Phillip N. Rauk

Interleukin-1 stimulates human uterine prostaglandin production through induction of cyclooxygenase-2 expression.

PROBLEM: Uterine infection occurs in as much as 20% of preterm labor and results in increased decidual cytokines. The objective of this study was to examine the effect of interleukin‐1 (IL‐1) and the cyclooxygenase‐2 (COX‐2) inhibitor, NS‐398, on myometrial prostaglandin (PG) production and COX‐2 expression.
 METHOD OF STUDY: Human uterine myocytes were stimulated with IL‐1 (0–50 ng/mL) over 24 hr. PGE2, PGF2α, and 6‐keto F1α were measured by enzyme‐linked immunosorbent assay. Both COX‐1 and COX‐2 proteins and mRNA were measured by western and northern blot, respectively.
 RESULTS: IL‐1 increased PG production beginning at 6 hr. COX‐2 protein increased beginning at 4 hr and continued to increase at 24 hr. COX‐2 mRNA increased at 2 hr and peaked at 4 hr. NS‐398 blocked PG production but had no effect on COX‐2 protein or mRNA.
 CONCLUSIONS: IL‐1 increases PG production by myometrium by increased COX‐2 expression. NS‐398 completely blocks IL‐1‐induced PG production. With intrauterine infection, IL‐1 may induce labor through the autocrine production of uterotonic PGs.

Interleukin-6 Up-Regulates the Oxytocin Receptor in Cultured Uterine Smooth Muscle Cells

PROBLEM: Intra‐uterine infection results in the production of inflammatory cytokines, including interleukin‐6 (IL‐6). Increased oxytocin‐receptor (OTR) concentrations are associated with the onset of preterm labor. We hypothesize that infection up‐regulates OTR expression through IL‐6‐induced transcription factors.
 METHOD OF STUDY: Primary cultures of human myometrium were treated for various time periods or with different concentrations of IL‐6 and OTR mRNA as well as OTR binding were measured by means of reverse transcription polymerase chain reaction and I‐ornithine‐vasotocin‐binding assay. To study underlying mechanisms of OTR changes with IL‐6 treated, cells were also incubated with genistein or H7 (tyrosine and serine phosphorylation inhibitors), respectively.
 RESULTS: OTR mRNA increased 2.5‐fold after 4 hr of IL‐6 treatment and OTR binding 1.4‐fold after 8 hr of cytokine stimulation. The IL‐6‐induced increase in binding was blocked by genistein and H7.
 CONCLUSIONS: IL‐6 up‐regulates uterine OTR mRNA expression and binding capacity in cultured human myocytes most likely through tyrosine and serine phosphorylation pathways involving the nuclear factor STAT‐3.

Mitogenic effect of basic fibroblast growth factor and estradiol on cultured human myometrial and leiomyoma cells

OBJECTIVE We compared the mitogenic effect of basic fibroblast growth factor with and without estradiol on myometrial and leiomyometrial cells. STUDY DESIGN The mitogenic effect of basic fibroblast growth factor on myometrial cells was measured by thymidine incorporation and cell count. The mitogenic effect of basic fibroblast growth factor with and without estradiol as measured by thymidine incorporation was compared between myometrial and leiomyometrial cells. RESULTS Both human myometrial and leiomyometrial cells showed significant (p = 0.004 and p = 0.001, respectively), dose-dependent incorporation of thymidine in response to basic fibroblast growth factor. Leiomyometrial cells showed significantly (p = 0.04) less thymidine incorporation compared with matched normal myometrial cells. The addition of estradiol with basic fibroblast growth factor did not result in a further increase in thymidine incorporation. CONCLUSIONS Both myometrial and leiomyometrial cells respond to basic fibroblast growth factor with increased thymidine incorporation; however leiomyometrial cells are less responsive than are matched normal myometrial cells. The addition of estradiol is not synergistic with basic fibroblast growth factor.

