The association between heavy metals, endometriosis and uterine myomas among premenopausal women: National Health and Nutrition Examination Survey 1999-2002.

BACKGROUND: It has been hypothesized that exposure to exogenous estrogens may be associated with endometriosis and uterine myomas. We sought to investigate the association between heavy metals which have been shown to be hormonally active and these disorders using data from the National Health and Nutrition Examination Survey, 1999-2002. METHODS: Women aged 20-49 years who had data on metals and the outcomes of interest, were premenopausal and neither pregnant nor breastfeeding were eligible (n = 1425). Lead, cadmium and mercury were measured in whole blood. Diagnosis of outcomes was based upon self-report. Logistic regression was used to examine the association between tertiles of heavy metals and disease adjusting for age, race/ethnicity, use of birth control pills prior to diagnosis and smoking status at diagnosis. RESULTS: A dose-response association between cadmium and endometriosis was observed [tertile 2 versus 1: adjusted odds ratio (OR) = 1.94, 95% confidence interval (CI): 0.73-5.18; tertile 3 versus 1: adjusted OR = 3.39, 95% CI 1.37-8.40]. This association persisted in subanalyses: (i) limiting analysis to women diagnosed in the past 10 years and (ii) limiting analysis to women diagnosed since last pregnancy, although limited by sample size. CONCLUSIONS: These results must be interpreted with caution given the cross-sectional study design. The observed association between cadmium and endometriosis deserves further investigation in properly designed studies.

Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial.

BACKGROUND: The objective of this prospective controlled trial was to investigate the ability of a group of serum and peritoneal fluid (PF) markers to predict, non-surgically, endometriosis. METHODS AND RESULTS: Serum and PF samples were obtained from 130 women while undergoing laparoscopy for pain, infertility, tubal ligation or sterilization reversal. Concentrations of six cytokines [interleukin (IL)-1beta, IL-6, IL-8, IL-12, IL-13 and tumour necrosis factor (TNF)-alpha] were measured in serum and PF, and reactive oxygen species (ROS) in PF, and levels were compared among women who were allocated to groups according to their post-surgical diagnosis. Fifty-six patients were diagnosed with endometriosis, eight with idiopathic infertility, 27 underwent tubal ligation or reanastomosis (control group) and 39 were excluded due to bloody PF. Only serum IL-6 and PF TNF-alpha could be used to discriminate between patients with and without endometriosis with a high degree of sensitivity and specificity (P < 0.001). A threshold of 15 pg/ml PF TNF-alpha provided 100% sensitivity and 89% specificity (positive likelihood ratio of 9.1 and negative likelihood ratio of 0). A threshold of 2 pg/ml for serum IL-6 provided a sensitivity of 90% and specificity of 67% (positive likelihood ratio of 2.7 and negative likelihood ratio of 0.14). CONCLUSIONS: By measuring serum IL-6 and PF TNF-alpha, it was possible to discriminate between patients with endometriosis and those without. Before these markers can be used as a non-surgical diagnostic tool, these data should be verified in a larger study.

Recurrent osseous metaplasia of the cervix after loop electrosurgical excision.

BACKGROUND: Osseous metaplasia of the uterus is a rare pathologic entity usually affecting the endometrial cavity without cervical extension. It has been reported after abortion, in cases of chronic endometritis, and as a result of metabolic disorders as hypervitaminosis D, hyperparathyroidism, hypercalcemia, and hyperphosphatemia. CASE: A woman developed osseous metaplasia of the cervix shortly after loop electrosurgical excision procedure (LEEP) for severe cervical dysplasia. Normal transvaginal ultrasonograms before the LEEP, and failure to detect osseous metaplasia after histologic review of the tissue obtained from that procedure indicate that the osseous metaplasia had been induced by the LEEP. The heterotopic bone formation rapidly recurred after initial removal. Her serum calcium, phosphorus, and vitamin D levels were normal. CONCLUSION: LEEP may result in healing with metaplastic bone formation.

Molecular characterization of calmodulin trapping by calcium/calmodulin-dependent protein kinase II.

