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Songbirds and humans share the ability to adaptively modify their vocalizations based on sensory feedback. Prior studies have focused primarily on the role that auditory feedback plays in shaping vocal output throughout life. In contrast, it is unclear whether and how non-auditory information drives vocal plasticity. Here, we first used a reinforcement learning paradigm to establish that non-auditory feedback can drive vocal learning in adult songbirds. We then assessed the role of a songbird basal ganglia-thalamocortical pathway critical to auditory vocal learning in this novel form of vocal plasticity. We found that both this circuit and its dopaminergic inputs are necessary for non-auditory vocal learning, demonstrating that this pathway is not specialized exclusively for auditory-driven vocal learning. The ability of this circuit to use both auditory and non-auditory information to guide vocal learning may reflect a general principle for the neural systems that support vocal plasticity across species.

Songbirds and humans share the ability to adaptively modify their vocalizations based on sensory feedback. Prior studies have focused primarily on the role that auditory feedback plays in shaping vocal output throughout life. In contrast, it is unclear how non-auditory information drives vocal plasticity. Here, we first used a reinforcement learning paradigm to establish that somatosensory feedback (cutaneous electrical stimulation) can drive vocal learning in adult songbirds. We then assessed the role of a songbird basal ganglia thalamocortical pathway critical to auditory vocal learning in this novel form of vocal plasticity. We found that both this circuit and its dopaminergic inputs are necessary for non-auditory vocal learning, demonstrating that this pathway is critical for guiding adaptive vocal changes based on both auditory and somatosensory signals. The ability of this circuit to use both auditory and somatosensory information to guide vocal learning may reflect a general principle for the neural systems that support vocal plasticity across species.

The garden was the cultural foundation of the early Mediterranean peoples; they acknowledged their reliance on and kinship with the land, and they understood nature through the lens of their diversely cultivated landscape. Their image of the garden underwrote the biblical book of Genesis and the region's three religions. For millennia, there was no sharp divide between humankind and the land that was home. To be sure, the elements could be harsh, their origins mysterious, but there was a widespread consensus that presumed a largely harmonious working relationship with Nature. Traditional agriculture in the ancient Mediterranean mimicked the key traits of naturally occurring ecosystems. It was diverse, complex, self-regulating, and resilient. This relationship effectively came to an end in the late eighteenth century, when "nature" was steadily equated with the untamed landscape devoid of human intervention. In the early part of the century, the human world, the agricultural realm, and the province of uncultivated nature were one continuous field with no internal boundaries. By century's end, however, key writers had created a sharp divide within this continuum and separated the agricultural world from the world of nature. This abrupt and dramatic change of sensibility upended ecological understanding and had enormous consequences-consequences with which we are still struggling. In Back to the Garden, James H. S. McGregor argues that the environmental crisis the world faces today is a result of Western society's abandonment of the "First Nature" principle-of the harmonious interrelationship of human communities and the natural world. This essential work offers a new understanding of environmental accountability while proposing that recovering the original vision of ourselves, not as antagonists of nature but as cultivators of a biological world to which we innately belong, is possible through proven techniques of the past. Much has been lost, the landscape has been degraded, and traditional knowledge has died away. But there is still much that can be recovered, studied, and reimagined.

The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1β, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1β is induced. Dependent on the levels of IL-1Ra, which regulates IL-1β activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1β or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1β and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.Summary SentenceThe IL-1 system has been shown to have an important role in pregnancy, and an IL-1 system assay may be used as a method to screen for women who are more likely to have a high-risk pregnancy and pregnancy complications.

Literature within residency education states that directly observing resident–patient visits with the goal of providing formative and summative feedback to learners is helpful for resident skill development. However, limited literature exists regarding what specifically is most effective to observe and evaluate. Furthermore, the perspectives of learners are not always taken into consideration in the development and implementation of direct observation or video review of resident–patient encounters. This article overviews some of the current literature relevant to family medicine training and provides a description of some of the changes in one residency’s use of recorded encounters. Suggestions are provided for future steps for family medicine residencies to effectively utilize video review.

Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms. PAPERCLIP.

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western countries. Many report moderate or severe symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition during pregnancy. Accordingly, a task force was chosen by the International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including reassurance, exercise and avoidance of exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated "may be considered" when RLS/WED is refractory to more conservative approaches. An algorithm summarizes the recommendations. These guidelines are intended to improve clinical practice and promote further research.

Objectives We evaluated the ability of population attributable fraction (PAF) assessments to alter significant modifiable risks for low birthweight (LBW) and the impact of high altitude as a risk for LBW in Colorado. Methods Logistic regression analysis of birth certificate parameters in 1995-1997 identified risk factors for PAF assessment. PAF for birth at high altitude, multiple births, and LBW in singleton births were determined. Subsequent analysis of singleton LBW risks, using number needed to treat (NNT) analysis, estimated how elimination of major modifiable risk factors could reduce LBW in the study population. Public health interventions were initiated and PAF analysis conducted 12 years afterward to determine the effect of interventions. Results PAF in singleton births revealed low maternal weight gain in pregnancy and maternal smoking as the greatest modifiable attributable risk factors for LBW (12.7/12.5 %, respectively, in 1995-1997 and 12.9/7.1 % in 2007-2009). Significant interaction between these variables resulted in PAF of 34.4 % when the two occurred together in 1995-1997, decreasing to 19.4 % in 2007-2009. NNT analysis of singleton births in 1995-1997 revealed that eliminating low maternal weight gain, smoking, late prenatal care in all women and interpregnancy intervals

