Biomedical subjects

Miles J Novy

Publications and source records attributed to Miles J Novy.

7 recordsLinked to original sources

PubMed2007

Proteomic analysis of cervical-vaginal fluid: identification of novel biomarkers for detection of intra-amniotic infection.

Intra-amniotic infection (IAI) is associated with preterm birth and perinatal mortality. To identify potential biomarkers, we performed a comprehensive survey of the cervical-vaginal fluid (CVF) proteome from a primate IAI model utilizing multidimensional protein identification technology (LC/LC-MS/MS) and MALDI-TOF-MS analyses. Analyses of CVF proteome identified 205 unique proteins and differential expression of 27 proteins in controls and IAI samples. Protein expression signatures and immunodetection of specific biomarkers identified can be employed for noninvasive detection of IAI.

Amniotic Fluid↗

PubMed2006

Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model.

OBJECTIVES: The purpose of this study was to determine the relative contributions of individual proinflammatory cytokines and chemokines to the triggering of preterm labor. STUDY DESIGN: Eighteen chronically instrumented pregnant rhesus monkeys at 135 +/- 3 days gestation (term = 167 days) received 1 of 5 intraamniotic infusions: (1) interleukin-1beta (IL-1beta) (10 microg; n = 5), (2) tumor necrosis factor-alpha (TNF-alpha) (10-100 microg; n = 5), (3) IL-6 (20 microg twice a day; n = 2), (4) IL-8 (20 microg twice a day; n = 2), and (5) saline control (n = 4). Primary study outcomes were the mean uterine hourly contraction area (mm Hg x s/h) in 24 hours during peak response to cytokine infusion (all groups) and the interval from cytokine infusion until labor onset (IL-1beta, IL-6, and IL-8 groups). Secondary outcomes were quantities of amniotic fluid cytokines and chemokines (IL-1beta, TNF-alpha, IL-6, and IL-8), prostaglandins E2 and F2alpha, leukocytes, and matrix metalloproteinase-9 (MMP-9). Histopathology of fetal lungs and placental membranes was assessed. RESULTS: IL-1beta stimulated the most intense contraction patterns, resulting in preterm labor in all cases. TNF-alpha induced a variable degree of uterine activity among individual animals stimulating either preterm labor (n = 2) or a uterine contraction pattern of moderate intensity (n = 3). Despite prolonged elevations in amniotic fluid levels, neither IL-6 nor IL-8 induced preterm labor or an increase in uterine activity until near term. The mean interval from the initiation of IL-6 and IL-8 infusion to the onset of labor was significantly longer than after IL-1beta (21.9 vs 1.1 days; P < .01), and did not differ from the saline control group (27.6 days; P = NS). Intraamniotic infusion of IL-1beta or TNF-alpha was associated with significant elevations in all tested amniotic fluid cytokines, IL-8, prostaglandins, MMP-9 and leukocytes compared with gestational age-matched saline controls. IL-6 and IL-8 infusions were not associated with increases in IL-1beta or TNF-alpha and only produced a moderate increase in amniotic fluid prostaglandins. All cytokine infusions induced histologic chorioamnionitis and an accumulation of neutrophils in fetal lungs. CONCLUSION: Preterm labor was induced by intraamniotic infusions of IL-1beta and TNF-alpha, but not by IL-6 or IL-8 although inflammatory changes in fetal membranes and lungs were uniformly present. Our results indicate a primary role for IL-1beta and TNF-alpha in the triggering of preterm labor associated with inflammation or infection.

Amniotic Fluid↗

PubMed2004

Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel biomarkers.

