Ariel Milwidsky

Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study.

kappaB activity and nitric oxide production in rejecting cardiac allografts. Transplantation 1998; 66: 838. 28. Boyd JH, Mathur S, Wang Y, et al. Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. Cardiovasc Res 2006; 72: 384. 29. Andrade CF, Kaneda H, Der S, et al. Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant 2006; 25: 1317. 30. Krieger NR, Yin DP, Fathman CG. CD4 but not CD8 cells are essential for allorejection. J Exp Med 1996; 184: 2013. 31. Phillips NE, Markees TG, Mordes JP, et al. Blockade of CD40-mediated signaling is sufficient for inducing islet but not skin transplantation tolerance. J Immunol 2003; 170: 3015. 32. Smiley ST, Csizmadia V, Gao W, et al. Differential effects of cyclosporine A, methylprednisolone, mycophenolate, and rapamycin on CD154 induction and requirement for NFkappaB: Implications for tolerance induction. Transplantation 2000; 70: 415.

Effect of viscous macromolecules on peritoneal plasminogen activator activity: A potential mechanism for their ability to reduce postoperative adhesion formation

Activity of peritoneal plasminogen activator and its regulation by dextran and other macromolecules that clinically suppress postoperative adhesions was studied. Plasminogen activator activity was assayed by a two-stage globinolytic assay that monitors formation of plasmin, as well as by cleavage of a chromogenic peptide substrate (S-2444) in the presence of aprotinin (Trasylol). Plasminogen activator activity was located on the outer surface of human peritoneum. Incubation of peritoneal tissue with buffer in vitro (conditioning) prompted release of plasminogen activator into the conditioning medium. The released plasminogen activator formed a single band on sodium dodecyl sulfate-gel electrophoresis at an apparent molecular weight of 174,000 and was markedly suppressed by antiserum raised against human melanoma tissue-type plasminogen activator. Nonspecific proteolytic activity did not accumulate in the medium during conditioning. The presence of dextran 80 during conditioning of peritoneum reversibly suppressed tissue-bound plasminogen activator activity and reduced plasminogen activator activity in the spent medium. A similar inhibition of peritoneal plasminogen activator was induced by dextran 500, methyl cellulose, and polyvinylpyrrolidone. Dextran, when added to the medium after conditioning, had no direct inhibitory effect on plasminogen activator activity. Dextran did not induce peritoneal production of inhibitor(s) of trypsin, chymotrypsin, or urokinase. On the basis of these findings, two possible mechanisms for the effect of viscous polymers in the reduction of adhesion formation are proposed. These mechanisms consider the importance of peritoneal tissue-type plasminogen activator for removal of fibrin clots and suggest that polymer coating either prevents the shedding of plasminogen activator into the abdominal cavity or reduces the access of fibrin clots to the serosal surfaces.

Cytokine-mediated regulation of rat ovarian function: interleukin-1 inhibits plasminogen activator activity through the induction of plasminogen activator inhibitor-1 (PAI-1)

Intraovarian IL-1 has recently been implicated as a mediator in the ovulatory process. Since PA activation is an established component of the ovulatory cascade, consideration was given in this report to the possibility that IL-1 may modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27-days-old) were cultured under serum-free conditions for 48 h in the absence or presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]-globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30% reduction in cell-associated PA activity (p < 0.001). The IL-1-mediated inhibition occurred concurrently with a 10-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. At similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and granulosa cells exhibited comparable PA activity in the absence of IL-1. However, only theca cells responded to IL-1 with inhibition of plasminogen activation and enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increase in urokinase inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1-induced inhibition of urokinase was abolished by the administration of a polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose-dependent fashion by the soluble IL-1 receptor (which specifically complexes with IL-1), and by a highly-specific IL-1 receptor antagonist suggesting that the IL-1 effects are receptor-mediated. The present observations indicate that ovarian PA activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca-interstitial origin. Inasmuch as IL-1 may be involved in initiating and maintaining the preovulatory cascade, the periovulatory activation of plasminogen must be accomplished by agents other than IL-1.

Severe Fetal Distress with Hydramnios due to Chorioangioma

Abstract. A case is described of antenatal detection of a placental mass by ultrasound in a patient with hydramnios due to chorioangioma and who had a sinusoidal‐like pattern and positive oxytocin challenge test (OCT). The importance of frequent fetal heart rate monitoring in cases of supected chorioangioma is emphasized.