Intrauterine infection affects placental development and function, and subsequently may lead to complications such as preterm delivery, intrauterine growth retardation, and preeclampsia; however, the molecular mechanisms are not clearly known. TLRs mediate innate immune responses in placenta, and recently, TLR2-induced trophoblast apoptosis has been suggested to play a role in infection-induced preterm delivery. Chlamydia trachomatis is the etiological agent of the most prevalent sexually transmitted bacterial infection in the United States. In this study, we show that in vitro chlamydial heat shock protein 60 induces apoptosis in primary human trophoblasts, placental fibroblasts, and the JEG3 trophoblast cell line, and that TLR4 mediates this event. We observed a host cell type-dependent apoptotic response. In primary placental fibroblasts, chlamydial heat shock protein 60-induced apoptosis was caspase dependent, whereas in JEG3 trophoblast cell lines it was caspase independent. These data suggest that TLR4 stimulation induces apoptosis in placenta, and this could provide a novel mechanism of pathogenesis for poor fertility and pregnancy outcome in women with persistent chlamydia infection.

This multicenter study was conducted to investigate the association of pelvic inflammatory disease (PID) and bacterial vaginosis. Participants were recruited from women who were attending family planning, health, gynecology, and sexually transmitted disease (STD clinics in 5 medical centers. Eligible patients were women not seeking care for STD, but who were considered at high risk for acquiring STDs according to an algorithm that weighed age, race parity, number of sexual partners, habit of douching, and a history. The vaginal swabs were self-collected. Participating patients were instructed in the use of a cotton swab to collect their vaginal specimens. At intervals of 6 to 12 months, the self-obtained specimens were examined for the characteristics of bacterial vaginosis. A vaginal microflora gram stain score of 7 to 10 was considered bacterial vaginosis. Women who developed pelvic pain or who were positive for Neisseria gonorrhoeae or Chlamydia trachomatis underwent a clinical examination and endometrial biopsy for detection of PID. A diagnosis of PID required the presence of histologic endometritis and/or pelvic pain and tenderness accompanied by either a fever of 101° F or higher, sedimentary rate greater than 15 mm/hr, elevated white blood count, or leukorrhea, mucopus, N. gonorrhea, or C. trachomatis in the lower genital tract. There were 1179 patients included in the analysis. The average follow up was 4 years. At the initial examination, 428 women had normal vaginal flora (36%), 280 had intermediate flora (29%), and 471 had bacterial vaginosis (40%). The baseline diagnosis was not associated with the rate of detection of PID over the 4 years of follow up. Nor was the development of PID significantly associated with age, race, education, income, smoking, sex during menses, condom use, or a history of STD or PID. Analyses according to various subgroups of patients (younger/older women, black/white women, women with/without a history of PID, with/without baseline gonococcal or chlamydia genital infection) found that only women who had a baseline report of 2 or more sexual partners in the previous 2 months and who had a baseline diagnosis of bacterial vaginosis were significantly more likely to have PID. An absence of hydrogen peroxide-producing lactobacillus was not associated with PID, even among the various subgroups. A baseline diagnosis of G. vaginalis or Gram-negative rod growth above 4 had no association with PID except in the subgroup of women who reported 2 or more sexual partners in the previous 2 months. Women with baseline diagnoses of N. gonorrhea or C. trachomatis were more likely to have PID.

Telomerase and human papillomavirus (HPV) DNA were evaluated as potential markers of high-grade dysplasia in cervical cytological specimens. Cytology specimens were collected from patients at the time of colposcopic evaluation for management of a previous abnormal cytology test result. Telomerase activity was evaluated by the telomeric repeat amplification protocol (TRAP), and HPV DNA was detected by polymerase chain reaction with L1 consensus-sequence primers and filter hybridization genotyping. Telomerase was detected in 8 of 97 (8.2%) cases with normal cytology or benign cellular changes, in 7 of 98 (7.1%) cases of atypical squamous cells of undetermined significance (ASCUS), in 3 of 95 (3.2%) cases of low-grade squamous intraepithelial lesion (LSIL), and in 17 of 48 (35.4%) cases with high-grade squamous intraepithelial lesion (HSIL). High-risk HPVs were detected in 23 of 97 (23.7%) cases with normal/reactive cellular changes (RCC) cytology, in 28 of 98 (28.6%) cases of ASCUS, in 69 of 95 (72.6%) cases of LSIL, and in 35 of 48 (72.9%) cases of HSIL. Telomerase expression did not correlate with the detection of high-risk HPVs in any cytological diagnostic categories. Telomerase and HPV test results of cytological specimens were correlated with the histological diagnoses of concurrent cervical biopsy specimens. Telomerase showed a sensitivity of 29.9% and a specificity of 94.0% for biopsy-confirmed cervical intraepithelial neoplasia (CIN) II/III. In contrast, high-risk HPVs were detected in 70.1% of cases with underlying CIN II/III, with a specificity of 62.5%. A relatively high proportion of normal/RCC or ASCUS cases with telomerase-positive test results had underlying high-grade dysplasia on cervical biopsy. Thus, technical and practical limitations of the TRAP assay in cervical cytology specimens limit the practical application of telomerase as a diagnostic adjunct in cervical cytopathology.