Autophosphorylation of alpha-Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) at Thr(286) results in calmodulin (CaM) trapping, a >10,000-fold decrease in the dissociation rate of CaM from the enzyme. Here we present the first site-directed mutagenesis study on the dissociation of the high affinity complex between CaM and full-length CaM kinase II. We measured dissociation kinetics of CaM and CaM kinase II proteins by using a fluorescently modified CaM that is sensitive to binding to target proteins. In low [Ca(2+)], the phosphorylated mutant kinase F293A and the CaM mutant E120A/M124A exhibited deficient trapping compared with wild-type. In high [Ca(2+)], the CaM mutations E120A, M124A, and E120A/M124A and the CaM kinase II mutations F293A, F293E, N294A, N294P, and R297E increased dissociation rate constants by factors ranging from 2.3 to 116. We have also identified residues in CaM and CaM kinase II that interact in the trapped state by mutant cycle-based analysis, which suggests that interactions between Phe(293) in the kinase and Glu(120) and Met(124) in CaM specifically stabilize the trapped CaM-CaM kinase II complex. Our studies further show that Phe(293) and Asn(294) in CaM kinase II play dual roles, because they likely destabilize the low affinity state of CaM complexed to unphosphorylated kinase but stabilize the trapped state of CaM bound to phosphorylated kinase.

Hysterectomy in Veterans Affairs Medical Centers.

OBJECTIVE: To examine the indications and surgical morbidity for women veterans who underwent hysterectomies in Department of Veterans Affairs Medical Centers (VAs). METHODS: Data on hysterectomies performed in VAs from 1991 to 1997 were abstracted from a surgical quality improvement program. RESULTS: Records of 1722 women who had hysterectomies in VAs over 6 years were examined. Women were predominately white (62%) and their average age was 42.5 years. Operations included abdominal (74%), vaginal (22%), and laparoscopic-assisted (4%) methods. The most common indications for surgery included uterine leiomyomas (31%), abnormal uterine bleeding (14%), and endometriosis (11%). Indications differed by race (P <.01); nonwhite women were most likely to have surgery for leiomyoma (51%), whereas white women had hysterectomies for leiomyomas (19%), abnormal bleeding (15%), endometriosis (13%), and genital prolapse (11%). The mean postoperative stay was significantly longer for abdominal hysterectomies (4.51 days) than either vaginal or laparoscopic-assisted hysterectomies (2.92 and 2.21 days, respectively; P <.001). The overall complication rate within 30 days was 9%, and the most frequent complication was urinary tract infection (3.3%). CONCLUSION: Women who underwent hysterectomies in VAs had low complication rates, comparable to hysterectomy complication rates in the United States generally.

Prolapsed cervical myoma after uterine artery embolization. A case report.

BACKGROUND: Cervical prolapse of myomas following uterine artery embolization is an infrequently reported occurrence. CASE: A 40-year-old woman with a history of three prior abdominal myomectomies underwent uterine artery embolization for severe menorrhagia due to myomas. Two weeks later a large cervical myoma prolapsed, requiring an abdominal hysterectomy. CONCLUSION: Cervical myomas should be considered a relative contraindication to uterine artery embolization.

A 4-year follow-up study of women with Norplant-2 contraceptive implants.

One-hundred-thirty of 178 women who received Norplant-2 implants were followed prospectively for 4 years. Menstrual disorders were the most common reason for discontinuation. Only one patient conceived, for a failure rate of 0.6%.

The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization.

OBJECTIVE: To examine the presence of reactive oxygen species (ROS) in the follicular fluid of women undergoing in vitro fertilization (IVF) and identify its role in pregnancy outcome. STUDY DESIGN: In this prospective study, ROS and total antioxidant capacity (TAC) levels were measured by the chemiluminescence method in the follicular fluid of 53 women. Age, number of oocytes recovered, percentage of oocytes fertilized, ROS and TAC levels were compared in women who did and did not become pregnant. RESULTS: Patients who become pregnant had significantly higher log-transformed ROS levels (1.01 +/- 0.14, P = 0.031 than those who did not (0.69 +/- 0.08). Women with endometriosis or male factor infertility who became pregnant had significantly higher ROS levels (1.44 +/- 0.23 and 1.31 +/- 0.19) than those who did not (0.60 +/- 0.17 and 0.67 +/- 0.16; P < .006 and P < .01). CONCLUSION: Follicular fluid ROS, at low concentrations, may be a potential marker for predicting success in IVF patients.