Educational intervention, revised instrument sterilization methods, and comprehensive preoperative skin preparation protocol reduce cesarean section surgical site infections

BACKGROUND In 2005, of the approximately 4 million births in the United States, 30% were by cesarean section (C-section) delivery, which translates to roughly over 1 million C-sections in 2005 alone. C-section is associated with higher morbidity than vaginal delivery. Women who undergo C-section are 5 times more likely to develop a postpartum infection after delivery than women who undergo vaginal delivery. OBJECTIVE Estimates of surgical site infection (SSI) after C-section range from 1.50 to 2.64. A quality improvement initiative was implemented at the University of Minnesota Medical School to reduce rates of SSI using changes based on recommended care initiatives. METHODS The multidisciplinary team developed a comprehensive staff education and training program, added a preoperative skin preparation protocol using chlorhexidine gluconate (CHG) no-rinse cloths, added CHG with alcohol for interoperative skin preparation, and modified instrument sterilization techniques. RESULTS Data analysis revealed a statistically significant reduction in the overall SSI rate from 7.5% (33/441) in January-July 2006 to 1.2% (5/436) in January-July 2007 (chi(2) test statistic, 21.2; P < .001; relative reduction of 84%). CONCLUSION Interventions, including staff education, use of CHG no-rinse cloths for preoperative skin prep, CHG with alcohol for intraoperative skin prep, and appropriate instrument sterilization management led to reductions in SSI rates in patients undergoing C-section at our institution. Rates of endometritis were also noted to be lower after implementation of the interventions.

Effect of IL-1β and IL-6 on oxytocin secretion in human uterine smooth muscle cells

PROBLEM: Infection‐mediated preterm labor results in the production of inflammatory cytokines, including interleukin‐1β (IL‐1β) and interleukin‐6 (IL‐6). Oxytocin (OT) plays a key role in the process of labor. This study investigates the effect of IL‐1β and IL‐6 on intra‐and extracellular OT in human smooth muscle cells and evaluates IL‐1β induced changes in IL‐6 production.
 METHOD OF STUDY: Primary cultures of human myometrium, obtained from term pregnant women (n=7) were incubated with either IL‐1β or IL‐6 for 0–24 hr. Intra‐ and extracellular OT peptide concentrations were measured by radioimmunoassay and IL‐6 mRNA and protein were evaluated by reverse transcription polymerase chain reaction and enzyme‐linked immunosorbent assay.
 RESULTS: Both, IL‐1β and IL‐6 led to an increase in OT secretion, which was accompanied by a reduction of the intracellular OT peptide pool. IL‐1β significantly induced IL‐6 mRNA expression and protein secretion, which did not further enhance IL‐1β induced OT secretion.
 CONCLUSIONS: The induction of OT secretion by proinflammatory cytokines in human myometrium in vitro, supports the concept of a thus regulated infection‐triggered preterm labor process in vivo.

The influence of interleukin-1β on oxytocin signalling in primary cells of human decidua

OBJECTIVE Oxytocin (OT) and its corresponding receptor (OTR), synthesized within the pregnant uterus, play a key role in the process of (preterm) labor as part of a paracrine system that regulates symmetrical contractility. In the setting of intrauterine infection, a major cause of preterm labour and birth, decidua serves as a major source of cytokine production. The present study evaluates the time-dependent effect [0-24 h] of the inflammatory cytokine Interleukin-1beta (IL-1beta) treatment on OT signalling and OT stimulated prostaglandin release in primary cultures of human decidua. STUDY DESIGN Primary cultures of human decidua (n=6) were treated with IL-1beta [5 ng/ml] for 0-24h and or indomethacin [100 microM]--an inhibitor of the prostaglandin synthesis--for 0-24 h or for 24 h. OT peptide expression, OTR binding, Inositol triphosphate production (IP(3)), and arachidonic acid (AA) as well as prostaglandin (PGE(2)) release were measured. RESULTS IL-1beta transiently reduced cytoplasmic OT peptide at 4-6 h of IL-1beta incubation, while its secretion into the media was increased after 6 h of stimulation. The later was completely blocked by indomethacin. A decrease in OTR mRNA expression and a loss of OTR binding were detected after 8 h and 16 h of IL-1beta treatment, respectively. IL-1beta also decreased IP(3) production and AA release, but significantly enhanced OT mediated PGE(2) production. This effect was completely suppressed by the cyclooxygenase-2 (COX-2) inhibitor NS-398. CONCLUSION Our data suggest, that IL-1beta indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade. These findings might explain the poor effectiveness of oxytocin receptor antagonists as tocolytic agents in the setting of intrauterine infection.