OBJECTIVE: To study how frequency, recentness, and reason for douching impact bacterial vaginosis-related vaginal microflora and the occurrence of cervical pathogens. Douching has been linked to bacterial vaginosis as well as to chlamydial cervicitis in some, but not all, studies. METHODS: A total of 1200 women at high risk for sexually transmitted infections were enrolled from five clinical sites around the United States. Cross-sectional, structured interviews were conducted and vaginal swabs were self-obtained for Gram stain, culture, and DNA amplification tests for Neisseria gonorrhoeae and Chlamydia trachomatis. RESULTS: Douching at least once per month was associated with an increased frequency of bacterial vaginosis. Those who douched recently (within 7 days) were at highest risk [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3, 3.1]. Douching for symptoms (OR 1.7, 95% CI 1.1, 2.6) and for hygiene (OR 1.3, 95% CI 1.0, 1.9) both related to bacterial vaginosis risk. The associations between douching and Gardnerella vaginalis, Mycoplasma hominis, and lack of hydrogen peroxide-producing lactobacilli were similar to those between douching and bacterial vaginosis. Gonococcal or chlamydial cervicitis was not associated with douching. CONCLUSION: Douching for symptoms or hygiene, particularly frequent or recent douching, was associated with bacterial vaginosis and bacterial vaginosis-associated vaginal microflora, but not with gonococcal or chlamydial cervicitis.

In the current study, the immunohistochemical localization of survivin was correlated with the histologic diagnosis in healthy transitional cell epithelium, transitional cell carcinoma (TCC) in situ, and TCC of the urinary bladder. Forty-five TCCs (grades 1-3, 15 of each), 14 cases of TCC in situ, and II healthy bladder mucosal specimens were selected from archival collections of formalin-fixed bladder tissues. Slides were reacted with an anti-survivin antibody using a conventional immunohistochemical method and then were scored for nuclear and cytoplasmic staining. Statistical analysis of survivin expression was performed to evaluate the correlation of staining pattern with histologic diagnosis and clinical outcome. Nuclear staining for survivin was detected in 26 of 45 TCCs and in 2 of 14 cases of TCC in situ, but was not detected in healthy bladder mucosa. The association of nuclear staining with TCC versus both healthy bladder mucosa and TCC in situ was statistically significant (P < 0.001). Patients with TCC and a nuclear pattern of survivin localization had a greater period of disease-free survival (27.2 months) than was observed in patients with TCC that showed no nuclear staining for survivin (9.9 months); however, the differences were not statistically significant. Nuclear localization of survivin is a marker of TCC but is rarely present in premalignant or benign bladder mucosal specimens.

Acta Obstet Gynecol Scand 2002; 81: 162-167. © Acta Obstet Gynecol Scand 2002 Background. The objective of this study was to determine if survivin mRNA expression is a marker of endometrioid adenocarcinoma and if survivin mRNA levels correlate with tumor grade and stage. Methods. Twenty-six samples of endometrioid adenocarcinoma and 18 cases of benign endometrium were obtained at surgery. RNA was extracted from tissues and was used for quantitative real-time RT-PCR, targeting a 91-bp sequence of survivin mRNA and the levels were standardized to the levels of ribosomal RNA. Statistical analysis of the correlation between histologic diagnosis and the corrected survivin mRNA levels was performed by the Fisher Exact test and the Kruskal-Wallis test. Results. Survivin mRNA was detected in all specimens. Survivin mRNA levels were increased in proliferative endometrium ( P = 0.0509) and was increased in correlation with ascending grade in endometrioid adenocarcinoma ( P = 0.01). Conclusion. Survivin mRNA is not ...

Objectives. In the current study, the quantitative levels of telomerase hTERT mRNA and the functional telomerase repeat amplification protocol (TRAP) assay were correlated with tumor grade in endometrial carcinomas and with the histologic phase of normal endometrium. Methods. Twenty-six samples of endometroid adenocarcinoma and 20 cases of benign endometrium were obtained from hysterectomy specimens. Total RNA was extracted from each tissue sample and used for quantitative real-time RT-PCR of hTERT mRNA and the levels were standardized to the levels of ribosomal RNA. Quantitative determination of telomerase activity was performed by the polymerase chain-based TRAP assay and the levels of expression were defined by the ratio of radioactivity incorporated into the 6-bp telomerase amplification products versus the radioactivity incorporated into an internal standard (telomerase/ITAS × 100=1 RU). Statistical analyses were performed using the Fisher exact test or χ 2 test, a Wilcoxon rank sum test, and a linear regression analysis. Results. hTERT mRNA and telomerase activity levels showed a linear association in the study group ( P = 0.006, R 2 = 0.139). hTERT mRNA levels and telomerase activity levels were significantly higher in endometrial cancer (179 pg/ng rRNA, 44 relative units (RU)) than in normal endometrium (45 pg/ng), (15 RU) ( P = 0.009, P = 0.006). In normal endometrium, hTERT mRNA and telomerase activity levels were highest in the proliferative phase (74 pg/ng rRNA, 25 RU) and were relatively low in secretory (13 pg/ng rRNA, 6 RU) and atrophic endometrium (9 pg/ng rRNA, 2 RU). Conclusion. These results suggest that the quantitative analysis of hTERT and telomerase activity may have potential roles as diagnostic or prognostic adjuncts for both premenopausal and postmenopausal patients with endometrial cancer.