Relationship between nulliparity and preeclampsia may be explained by altered circulating soluble fms-like tyrosine kinase 1

Objective: To test the hypothesis that the risk of preeclampsia in nulliparous women may be due to an anti-angiogenic state. Methods: Maternal serum samples obtained in the third trimester from nulliparous (n = 86) and multiparous (n = 165) singleton uncomplicated pregnancies were analyzed for levels of angiogenic factors – soluble fms like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) by enzyme-linked immunosorbent assay (ELISA). Results: For nulliparous and multiparous pregnancies, serum sFlt1 levels were 12 732 ± 832 and 10 162 ± 666 (p = 0.020), serum PlGF levels were 215 ± 15 and 249 ± 14 (p = 0.093) (all reported as mean SD in pg/ml) and mean ratios of sFlt1/PlGF were 93 ± 12 and 62 ± 5 (p = 0.023), respectively. Adjustment for maternal age and fetal birth weight did not alter the results. Conclusions: Nulliparous pregnancies had higher circulating sFlt1 levels and sFlt1/PlGF ratios than multiparous pregnancies, suggesting an association with an angiogenic imbalance. Taken together with the pathogenic role of anti-angiogenic factors in preeclampsia, our data may be one explanation for the epidemiological observation that nulliparity is a risk factor for the development of preeclampsia.

Interleukin-1-mediated regulation of plasminogen activation in pregnant mare serum gonadotropin-primed rat granulosa cells is independent of prostaglandin production.

Objectives: This study examines the effects of interleukin-1 (IL-1) on plasminogen activator (PA) activity and prostaglandin (PG) E production in pregnant mare serum gonadotropin (PMSG)-primed granulosa cells and the potential involvement of PGE in the regulation of ovarian plasminogen activation. Methods: Granulosa cells were obtained from PMSG-primed rat (27-day-old) ovaries and cultured in serum-free conditions for 48 hours in the absence or presence of IL-1β (10 ng/mL) with and without transforming growth factor-β1 (10 ng/mL). Cellular PA activity was measured through the conversion of plasminogen to plasmin and assay of the plasmin-mediated cleavage of [14C]-labeled globin to acid-soluble products. Results: Exposure of PMSG-primed granulosa cells to IL-1 resulted in a 30% reduction (P < .05) in PA activity. Addition of hCG (1 IU/mL) to the granulosa cell cultures resulted in a 2.3-fold increase in PA activity, an effect significantly attenuated by co-administration of IL-1. The IL-1-mediated inhibition occurred concurrent with a 6.6-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. This latter inhibitory capacity was the result of a significant increase in plasminogen activator inhibitor type 1 (PAI-1), given its abolition by a polyclonal anti-rat PAI-1 immunoglobulin G. The IL-1-mediated effects on PA/PAI-1 were accompanied by a sevenfold increase in PGE content of the spent culture medium. This response was dose dependent. The IL-1 effects on plasminogen activation and PG production were abolished by the IL-1 receptor antagonist, suggesting specific IL-1 receptor-mediated responses. Indomethacin, an inhibitor of PG biosynthesis, prevented the IL-1-induced increase in PGE accumulation but failed to affect the response of the PA system. Transforming growth factor-β1, a known regulator of IL-1 action, significantly attenuated the IL-1-stimulated PGE production but did not interfere with the ability of IL-1 to affect the PA system. Conclusion: The present observations suggest a pleiotropic response of PMSG-primed granulosa cells to IL-1, characterized by the induction of PAI-1 concurrent with but independent of PG production. These findings corroborate and extend earlier observations suggesting that IL-1 affects PA activity and PGE production in immature rat ovaries. Moreover, these observations support our contention that IL-1 may play a major regulatory role in the cellular events leading to ovulation and early corpus luteum formation.