Oxytocin Signaling in Human Myometrium Is Impaired by Prolonged Exposure to Interleukin-1

Abstract Intra-amniotic infection leads to preterm labor and is associated with the local release of inflammatory cytokines by fetal membranes, resulting in the production of uterotonic prostaglandins. Oxytocin, however, also plays a key role in the initiation of labor. Short-term exposure of myometrium to interleukin (IL)-1 enhances oxytocin signaling and contractility. With intrauterine infection, however, myometrium is exposed to inflammatory cytokines for prolonged periods. The present study was conducted to demonstrate that myometrial oxytocin signaling is significantly impaired following prolonged exposure to IL-1. Myometrial cells were treated with IL-1 for 24 h. Oxytocin-stimulated inositol trisphosphate (IP3) production was measured in tritiated myoinositol-loaded myometrial cells. Arachidonic acid (AA) release was measured in tritiated AA-loaded myometrial cells. Increases in intracellular calcium were measure with fluo-3. Prostaglandin (PG) F2α and 6-keto-PGF1α were measured by ELISA assay. Prolonged exposure of myometrial cells to IL-1 resulted in a significant reduction in oxytocin-mediated signaling as measured by IP3 production and AA release, as well as a decrease in intracellular calcium. Prolonged exposure of myometrial cells to IL-1, however, resulted in enhanced PG release. Oxytocin may not contribute significantly to the labor-inducing action of IL-1 in the setting of preterm labor with prolonged infection.

Estradiol and progesterone regulate oxytocin receptor binding and expression in human breast cancer cell lines

The effects of estradiol (E2) and progesterone on the oxytocin receptor (OTR) were investigated in MCF-7 and Hs 578T human breast cancer cell lines. OTR messenger RNA and protein were identified by reverse transcriptase polymerase chain reaction (PCR) and solution-phase hybridization-RNase protection assay, and Western blot analysis, respectively, in cell lines and in cancerous breast tissue removed from women at mastectomy. Cells were exposed to E2, progesterone, or vehicle (each steroid, 10−10−10−6M) for 24 h and harvested for extraction of RNA. The OTR PCR product was increased by E2 (10−7M, p<0.05, or 10−6M, p<0.01 vs control) and decreased by progesterone (control vs 10−7 or 10−6M, each p<0.005). Hs578T cells were cultured in the presence or absence of E2 (10−6M) or progesterone (10−6M) for 24 h and binding was measured. For the E2-exposed cells, the Kd (p<0.05), and Bmax (p<0.01) were higher whereas for the progesterone-treated cells the Kd (p<0.05) and Bmax were lower than control cells. E2 and progesterone not only regulate OTR expression and binding in normal mammary myoepithelium but also in malignant mammary cell lines.

A Perinatal Care Quality and Safety Initiative: Are There Financial Rewards for Improved Quality?

BACKGROUND Although costs of providing care may decrease with hospital initiatives to improve obstetric and neonatal outcomes, the accompanying reduced adverse outcomes may negatively affect hospital revenues. METHODS In 2008 a Minnesota-based hospital system (Fairview Health Services) launched the Zero Birth Injury (ZBI) initiative, which used evidence-based care bundles to guide management of obstetric services. A pre-post analysis of financial impacts of ZBI was conducted by using hospital administrative records to measure costs and revenues associated with changes in maternal and neonatal birth injuries before (2008) and after (2009-2011) the initiative. RESULTS For the Fairview Health Services hospitals, after adjusting for relevant covariates, implementation of ZBI was associated with a mean 11% decrease in the rate of maternal and neonatal adverse outcomes between 2008 and 2011 (adjusted odds ratio [AOR] = 0.89, p = .076). As a result of the adverse events avoided, the hospital system saved

Use of the fetal chest in estimating fetal weight

284,985 in costs but earned