Increased CRH secretion by the placenta of pregnant women has been associated with preterm birth. Certain indices of risk, both medical and psychosocial in nature, have been linked to preterm delivery. Levels of total, bound, and free CRH, CRH-binding protein (CRH-BP), and cortisol were measured prospectively in a large sample of pregnant Danish women who delivered preterm and term infants. Measures of maternal serum hormones were taken at 7--23 and 27--37 weeks gestation and, for those who delivered at term, at 37--43 weeks gestation. At 7--23 weeks gestation, maternal levels of total CRH (P = 0.01), bound CRH (P = 0.03), and CRH-BP (P = 0.01) were higher in the preterm than in the term group. At 27--37 weeks gestation, levels of total CRH (P < 0.0001), bound CRH (P < 0.0001), free CRH (P < 0.0001), and cortisol (P < 0.0001) were all higher in the preterm than the term group, whereas levels of CRH-BP (P < 0.0001) were lower in the preterm than in the term group. The best medical and behavioral factors associated with preterm delivery were, respectively, previous preterm delivery (P < 0.0001) and engagement in certain risk-taking behaviors (P = 0.008). The positive relations between preterm delivery and various adverse medical and socioeconomic variables with increases in placental secretion of CRH suggest that the latter may participate in the pathophysiology of preterm delivery.

Objective: To evaluate serial measurements of salivary estriol (E3) to detect increased risk of spontaneous preterm labor and preterm birth. Methods: A masked, prospective, multicenter trial of 956 women with singleton pregnancies was completed at eight United States medical centers. Saliva was collected weekly, beginning at the 22nd week of gestation until birth, and tested for unconjugated E3 by enzyme-linked immunosorbent assay. Women were separated into high-risk and low-risk groups using the Creasy scoring system. Results: A single, positive (at or above 2.1 ng/mL) salivary E3 test predicted an increased risk of spontaneous preterm labor and delivery in the total population (relative risk [RR] 4.0, P < .005), in the low-risk population (RR 4.0, P ≤ .05), and in the high-risk population (RR 3.4, P = .05). Two consecutive positive tests significantly increased the RR in all study groups, with a dramatic improvement in test specificity and positive predictive value but only a modest decrease in sensitivity. In women who presented with symptomatic preterm labor, salivary E3 identified 61% of those who delivered within 2 weeks, using a threshold of 1.4 ng/mL. Conclusion: Elevated salivary E3 is associated with increased risk of preterm birth in asymptomatic women and symptomatic women who present for evaluation of preterm labor.

To test the hypothesis that at midgestation younger adolescents (16 years of age at conception) have shorter cervices than older adolescents (16-19 years of age at conception).At midgestation (22.9 +/- 2.4 weeks) we measured cervical length by transvaginal ultrasound in a group of 46 13-19-year-old participants in an intensive, adolescent-oriented, antenatal program. Subjects were also comprehensively screened and treated for other recognized physiologic, microbiologic, obstetric, behavioral, and psychosocial factors associated with preterm delivery. Univariate, bivariate, and logistic regression analyses were used.The 18 younger adolescents had significantly shorter cervices than the 28 older adolescents (30 +/- 11 mm vs. 39 +/- 8 mm; P = 0.002). The younger adolescents' cervices were also more likely to beor =25 mm long (33% and 4%, respectively; P = 0.02) and to exhibit funneling (39% vs. 4%; P = 0.01). Teenagers with cervicesor =25 mm long were younger, thinner, more apt to report vaginal bleeding and substance abuse, and to be treated for preterm labor (71% vs. 21%; P = 0.005). Logistic regression analyses revealed that age16 years at conception (odds ratio = 13.7; 95% CI: 1.3-151.4) and substance abuse (odds ratio = 8.5; 95% CI: 1.2-62.8) were associated with cervical lengthor =25 mm. Cervical lengthor =25 mm was the only significant predictor of preterm delivery (odds ratio = 26.2; 95% CI: 2.1-333.6; P = 0.01) in this population of adolescents who were routinely treated for other recognized causes of preterm delivery.Cervical lengthor =25 mm and cervical funneling may be complications of conception prior to 16 years of age. Randomized trials are needed to determine if younger adolescents benefit preferentially from ultrasound screening for short cervix at midgestation.

