Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.

Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p=0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.

SJL and NOD macrophages are uniquely characterized by genetically programmed, elevated expression of the IL-12(p40) gene, suggesting a conserved pathway for the induction of organ-specific autoimmunity.

Genetic susceptibility of the SJL mouse to experimental autoimmune encephalomyelitis (EAE) appears, in part, to be a result of genes that promote abnormal development of the pathogenic Type 1 (Th1) phenotype of neuroantigen-specific T-cells. Because antigen-presenting/accessory cells (APCs) produce cytokines that can modulate the development of Th1 and Th2 phenotypes, we addressed whether APCs from SJL mice were genetically programmed for elevated expression of the Th1-promoting cytokine, IL-12. Activated peritoneal macrophages (Mphi; i.e., APC) from naïve SJL mice produced levels of TNF-alpha, IL-1, IL-6, IL-10, and TGF-beta within the range of six normal strains. In contrast, SJL IL-12p40 (in addition to IL-12p70) production was consistently five- to 20-fold greater than that of any normal strain tested, which arose from elevated expression of the IL-12p40 but not the IL-12p35 gene, because p40 mRNA levels were eight- to 15-fold greater than those of normal strains. This aberrancy in IL-12p40 expression appears identical to that observed in the NOD mouse, another strain prone to organ-specific autoimmunity. A genetically programmed bias toward elevated expression of IL-12 in Mphi from the SJL and NOD strains of autoimmunity provides a conserved mechanism for the dominant Th1 development of naive, autoantigen-specific T-cells in these strains. This study is the first demonstration of a genetically programmed aberrant phenotype that is intrinsically expressed within a cell type in the SJL mouse and provides insight into its predisposition for EAE.

Phytoestrogen supplementation and endometrial cancer.

BACKGROUND: Phytoestrogens are increasingly used by patients as "natural" alternatives to hormone replacement. Attention in scientific and lay literature has focused on their potential to prevent menopausal symptoms, bone loss, heart disease, or breast cancer. Less is known about effects on the endometrium, specifically, whether prolonged exposure to phytoestrogens could promote hyperplasia or neoplasia, as does unopposed estrogen. CASE: We report the case of a woman diagnosed with grade 1 endometrioid adenocarcinoma of the endometrium whose history was notable for extensive use of supplemental phytoestrogens. CONCLUSION: The effects of phytoestrogens on endometrial tissue are not known. Given their increasing popularity and availability in concentrated form as dietary supplements, additional research is warranted before we can counsel our patients regarding the safety of such supplements.

A multicenter investigation with D-FISH BCR/ABL1 probes.

Twenty-eight laboratories evaluated a new fluorescence in situ hybridization (FISH) strategy for chronic myeloid leukemia. In a three-part study, bcr/abl1 D-FISH probes were used to study bone marrow specimens. First, laboratories familiarized themselves with the strategy by applying it to known normal and abnormal specimens. Then, collectively the laboratories studied 20 normal and 20 abnormal specimens blindly and measured workload. Finally, each laboratory and two experts studied six serial dilutions with 98-0% abnormal nuclei. Using the reported normal cutoff of < 1% abnormal nuclei, participants reported no false-negative cases and 15 false-positive cases (1-6.6% abnormal nuclei). Results provided by participants for serial dilutions approximated the expected percentages of abnormal nuclei, but those from the experts exhibited greater precision. The clinical sensitivity, precision, nomenclature, workload, recommendations for training, and quality assurance in methods using D-FISH in clinical practice are discussed.

Emergency department thrombolysis critical pathway reduces door-to-drug times in acute myocardial infarction.

BACKGROUND: Rapid time to treatment with thrombolytic therapy is an important determinant of survival in acute myocardial infarction (AMI). HYPOTHESIS: We hypothesized that establishment of an AMI thrombolysis critical pathway in the Emergency Department could successfully reduce the "door-to-drug" time, the time between patient arrival and start of thrombolysis. METHODS AND RESULTS: Before establishment of the AMI critical pathway, median door-to-drug time was 73 min, which was reduced to 37 min after critical pathway implementation (p < 0.05). The percentage of patients treated within 30 min rose from 0% prior to establishment of the pathway to 43% (p = 0.03). Similarly, the percentage treated in within 45 min rose from 0 to 67% (p = 0.0005). Door-to-drug times were longer for women than for men (median 105 min for women vs. 70 min for men before pathway implementation). The pathway reduced door-to-drug time for both genders, but the median door-to-drug times were higher for women than for men (Mann-Whitney p = 0.013). The difference between men and women was 35 min before establishment of the pathway to 10 min by the end of the study period. CONCLUSIONS: Our critical pathway was successful in reducing door-to-drug times. We observed a "gender gap" in door-to-drug times, with longer mean times for women, which was reduced by the AMI critical pathway. Thus, our data provide support for the use of critical pathways to reduce door-to-drug times, as recommended by the National Heart Attack Alert Program.