Case-control study of laparoscopic versus abdominal myomectomy.

PURPOSE: To compare laparoscopic with abdominal approaches to myomectomy. PATIENTS AND METHOD: Frequency matching was used to ensure similar fibroid weights among the laparoscopic and abdominal groups in this case-control study. The study group consisted of prospectively recruited patients undergoing laparoscopic (N = 5) or laparoscopically assisted (N = 20) myomectomy (lap). The control group represented both prospectively (N = 14) and retrospectively (N = 37) identified abdominal myomectomy patients (abd). Analysis of the variables was performed using a t-test, Wilcoxon rank-sum test, chi-square test, or analysis of covariance at the 0.01 significance level. RESULTS: All results are reported after matching for fibroid weight, with the median (quartiles) aggregate weight measuring 151 g (31.0, 262.0) and 170.0 g (81.0, 285.0) for the lap and abd patients, respectively (P = 0.15). Median (quartiles) length of hospital stay (30.5 hours [25.0, 52.5] v 65.0 hours [45.0, 76.0]; P < 0.001) and duration of postoperative intravenous narcotic use (14.8 hours [3.0, 18.5] v 24.0 hours [18.0, 40.0]; P = 0.001) were significantly shorter for the lap patients. The laparoscopic cases required a longer median operative time (222.5 minutes [192.5, 270.0]) than the abdominal cases (180.0 minutes [160.0, 220.0]; P = 0.001). No difference was detected in estimated blood loss from surgery (P = 0.57). CONCLUSIONS: A laparoscopic approach to myomectomy may be safely chosen for patients with fibroids and offers the benefits of less postoperative intravenous narcotic use, a shorter hospital stay, and no greater intraoperative blood loss than abdominal myomectomy.

Laparoscopic repair of ureteral transection.

Injury to the ureter is a possible complication of laparoscopic surgery. Traditionally, it is repaired by laparotomy. During laparoscopic surgery for bilateral ovarian remnants in a 29-year-old woman, the left ureter was transected. The ureter was repaired by primary end-to-end anastomosis by laparoscopy. The patient recovered uneventfully, and postoperative intravenous puelogram confirmed the repair to be intact.

Robotic-assisted laparoscopic microsurgical tubal anastomosis: a human pilot study.

OBJECTIVE: To evaluate the feasibility and safety of a robotic device to perform a laparoscopic tubal anastomosis. DESIGN: Prospective pilot study. SETTING: Tertiary care medical center. PATIENT(S): Ten patients with previous tubal ligations underwent laparoscopic tubal ligation reversal using a robotic suturing device. INTERVENTION(S): Tubal surgery was performed with a robotic system. A two-layered closure was used for all tubes. Four stitches of 8-0 polygalactin sutures were used for each layer. MAIN OUTCOME MEASURE(S): Tubal patency; secondary measures were pregnancy rates, complications, and operative time. RESULT(S): The procedure was completed successfully in all 10 patients. No patient required conversion to an open procedure. The mean time (+/-SD) required to complete the anastomosis of both tubes was 159 +/- 33.8 minutes. Chromotubation at the end of the procedure showed patency in all tubes anastomosed. A postoperative hysterosalpingogram 6 weeks after surgery demonstrated patency in 17 of the 19 (89%) tubes anastomosed. There have been five pregnancies so far. There were no complications. CONCLUSION(S): Robotic technology can be used safely to create laparoscopic microsurgical anastomoses with adequate patency rates. Robotic technology has the potential to make laparoscopic microsuturing easier.

Afferent diversity and the organization of central vestibular pathways.