Objective: To examine associations between bacterial vaginosis and other prevalent lower genital tract infections and clinically recognized first-trimester bleeding; possible independent and joint effects of gestational bleeding and bacterial vaginosis or other prevalent infections on preterm birth and premature rupture of membranes; and effects of antimicrobial treatment on reducing risks of preterm birth among these women. Methods: A secondary analysis was conducted of 1100 pregnant women enrolled in a prospective observational study that examined the effects of standardized diagnosis and treatment of lower genital tract infections to prevent preterm birth. Results: Sixty percent of women with first-trimester bleeding had one or more study infections detected at the initial examination. First-trimester bleeding was associated independently with the presence of bacterial vaginosis (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0, 2.3), Trichomonas vaginalis (OR 2.3, 95% CI 1.3, 4.2), and Chlamydia trachomatis (OR 2.7, 95% CI 1.4, 5.1). Preterm birth was increased among women with first-trimester bleeding and bacterial vaginosis (relative risk [RR] 4.4, 95% CI 2.0, 9.5) and bacterial vaginosis and T vaginalis (RR 3.0, 95% CI 1.0, 8.8). Systemic antimicrobial treatment reduced the rate of preterm birth among women with bacterial vaginosis without first-trimester bleeding (RR 0.37, 95% CI 0.16, 0.88). Treatment of women with both first-trimester bleeding and bacterial vaginosis reduced preterm birth (RR 0.52, 95% CI 0.18, 1.55), but not significantly. Conclusion: First-trimester bleeding was increased among women with bacterial vaginosis, T vaginalis, C trachomatis, and combinations of these infections. Women with bacterial vaginosis who also experienced first-trimester bleeding were at heightened risk for preterm birth. Treatment of studied infections reduced significantly the risks of preterm birth among women without first-trimester bleeding.

A novel murine model of intrauterine infection/inflammation-induced preterm birth based on direct endoscopic intracervical inoculation is described. Using this model, we investigated infection-induced premature pregnancy loss in normal and interleukin (IL) 1beta-deficient mice. Seventy-four CD-1, HS, C57BL/6J wild type (IL-1beta+/+), and C57BL/6J IL-1beta-deficient (IL-1beta-/-) mice were inoculated intracervically using a micro-endoscope, at a time corresponding to 70% of average gestation. Intracervical injection of lipopolysaccharide (LPS) or Escherichia coli reliably induced premature birth: 100% of mice intracervically injected with LPS and 92% of mice with a positive endometrial E. coli culture delivered prematurely within 36 h after inoculation. No losses were observed in mice inoculated with saline. Pregnancy loss was associated with increased uterine tissue cyclooxygenase-2 gene expression and uterine content of IL-1beta, tumor necrosis factor alpha, macrophage inflammatory protein-1alpha, and IL-6, as well as elevation of nuclear factor-kappaB activity in uterine tissues. Although IL-1beta-/- mice exhibited decreased uterine cytokine production in response to bacteria and LPS, IL-1beta deficiency did not affect the rate of pregnancy loss. This model using direct intracervical bacterial or LPS inoculation is useful for studying preterm pregnancy loss in genetically altered mice in order to develop novel interventions for infection-associated preterm labor.

Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releasing hormone and its duration through time have been linked to the time of onset of labor. Paradoxically, although glucocorticoids are known to inhibit corticotropin-releasing hormone production within the hypothalamic-pituitary-adrenal axis, cortisol actually increases corticotropin-releasing hormone levels in several areas outside the hypothalamus, including the placenta. Placental corticotropin-releasing hormone may be an important component of a system that controls the normal maturation of the fetus and signals the initiation of labor. Abnormal elevations in corticotropin-releasing hormone, which may be a hormonal response to stressors arising in either the mother, placenta, or fetus, may prove to participate in the premature onset of parturition.

Objective: The objective was to compare the predictive accuracy (percentage of correct vs incorrect predictions) of salivary estriol levels (SalEst; Biex, Inc, Dublin, Calif) with that of the modified Creasy score for predicting preterm labor followed by preterm delivery. Study Design: A triple-blinded prospective trial was conducted at 8 US centers. Results: Among 601 evaluable patients, serial salivary estriol testing correctly predicted the appropriate outcome 91% of the time and the Creasy scoring method correctly predicted the appropriate outcome 75% of the time (McNemar test P < .001). Among subjects with Creasy scores ≥10 (high-risk group, n = 152), use of salivary estriol testing correctly predicted the end point 87% of the time, compared with only 7.2% correctly predicted by modified Creasy scoring (McNemar test P < .001). Conclusion: Salivary estriol assessment was more accurate in predicting outcome than was modified Creasy scoring. (Am J Obstet Gynecol 1999;180:S214-8)

Telomerase activity has been detected in a broad range of human malignant neoplasms, and its expression may represent an essential step in the malignant transformation of tissues; however, the expression of telomerase in premalignant lesions remains relatively unexplored. We tested tissue sections of cervical squamous cell carcinomas and squamous intraepithelial lesions, samples of benign reactive atypia, and normal cervical mucosa from hysterectomy and cone biopsy specimens for the expression of telomerase. Mirror-image sections from each sample were paraffin embedded and processed for histologic analysis. The test samples of cervical tissue were crushed under liquid nitrogen, and telomerase activity was determined by the telomeric repeat amplification protocol. Telomerase activity was detected in 18 of 18 cases (100%) of invasive squamous cell carcinoma. Twenty-five of 26 samples (96%) of high-grade squamous intraepithelial lesion also tested positively for telomerase activity, including 10 of 10 samples of moderate dysplasia, 12 of 13 samples of severe dysplasia, and 3 of 3 samples of carcinoma in situ. Telomerase activity was detected in 14 of 25 samples (56%) of low-grade squamous intraepithelial lesion and in 10 of 18 samples (56%) of reactive atypia but was detected in only 9 of 50 samples (18%) of histologically normal cervical mucosa. These results suggest that telomerase expression may be a marker of premalignant and malignant squamous cell lesions of the uterine cervix, although it is also expressed in a high proportion of cases of reactive atypia.