Single-transverse-spin asymmetries of identified charged hadrons in polarized pp collisions at sqrt[s]=62.4 GeV.

The first measurements of xF-dependent single-spin asymmetries of identified charged hadrons, pi+/-, K+/-, and protons, from transversely polarized proton-proton collisions at 62.4 GeV at RHIC are presented. Large asymmetries are seen in the pion and kaon channels. The asymmetries in inclusive pi+ production, AN(pi+), increase with xF from 0 to approximately 0.25 and AN(pi-) decrease from 0 to approximately -0.4. Observed asymmetries for K- unexpectedly show positive values similar to those for K+, increasing with xF, whereas proton asymmetries are consistent with zero over the measured kinematic range. Comparisons of the data with predictions of QCD-based models are presented.

Production of mesons and baryons at high rapidity and high p(T) in proton-proton collisions at square root[s] = 200 GeV.

We present particle spectra for charged hadrons pi(+/-), K(+/-), p, and p[over] from pp collisions at square root[s] = 200 GeV measured for the first time at forward rapidities (2.95 and 3.3). The kinematics of these measurements are skewed in a way that probes the small momentum fraction in one of the protons and large fractions in the other. Large proton to pion ratios are observed at values of transverse momentum that extend up to 4 GeV/c, where protons have momenta up to 35 GeV. Next-to-leading order perturbative QCD calculations describe the production of pions and kaons well at these rapidities, but fail to account for the large proton yields and small p[over]/p ratios.

End-tidal carbon dioxide monitoring during cardiopulmonary resuscitation.

The end-tidal carbon dioxide (CO2) concentration has been found to correlate with cardiac output during and after cardiopulmonary resuscitation (CPR) in animal models. We monitored end-tidal CO2 values continuously during cardiac resuscitation in 23 humans while ventilation was held constant with a computer-controlled CPR Thumper. This report focuses on ten of the 23 patients who experienced return of spontaneous circulation (ROSC) during monitoring. There was no significant difference in the end-tidal CO2 value of patients without ROSC (1.8% +/- 0.9%) and the end-tidal CO2 value of patients before ROSC in patients who had ROSC (1.7% +/- 0.6%). The end-tidal CO2 concentration increased immediately in all patients who had ROSC, from 1.7% +/- 0.6% to 4.6% +/- 1.4%, then gradually returned to a new baseline (3.1% +/- 0.9%). Change in the end-tidal CO2 value was often the first clinical indicator that ROSC had occurred. Our findings suggest that end-tidal CO2 monitoring may provide clinically useful information that can be used to guide therapy during CPR.

Methamphetamine abuse and rhabdomyolysis in the ED: a 5-year study.

Patients with methamphetamine toxicity are presenting in greater numbers each year to emergency departments (ED) in the US. These patients are frequently agitated, violent, and often require physical and chemical restraint. The incidence and risk of rhabdomyolysis in this subpopulation is unknown. We conducted a 5-year retrospective review of all ED patients who received the final diagnosis of rhabdomyolysis. Patients with toxicology screens positive for methamphetamine were identified, and demographics, laboratory results, resource utilization, disposition, and outcome were compared to the remaining patients. Of the total 367 patients identified, 166 (43%) were toxicology positive for methamphetamine. Methamphetamine patients differed significantly from nonmethamphetamine patients with regard to demographics and hospital utilization. Methamphetamine patients had significantly higher mean initial creatine phosphokinase (CK), 12,439 U/L versus 5,678 U/L (P = 0.02), and lower mean peak CK, 16,827 U/L versus 19,426 U/L (P = 0.03). The development of acute renal failure was not significantly different between the 2 groups. There were 16 total deaths in the study population, 11 from concomitant infection/sepsis. An association between methamphetamine abuse and rhabdomyolysis may exist, and CK should be measured in the ED as a screen for potential muscle injury in this subpopulation. Patients with rhabdomyolysis with an unclear cause should be screened for methamphetamine or other illicit drugs.

Methamphetamine abuse and emergency department utilization.

Methamphetamine (MAP) abuse continues to increase worldwide, based on morbidity, mortality, drug treatment, and epidemiologic studies and surveys. MAP abuse has become a significant health care, environmental, and law enforcement problem. Acute intoxication often results in agitation, violence, and death. Chronic use may lead to infection, heart failure, malnutrition, and permanent psychiatric illness. MAP users frequently use the emergency department (ED) for their medical care. Over a 6-month period we studied the demographics, type, and frequency of medical and traumatic problems in 461 MAP patients presenting to our ED, which serves an area noted for high levels of MAP production and consumption. Comparison was made to the general ED population to assess use patterns. MAP patients were most commonly Caucasian males who lacked health insurance. Compared to other ED patients during this time, MAP patients used ambulance transport more and were more likely to be admitted to the hospital. There was a significant association between trauma and MAP use in this patient population. Our data suggest MAP users utilize prehospital and hospital resources at levels higher than the average ED population. Based on current trends, we can expect more ED visits by MAP users in the future.