CONTEXT: Intra-amniotic infection (IAI) is commonly associated with preterm birth and adverse neonatal sequelae. Early diagnosis of IAI, however, has been hindered by insensitive or nonspecific tests. OBJECTIVE: To identify unique protein signatures in rhesus monkeys with experimental IAI, a proteomics-based analysis of amniotic fluid was used to develop diagnostic biomarkers for subclinical IAI in amniotic fluid and blood of women with preterm labor. DESIGN, SETTING, AND PARTICIPANTS: Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry, gel electrophoresis, and tandem mass spectrometry were used to characterize amniotic fluid peptides in 19 chronically instrumented pregnant rhesus monkeys before and after experimental IAI. Candidate biomarkers were determined by liquid chromatography-tandem mass spectrometry. Polyclonal antibodies were generated from synthetic peptides for validation of biomarkers of IAI. Amniotic fluid peptide profiles identified in experimental IAI were subsequently tested in a cohort of 33 women admitted to Seattle, Wash, hospitals between June 25, 1991, and June 30, 1997, with preterm delivery at 35 weeks or earlier associated with subclinical IAI (n = 11), preterm delivery at 35 weeks or earlier without IAI (n = 11), and preterm contractions with subsequent term delivery at later than 35 weeks (n = 11). MAIN OUTCOME MEASURES: Identification of peptide biomarkers for occult IAI. RESULTS: Protein expression profiles in amniotic fluid showed unique signatures of overexpression of polypeptides in the 3- to 5-kDa and 10- to 12-kDa molecular weight ranges in all animals after infection and in no animal prior to infection. In women, the 10- to 12-kDa signature was identified in all 11 patients with subclinical IAI, in 2 of 11 with preterm delivery without IAI, and in 0 of 11 with preterm labor and term delivery without infection (P<.001). Peptide fragment analysis of the diagnostic peak in amniotic fluid identified calgranulin B and a unique fragment of insulinlike growth factor binding protein 1, which were also expressed in maternal serum. Mapping of other amniotic fluid proteins differentially expressed in IAI identified several immunoregulators not previously described in amniotic fluid. CONCLUSIONS: This proteomics-based characterization of the differential expression of amniotic fluid proteins in IAI identified a distinct proteomic profile in an experimental primate chorioamnionitis model that detected subclinical IAI in a human cohort with preterm labor. These diagnostic protein expression signatures, complemented by immunodetection of specific biomarkers in amniotic fluid and in maternal serum, might have application in the early detection of IAI.

Adult↗

PubMed2004

The diagnosis and reproductive outcome after surgical treatment of the complete septate uterus, duplicated cervix and vaginal septum.

OBJECTIVE: This study was undertaken to evaluate the diagnostic management and the reproductive outcome after surgical repair of a rare reproductive malformation. STUDY DESIGN: Sixteen women with a complete septate uterus, double cervix, and a longitudinal vaginal septum were referred for evaluation. Presenting complaints were chiefly pregnancy loss in parous women (n=9) and dyspareunia in nulligravid women (n=7). The combination of hysterosalpingography, ultrasonography, and/or magnetic resonance imaging was used to correctly identify the anomaly in 15 of the 16 cases. Both hysteroscopic (n=11) and transabdominal (n=5) surgical techniques were used to repair the uterine septum. RESULTS: In no case was the correct diagnosis made before referral; the uterus didelphys was the most common misdiagnosis. The preoperative pregnancy loss was 81%. Postoperatively, 12 women conceived for a total of 17 pregnancies; there were 14 term live births or ongoing pregnancies in the third trimester (82%), with a first trimester spontaneous abortion rate of 18%. In 9 women who conceived after hysteroscopic surgery, term live births occurred in 9 of 12 (75%) conceptions. A modified Tompkins metroplasty was performed in 5 women with subsequent term live births or ongoing third trimester pregnancies in 5 of 5 (100%) patients. CONCLUSION: The identification of a duplicated cervix and a vaginal septum is consistent with several uterine malformations, which leads to frequent misdiagnosis and errors in management. Significant pregnancy wastage, obstetric complications, and dyspareunia are common, and surgical treatment is therefore advisable. Making the best choice between hysteroscopic or transabdominal metroplasty depends on the anatomic features of the cervix and the uterine cavity, but optimal patient management requires familiarity with both techniques.

Abnormalities, Multiple↗

PubMed2003

Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys.

OBJECTIVE: The purpose of this study was to determine whether treatment with the immune modulators dexamethasone or interleukin-10 prevents interleukin-1beta-induced uterine contractions in a nonhuman primate model. STUDY DESIGN: Thirteen chronically instrumented rhesus monkeys at 135 +/- 1 days of gestation (term, 167 days) received one of three interventions: (1) intra-amniotic interleukin-1beta (10 microg) infusion with maternal dexamethasone (1 mg/kg) intravenously every 6 hours for 1 day before interleukin-1beta and for 2 days thereafter (n = 4), (2) intra-amniotic interleukin-1beta infusion with maternal interleukin-10 (25 microg/kg) given intravenously and 100 microg interleukin-10 given intra-amniotically before the interleukin-1beta and continued every 8 hours for 3 days (n = 5), and (3) intra-amniotic interleukin-1beta administered alone (n = 5). Uterine activity was monitored continuously and quantified as the hourly contraction area (millimeters of mercury times seconds per hour) in all groups until delivery. Amniotic fluid was sampled for leukocyte counts and assayed for prostaglandins E(2) and F(2)alpha, cytokines interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 receptor antagonist by specific assays. Maternal and fetal blood were assayed for cortisol, dehydroepiandrosterone sulfate, and estradiol. RESULTS: Interleukin-1beta infusion in the absence of immune modulators resulted in an increase in uterine activity and amniotic fluid proinflammatory cytokines, prostaglandins, and leukocytes. Dexamethasone and interleukin-10 treatment significantly reduced interleukin-1beta-induced uterine contractility (P <.05) and amniotic fluid prostaglandins (P <.05) but not interleukin-8 or interleukin-1 receptor antagonist. Amniotic fluid interleukin-6 and maternal and fetal cortisol, dehydroepiandrosterone sulfate, and estradiol concentrations were reduced by dexamethasone (P <.05), whereas tumor necrosis factor-alpha levels and leukocyte counts were attenuated by interleukin-10 treatment (P <.05). An inverse relationship was noted between amniotic fluid interleukin-10 concentrations and interleukin-1beta-induced uterine activity (r = -0.74, P <.05). CONCLUSION: Dexamethasone and interleukin-10 exert similar inhibitory effects on interleukin-1beta-induced uterine activity, which appears to be mediated by a decrease in prostaglandin production. Reduced estrogen biosynthesis or suppression of tumor necrosis factor-alpha and leukocyte migration may contribute to the tocolytic actions of dexamethasone and interleukin-10, respectively. Dexamethasone and interleukin-10 are likely to be useful adjuncts in the treatment of preterm labor that is associated with inflammation or infection.