Objective:Survey office-based obstetric-gynecologic practitioners regarding their knowledge of infectious disease care and antibiotic use.Methods:A survey questionnaire of multiple-choice questions was mailed to Fellows of the American College of Obstetricians and Gynecologists about clinical entities for which recommendations have undergone recent changes or about which there was a lack of consensus in a prior similar survey (Gibbs RS, McGregor JA, Mead PB, et al.: Obstet Gynecol 83:631–636, 1994).Results:Respondents indicated that oral metronidazole was their most frequent choice to treat bacterial vaginosis. Ampicillin (57%) was used more often than penicillin (39%) for intrapartum group B streptococcus prophylaxis. Azithromycin was preferred (61%) over erythromycin-base (38%) for chlamydia treatment during pregnancy. There were several modes of practice that deviated from accepted care: 27% and 29% did not screen for chlamydia and gonorrhea, respectively, in pregnancy; 17% used cultures forGardnerella vaginalisto diagnose bacterial vaginosis; 25% considered quinolones to be safe in pregnancy; 93% felt metronidazole should never be used in pregnancy; and the majority (66%) would send a patient treated successfully for pelvic cellulitis home with an oral antibiotic.Conclusion:Respondents’ infectious disease knowledge and practices in obstetrics and gynecology is appropriate in treating sexually transmitted diseases, bacterial vaginosis, and group B streptococcus. Numerous deficiencies still exist in screening for sexually transmitted diseases in pregnancy and diagnosing bacterial vaginosis, as well as in the choice of antibiotics to use or avoid for certain infections.

Prevention of preterm birth and subsequent newborn immaturity is a primary goal of health care in Canada and throughout North America. Much accumulated evidence shows that (I) as many as 30 to 50 percent of preterm births are caused by common genital tract infections and subsequent maternal/fetal inflammatory responses; (2) microbial and maternal host factors (phospholipases, proteases) play roles in preterm labour and preterm premature rupture of membranes (pPROM); (3) identification and systemic treatment of common genitourinary infections, most importantly bacterial vaginosis (BV), reduces risks of preterm delivery and PROM; and, (4) antimicrobial treatment with erythromycin, clindamycin or other antibiotics can significantly delay delivery and reduce the risks of maternal and neonatal morbidity as well as reduce the risk of early onset group B streptococcal sepsis in women with pPROM or preterm labour prior to 34 completed weeks gestation. Diagnosis of EV can be made inexpensively and accurately by using Amsel’s clinical criteria: homogeneous discharge, pH ≥4.5, positive amine test, and “clue” cell identification (3 of 4). Optimal treatment for BV during pregnancy is either prompt administration of oral metronidazole or clindamycin followed by a “test of cure” evaluation and retreatment as necessary. Screening and treatment for BV and other prevalent reproductive tract infections and bacteriuria are most easily and effectively performed during the initial antepartum visit. Screening and treatment can be repeated at 20 or 28 weeks gestation in patients judged at risk for repeated infection. Partners of women with sexually transmitted diseases should be treated; both patients and partners should have “tests of cure.” Both asymptomatic and symptomatic infections should be treated. Potentially powerful interactions of reproductive tract infection and inflammation with other obstetric factors, including a prior history of preterm birth, first trimester bleeding, and possibly, short cervix and multiple gestation can be mitigated by effective treatment of reproductive tract infections. Medical care providers now have the opportunity and the obligation to reduce infection-mediated preterm birth by expeditiously identifying and treating prevalent reproductive tract infections in their pregnant patients.

The real cost savings arising from effectively preventing or treating preterm birth ascribable to prevalent reproductive tract infections are demonstrated in the lives of children saved from premature death and personal, biologic and economic impairment. Three meta-analyses demonstrate neonatal and maternal benefits from adjunctive antibiotic treatment of mothers suffering preterm premature rupture of membranes. The effects of adjunctive antibiotic treatment of women with preterm labor are inconsistent, but single-agent regimens using erythromycin and clindamycin are effective and provide coverage for group B streptococcus. Providers and payers now have evidence-based, clinically proven and cost-saving opportunities to prevent important numbers of preterm births, as well as preventing individual children suffering from being 'born too soon'.

Premature rupture of membranes arises from what are likely multifaceted and multistep pathogenic pathways. Pathophysiological processes may involve both endogenous and exogenous fetal and maternal factors. This article reviews and analyzes information regarding, first, the form and function of fetal membranes; second, how membranes physically fail (rupture) at term and preterm gestations; and third, evaluates if we can reduce risks of rupture using physiological understanding and evidence-based clinical studies.

Political scientists seek to explain political behavior. In so doing, they frequently rely on factors such as class, income, religion, age, sex, education, race, residence, and the like, or their aggregate in the case of comparative and international studies. What is conspicuously missing from almost all mainstream political science literature is the mention of constitutions or law as influences on individual or collective behavior. The underlying premise of this article is that political behavior may take place in a certain form simply because the law commands it, the law permits it, or the law prohibits other types of behavior . This article argues that constitutions in Central and Eastern Europe play a critical role in channeling political activity and that the outcome of many struggles over power and policy can be traced to the general and sometimes even specific influence of those constitutions.