Human Factors–Focused Reporting System for Improving Care Quality and Safety in Hospital Wards

Objective: The aim was to develop a reporting system for collecting human factors problem reports to establish a database to guide activities for improving health care quality and patient safety. Background: The current error and incident report systems do not provide sufficient and adequate coverage of the factors contributing to impaired safety and care quality. They fail to examine the range of difficulties that clinical staff encounters in the conduct of daily work. Method: A voluntary problem-reporting system was developed to be used by hospital wards’ clinicians and was tested in four wards of two hospitals in Israel. The system is based on human factors–formatted problem reports submitted by physicians and nurses on difficulties and hazards they confront in their daily work. Reports are grouped and evaluated by a team of human factor professionals. Results: A total of 359 reports were collected in the wards during 12 weeks, as compared with a total of 200 incidents reports that were collected during a period of 5 years with the existing obligatory incident reporting system. In-depth observational studies conducted on the wards confirmed the ability of the new system to highlight major human factors problems, differentially identifying specific problems in each of the wards studied. Problems reported were directly related to general factors affecting care quality and patient safety. Conclusion: Validation studies confirmed the reliability of the reporting system in pinpointing major problems per investigated unit according to its specific characteristics. Application: This type of reporting system could fill an important information gap with the potential to be a cost-effective initial database source to guide human factors efforts to improve care quality, reduce errors, and increase patient safety.

Direct inhibition of proteases and cervical plasminogenactivator by antibiotics

Summary OBJECTIVES : Preterm premature rupture of the fetal membranes and premature delivery are sometimeslinked to genital tract infection and activation of proteolytic enzymes that degrade the extracellular matrix. The possible beneficial effect of antibiotics in prevention of preterm premature rupture of fetal membranes and retardation of the onset of labor in some patients with clinical or subdinical infection was explained via their antibacterial efficacy. The aim of this study was to determine the effect of antibiotics on proteolytic enzymes as a possible explanation for the ability of antibiotics to retard preterm labor. STUDY DESIGN : The direct effect of four antibiotics on the proteolytic activities of purified collagenase,elastase, plasmin, trypsin, and chymotrypsin and on streptokinase and human cervical plasminogen activator was measured. RESULTS : The macrolide antibiotic erythromycin and the beta-lactam antibiotics penicillin G, cloxacillin,and ampicillin exerted, in most of the tested combinations with the different proteases, inhibitory effects on the proteolytic activities. CONCLUSION : The present finding that antibiotics directly inhibit proteases may offer an explanation forthe beneficial response to antibiotic therapy in some cases of idiopathic preterm labor even in absence of pathogenic bacterial infection

Plasminogen activator activity and urokinase inhibitor activity in human amniotic fluid and fetal membranes

This study reports on the presence of latent plasminogen activator (PA) activity in human amniotic fluid (HAF). To measure PA, HAF was incubated with plasminogen, and the formation of plasmin was followed by its ability to cleave globin. The latent proenzyme in HAF was converted to active PA by treatment with sodium dodecyl sulphate (SDS) but not by tryptic digestion. The level of SDS-activatable PA activity in HAF increased with increasing gestational age. In an alternative, direct assay of PA based on its amidolytic activity upon L-pyroglutamyl-glycyl-L-arginine-p-nitroanilide (S-2444), HAF PA activity could be demonstrated even without prior exposure to SDS. Medium conditioned with either chorion or amnion produced PA activity suggesting that HAF PA is derived from the fetal membranes. Treatment of the conditioned medium with SDS or trypsin further increased the enzyme activity. The fetal membranes also produce inhibitory activities towards exogenous trypsin, plasmin, and urokinase. The inhibition of plasmin could be separated from the inhibitory activities towards trypsin and urokinase by DEAE-sephadex ion-exchange chromatography. The function of PA in the normal physiology and in pathological processes involving HAF and the fetal membranes remains to be elucidated.

The Significance of Human Chorionic Gonadotropin in Blood Serum for the Early Diagnosis of Ectopic Pregnancy

Abstract. Determination of human chorionic gonadotropin (HCG) values in the serum by the radioimmunoassay technique, was performed in 23 women with suspected ectopic pregnancies. in 16 cases the values of HCG were high and the diagnosis of ectopic pregnancy was verified by laparoscopy and laparotomy. in 7 cases low HCG values were found and ectopic pregnancy was excluded. the detection of HCG in the serum was found to be an excellent tool for the early diagnosis of ectopic pregnancy, thus helping to prevent the dangerous sequelae which follow the late diagnosis of this condition.