Amniotic Fluid↗

PubMed2002

Identification of matrix metalloproteinase-9 in amniotic fluid and amniochorion in spontaneous labor and after experimental intrauterine infection or interleukin-1 beta infusion in pregnant rhesus monkeys.

OBJECTIVE: The purpose of this study was to examine the roles of intrauterine infection, inflammation, and spontaneous labor on the expression of matrix metalloproteinase-9 in fetal membranes and amniotic fluid of late pregnant rhesus monkeys. STUDY DESIGN: Pregnant rhesus monkeys with timed gestations were chronically catheterized to allow serial sampling of amniotic fluid before and during experimentally induced intrauterine inflammation. Six animals received group B streptococci into the chorionic-decidual space, and 4 animals received intra-amniotic interleukin-1 beta infusions (10 microg). Three additional animals were serially sampled by amniocentesis through late pregnancy until spontaneous term labor. Amniotic fluid samples were examined by zymography for matrix metalloproteinase-9 and -2 and Western immunoblot for matrix metalloproteinase-9 and -2 and tissue inhibitors of metalloproteinase-1 and -2. Fetal membranes were obtained at cesarean delivery during labor (before rupture), formalin fixed, and embedded in paraffin for immunocytochemistry of matrix metalloproteinase-9 and in situ hybridization of matrix metalloproteinase-9 messenger RNA. Tissues from 2 additional animals were collected as age-matched non-labor controls. RESULTS: In amniotic fluid, the 92-kd latent matrix metalloproteinase-9 was detectable in late pregnancy and increased dramatically, followed by the appearance of the 83-kd active form before spontaneous term delivery. Amniotic fluid matrix metalloproteinase-2 levels (both latent and active forms) remained relatively constant throughout pregnancy and in labor. Both bacteria and interleukin-1 beta rapidly increased the signal of latent matrix metalloproteinase-9 without a consistent increase in the active form before the onset of labor. Chorionic-decidual inoculation of group B streptococci was followed by the expression of latent matrix metalloproteinase-9 before the appearance of group B streptococci in amniotic fluid or the onset of labor. Matrix metalloproteinase-2 increased to a new steady-state level or remained unchanged after group B streptococci inoculation or interleukin-1 beta infusion, respectively. Amniotic fluid tissue inhibitors of metalloproteinase-1 declined and tissue inhibitors of metalloproteinase-2 remained unchanged during early group B streptococci infection, after interleukin-1 beta infusion and on the day of spontaneous term labor. However, both tissue inhibitors of metalloproteinase-1 and -2 levels increased after preterm labor that was induced by group B streptococci. Immunocytochemistry localized matrix metalloproteinase-9 protein to amnion and chorion epithelial and mesenchymal cells and decidual stromal cells. Granular matrix metalloproteinase-9 staining was observed in the connective tissue layer of inflamed fetal membranes. In situ hybridization for messenger RNA confirmed the production of matrix metalloproteinase-9 by amnion and chorion. CONCLUSION: Bacterial- and interleukin-1 beta-induced preterm labor and spontaneous term labor are preceded and accompanied by progressive increases in amniotic fluid matrix metalloproteinase-9 (92 kd) in rhesus monkeys. Amniotic fluid matrix metalloproteinase-9 may serve as a clinical marker for the onset of both preterm and term labor.

Amnion↗

PubMed2002

Cervical cerclage.

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Cerclage, Cervical↗