OBJECTIVE: Our purpose was to compare Affirm VP, a new deoxyribonucleic acid probe test, with standard "wet preparation" microscopic examinations and culture for the identification of Trichomonas vaginalis organisms in vaginal secretions. STUDY DESIGN: We examined vaginal samples from 615 women with symptoms or signs of vaginitis for T. vaginalis using the deoxyribonucleic acid probe test, microscopic examination of wet preparations of vaginal secretions, and culture in modified Diamond's medium. RESULTS: T. vaginalis was identified in specimens from 95 (15.4%) of the 615 patients. Cultures in Diamond's medium identified 93 (98%) of the 95 infected patients. Vaginal wet preparation identified 76 (80%) of the infected women. The deoxyribonucleic acid probe test detected 86 (90.5%) of the 95 infected patients. There was one false-positive deoxyribonucleic acid probe test (specificity 519/520: 99.8%). CONCLUSION: The Affirm VP deoxyribonucleic acid probe test had a sensitivity of 90% and a specificity of 99.8% for the identification of T. vaginalis organisms in women with symptoms with a high prevalence of trichomoniasis. Such a nonculture test may be of considerable benefit in diagnosing T. vaginalis infections, especially in settings where microscopy, culture, or both are unavailable, inconvenient, or unreliably performed. (AM J OBSTET GYNECOL 1996;174:1339-42.)

Objective: We sought to compare the efficacy of metronidazole gel vs. triple-sulfa cream in the treatment of bacterial vaginosis (BV). Methods: In a double-blinded study, 247 women with symptomatic BV were randomly assigned to receive either 5 g of 0.75% metronidazole gel twice daily for 5 days or triple-sulfa cream twice daily for 5 days. There were 205 (96 treated with metronidazole and 109 treated with triple-sulfa) evaluable patients to compare efficacy at the final visit. Approximately 60% of these patients had been previously treated for BV, reflecting the recurrent nature of the disease in this patient population. Results: At the first (12-16 days) return visit, 81/103 (79%) patients in the metronidazole group were cured compared with 80/113 (71%) patients in the triple-sulfa cream group (P 0.333). At the final (28-35 days) return visit, 63/96 (66%) in the 96 metronidazole group remained cured compared with only 51/109 (47%) in the triple-sulfa group (P 0.02). An intent-to-treat analysis similarly showed that the cure rate with metronidazole was superior to triple-sulfa (P-< 0.02). The clinical diagnosis demonstrated a high correlation (88%) with the diagnosis made by an independent assessment by Gram’s stain. The side effects reported by the patients using metronidazole gel were infrequent and mild and were similar to those reported with triple-sulfa. Conclusions: Metronidazole gel is a safe, effective, and well-tolerated treatment for BV. (C) 1996 Wiley-Liss, Inc.

Objective: Trichomonas vaginalis (TV)infection is associated with preterm rupture of membranes (PROM) and preterm birth. We evaluated the effects ofTVgrowth and metabolism on preparations of human amniochorion to understand and characterize howTVmay impair fetal-membrane integrity and predispose to PROM and preterm birth.Methods:Term fetal membranes were evaluated using an established in vitro fetal-membrane model. FreshTVclinical isolates were obtained from pregnant women. The protozoa (5.0×105to1.5×106/ml) were incubated with fetal membranes in modified Diamond's medium for 20 h at 37°C in 5%CO2.The effects of fetal-membrane strength (bursting tension, work to rupture, and elasticity) were measured using a calibrated Wheatstone-bridge dynamometer. Tests were also performed to evaluate the effects of 1) inoculum size; 2) metronidazole (50 μg/ml); and 3) cell-free filtrate.Results:TheTV-induced membrane effects were 1) isolate variable; 2) inoculum dependent; 3) incompletely protected by metronidazole; and 4) mediated by both live organisms as well as protozoan-free culture filtrates. Six of 9 isolates significantly reduced the calculated work to rupture (P≤ 0.02); 7 of 9 reduced bursting tension; and 1 of 9 reduced elasticity. One isolate significantly increased the work to rupture and bursting tension (P≤ 0.002).Conclusions:In vitro incubation of fetal membranes withTVcan significantly impair the measures of fetal-membrane strength. This model may be used to delineate the mechanisms ofTV-induced membrane damage. This study suggests that there are enzyme-specific effects as well as pH effects.

Positron emission tomography (PET) with fluorine-18 (18F)-fluoro-2-deoxyglucose (FDG) has been proven to be a valuable noninvasive imaging modality for the diagnosis, staging, and monitoring of therapy for various malignancies. In addition, studies are demonstrating the value of FDG-PET for the evaluation of nononcologic conditions. Based on the literature, conditions such as osteomyelitis, fever of unknown origin (FUO), acquired immunodeficiency syndrome (AIDS), vasculitis, and inflammatory bowel disease can be successfully imaged with FDG-PET. With the approval of additional PET radiotracers in the future, there will be more widespread applications of PET for inflammatory and infectious disorders.

