.

UNLABELLED: Pregnancy alters bile acid homeostasis and can unmask cholestatic disease in genetically predisposed but otherwise asymptomatic individuals. In this report, we show that normal pregnant mice have raised hepatic bile acid levels in the presence of procholestatic gene expression. The nuclear receptor farnesoid X receptor (FXR) regulates the transcription of the majority of these genes, and we show that both ablation and activation of Fxr prevent the accumulation of hepatic bile acids during pregnancy. These observations suggest that the function of Fxr may be perturbed during gestation. In subsequent in vitro experiments, serum from pregnant mice and humans was found to repress expression of the Fxr target gene, small heterodimer partner (Shp), in liver-derived Fao cells. Estradiol or estradiol metabolites may contribute to this effect because coincubation with the estrogen receptor (ER) antagonist fulvestrant (ICI 182780) abolished the repressive effects on Shp expression. Finally, we report that ERα interacts with FXR in an estradiol-dependent manner and represses its function in vitro. CONCLUSION: Ligand-activated ERα may inhibit FXR function during pregnancy and result in procholestatic gene expression and raised hepatic bile acid levels. We propose that this could cause intrahepatic cholestasis of pregnancy in genetically predisposed individuals.