This review considers whether the vestibular system includes separate populations of sensory axons innervating individual organs and giving rise to distinct central pathways. There is a variability in the discharge properties of afferents supplying each organ. Discharge regularity provides a marker for this diversity since fibers which differ in this way also differ in many other properties. Postspike recovery of excitability determines the discharge regularity of an afferent and its sensitivity to depolarizing inputs. Sensitivity is small in regularly discharging afferents and large in irregularly discharging afferents. The enhanced sensitivity of irregular fibers explains their larger responses to sensory inputs, to efferent activation, and to externally applied galvanic currents, but not their distinctive response dynamics. Morphophysiological studies show that regular and irregular afferents innervate overlapping regions of the vestibular nuclei. Intracellular recordings of EPSPs reveal that some secondary vestibular neurons receive a restricted input from regular or irregular afferents, but that most such neurons receive a mixed input from both kinds of afferents. Anodal currents delivered to the labyrinth can result in a selective and reversible silencing of irregular afferents. Such a functional ablation can provide estimates of the relative contributions of regular and irregular inputs to a central neuron's discharge. From such estimates it is concluded that secondary neurons need not resemble their afferent inputs in discharge regularity or response dynamics. Several suggestions are made as to the potentially distinctive contributions made by regular and irregular afferents: (1) Reflecting their response dynamics, regular and irregular afferents could compensate for differences in the dynamic loads of various reflexes or of individual reflexes in different parts of their frequency range; (2) The gating of irregular inputs to secondary VOR neurons could modify the operation of reflexes under varying behavioral circumstances; (3) Two-dimensional sensitivity can arise from the convergence onto secondary neurons of otolith inputs differing in their directional properties and response dynamics; (4) Calyx afferents have relatively low gains when compared with irregular dimorphic afferents. This could serve to expand the stimulus range over which the response of calyx afferents remains linear, while at the same time preserving the other features peculiar to irregular afferents. Among those features are phasic response dynamics and large responses to efferent activation; (5) Because of the convergence of several afferents onto each secondary neuron, information transmission to the latter depends on the gain of individual afferents, but not on their discharge regularity.

Morphological identification of physiologically characterized afferents innervating the turtle posterior crista.

The turtle posterior crista consists of two hemicristae. Each hemicrista extends from the planum semilunatum to the nonsensory torus and includes a central zone (CZ) surrounded by a peripheral zone (PZ). Type I and type II hair cells are found in the CZ and are innervated by calyx, dimorphic and bouton afferents. Only type II hair cells and bouton fibers are found in the PZ. Units were intraaxonally labeled in a half-head preparation. Bouton (B) units could be near the planum (BP), near the torus (BT), or in midportions of a hemicrista, including the PZ and CZ. Discharge properties of B units vary with longitudinal position in a hemicrista but not with morphological features of their peripheral terminations. BP units are regularly discharging and have small gains and small phase leads re angular head velocity. BT units are irregular and have large gains and large phase leads. BM units have intermediate properties. Calyx (C) and dimorphic (D) units have similar discharge properties and were placed into a single calyx-bearing (CD) category. While having an irregular discharge resembling BT units, CD units have gains and phases similar to those of BM units. Rather than any single discharge property, it is the relation between discharge regularity and either gain or phase that makes CD units distinctive. Multivariate statistical formulas were developed to infer a unit's morphological class (B or CD) and longitudinal position solely from its discharge properties. To verify the use of the formulas, discharge properties were compared for units recorded intraaxonally or extracellularly in the half-head or extracellularly in intact animals. Most B units have background rates of 10-30 spikes/s. The CD category was separated into CD-high and CD-low units with background rates above or below 5 spikes/s, respectively. CD-low units have lower gains and phases and are located nearer the planum than CD-high units. In their response dynamics over a frequency range from 0.01-3 Hz, BP units conform to an overdamped torsion-pendulum model. Other units show departures from the model, including high-frequency gain increases and phase leads. The longitudinal gradient in the physiology of turtle B units resembles a similar gradient in the anamniote crista. In many respects, turtle CD units have discharge properties resembling those of calyx-bearing units in the mammalian central zone.

Responses to efferent activation and excitatory response-intensity relations of turtle posterior-crista afferents.