OBJECTIVE: Low birth weight remains the leading cause of perinatal morbidity and mortality, but mechanisms mediating impaired fetal growth are poorly understood. To further define the role of abnormal immune activation and suppression in mediating impaired fetal growth, we measured levels of interleukin-10, a potent immunosuppressive cytokine not previously identified in association with pregnancy, in amniotic fluid samples obtained at genetic amniocentesis. STUDY DESIGN: In a case-control study with an enzyme-linked immunoassay we compared amniotic fluid levels of interleukin-10 in midtrimester samples obtained from appropriate-for-gestational age ( n = 42) and small-for-gestational-age ( n = 24) pregnancies. RESULTS: Interleukin-10 levels in small-for-gestational-age samples were elevated (median 78 pg/ml) compared with levels in control samples (median p = 0.02. In small-for-gestational-age pregnancies elevated levels were associated with nulliparity, p = 0.003. CONCLUSION: Our data support the role of abnormal immune activation, as opposed to inadequate immune suppression, in mediating impaired fetal growth.

Objective: To evaluate the efficacy and safety of ampicillin-sulbactam (3 g every 6 hours) in patients with pelvic inflammatory disease or postpartum endometritis using a randomized, comparative, multicenter study of parallel design. Methods: Eligible patients with pelvic inflammatory disease were randomized to receive either ampicillin-sulbactam or cefoxitin (2 g every 6 hours) plus doxycycline (100 mg every 12 hours). Those with endometritis were randomized to ampicillin-sulbactam or clindamycin (900 mg every 8 hours) plus gentamicin (1.5 mg/kg every 8 hours). In the ampicillin-sulbactam group, chlamydia-positive patients also received oral doxycycline. Results: For pelvic inflammatory disease, the clinical response rates (cure or improvement) were 85.5% (47 of 55) and 89.6% (43 of 48) in the ampicillin-sulbactam and cefoxitin and doxycycline groups, respectively (X2 = 0.10,P= .76). For endometritis, the clinical response rates were 88.7% (141 of 159) and 90.8% (139 of 153) in the ampicillinsulbactam and clindamycin and gentamicin groups, respectively (X2 = 0.15,P= .70). The percentages of patients with pelvic inflammatory disease who had adverse experiences were not significantly different in the cefoxitin and doxycycline group (47% [29 of 62]) than in those receiving ampicillin-sulbactam (33% [22 of 66]) (P= .12). These adverse effects were mostly mild or moderate. In the endometritis subjects, the incidence of adverse experiences in the ampicillin-sulbactam group (11% [20 of 179]) was comparable to that during treatment with clindamycin and gentamicin (12% [22 of 180]). These adverse experiences were also mostly mild to moderate. Conclusion: Ampicillin-sulbactam is as effective and well tolerated as combination regimens using cefoxitin plus doxycycline and clindamycin plus gentamicin for the treatment of pelvic inflammatory disease or endometritis, respectively.(Obstet Gynecol 1994;83:998-1004)

OBJECTIVE : The pathogenesis of preterm birth and other adverse pregnancy outcomes linked with reproductive tract infection remains poorly understood. Mucolytic enzymes, including mucinases and sialidases (neuraminidase), are recognized virulence factors among enteropathogens and bacteria that cause periodontal infection. Perturbation of maternal cervicovaginal mucosal membrane host defenses by such enzyme-producing microorganisms may increase the risk of subclinical intrauterine infection during pregnancy and thus increase risks of preterm birth. STUDY DESIGN : We prospectively evaluated vaginal fluid mucinase and sialidase and selected cervicovaginal bacteria along with pregnancy outcomes in 271 women. Within this study, women with bacterial vaginosis (16 to 27 weeks' gestation) were treated with 2% clinadmycin vaginal cream or placebo. Enzyme, microbial findings, treatment effects, and pregnancy outcomes were compared among drug- and placebo-treated women and control women without bacterial vaginosis. RESULTS : Presence of bacterial vaginosis at intake was associated with increased risk of preterm birth (relative risk 3.3, 95% confidence interval 1.2 to 9.1, p = 0.02), premature rupture of membranes (relative risk 3.8, 95% confidence interval 1.6 to 9.0, p = 0.002), and preterm premature rupture of membranes. Mucinase and sialidase activities were more commonly identified, and they occurred in higher concentrations, if present, in women with bacterial vaginosis (mucinase: 44.3% with bacterial vaginosis vs 27.4% without, p = 0.007; sialidase: 45% with bacterial vaginosis vs 12% without, p Gardnerella vaginalis, Mobiluncus spp, and Mycoplasma hominis ) and Chlamydia trachomatis and yeast species; mucinase activity was associated only with bacterial vaginosis - linked microorganisms. Clindamycin, 2% cream, was effective treatment for bacterial vaginosis and temporarily reduced mucinase and sialidase activities. Topical treatment of bacterial vaginosis did not reduce risks of perinatal morbidity. Women with persistent or recurrent sialidase 8 weeks after treatment were at increased risk of preterm birth (15.6% vs 7.4%) premature rupture of membranes (30% vs 15%), and low birth weight (20% vs 3%, relative risk 6.8, 95% confidence interval 1.6 to 28.1). CONCLUSIONS : Persistence of sialidase-producing vaginal microorganisms in numbers sufficient to increase vaginal fluid sialidase activity may be a risk factor for possibly preventable subclinical intrauterine infection and preterm birth. This study confirms and further informs our understanding of the association of bacterial vaginosis and preterm birth; studies to evaluate whether systemic treatment for bacterial vaginosis can effectively reduce vaginal mucolytic enzymes and risks of prematurity and other morbid outcomes are continuing. (AM J OBSTET GYNECOL 1994; 170:1048-60.)