Multivariate statistical formulas were used to infer the morphological type and longitudinal position of extracellularly recorded afferents. Efferent fibers were stimulated electrically in the nerve branch interconnecting the anterior and posterior VIIIth nerves. Responses of bouton (B) units depended on their inferred position: BP units (near the planum semilunatum) showed small excitatory responses; BT units (near the torus) were inhibited; BM units (in an intermediate position) had a mixed response, including an initial inhibition and a delayed excitation. Calyx-bearing (CD-high) units with an appreciable background discharge showed large per-train excitatory responses followed by smaller post-train responses that could outlast the shock train by 100 s. Excitatory responses were smaller in calyx-bearing (CD-low) units having little or no background activity than in CD-high units. Excitatory response-intensity functions, derived from the discharge during 2-s angular-velocity ramps varying in intensity, were fit by empirical functions that gave estimates of the maximal response (r(MAX)), a threshold velocity (v(T)), and the velocity producing a half-maximal response (v(1/2)). Linear gain is equal to r(MAX)/v(S), v(S) = v(1/2) - v(T). v(S) provides a measure of the velocity range over which the response is nearly linear. For B units, r(MAX) declines by as much as twofold over the 2-s ramp, whereas for CD units, r(MAX) increases by 15% during the same time period. At the end of the ramp, r(MAX) is on average twice as high in CD as in B units. Thresholds are negligible in most spontaneously active units, including almost all B and CD-high units. Silent CD-low units typically have thresholds of 10-100 deg/s. BT units have very high linear gains and v(S) < 10 deg/s. Linear gains are considerably lower in BP units and v(S) > 150 deg/s. CD-high units have intermediate gains and near 100 deg/s v(S) values. CD-low units have low gains and v(S) values ranging from 150 to more than 300 deg/s. The results suggest that BT units are designed to measure the small head movements involved in postural control, whereas BP and CD units are more appropriate for monitoring large volitional head movements. The former units are silenced by efferent activation, whereas the latter units are excited. This suggests that the efferent system switches the turtle posterior crista from a "postural" to a "volitional" mode.

Successful management of a viable cervical pregnancy by single-dose methotrexate.

Cervical pregnancy is very uncommon and carries a high risk for hysterectomy with surgical treatment. Prior reports of medical treatment included various regimens of high-dose systemic methotrexate (MTX) with citrovorum rescue and local injection. This is the first report of successfully treating a viable cervical pregnancy with single-dose i.m. MTX, followed by a vaginal delivery.

Comparison of intrauterine and intracervical insemination with frozen donor sperm: a meta-analysis.

OBJECTIVE: To determine whether artificial insemination with frozen donor sperm yielded a higher pregnancy rate per cycle by intracervical (ICI) or intrauterine (IUI) techniques. A meta-analysis was performed. DATA IDENTIFICATION: A computerized MEDLINE search of the English-language literature on artificial insemination with donor sperm was performed and augmented by a review of meeting abstract books and references in published papers. STUDY SELECTION: Only prospective randomized studies that reported monthly fecundity rates for IUI and ICI with frozen donor sperm were included. DATA ANALYSIS: Seven studies were identified. The odds ratios (OR) and 95% confidence intervals (CI) were determined with use of the general estimating equation method for the three studies for which raw data could be obtained. For the remaining four studies, the OR and CI were assessed with use of the published summary data. A random-effects meta-analysis was then performed. RESULT: Intrauterine insemination resulted in a significantly higher monthly fecundity rate with a common OR of 2.4 (CI 1.5-3.8). CONCLUSION: On the basis of this meta-analysis of the seven prospective studies, IUI results in higher pregnancy rates than ICI for frozen donor insemination.

Risk factors for multiple gestation in women undergoing intrauterine insemination with ovarian stimulation.

OBJECTIVE: To identify whether sperm characteristics after washing and/or ovulation induction cycle characteristics can predict the occurrence of multiple conception in patients undergoing ovarian stimulation and IUI. DESIGN: Retrospective study. SETTING: A gynecology clinic and an andrology laboratory at a tertiary care facility. PATIENT(S): One hundred patients with single pregnancies and 22 patients with multiple pregnancies. INTERVENTION(S): Patients underwent ovarian stimulation and IUI with their partner's sperm. MAIN OUTCOME MEASURE(S): Relation of patient characteristics, ovarian stimulation, and sperm characteristics after washing to the occurrence of multiple pregnancy. RESULT(S): The mean serum E2 level on the day of hCG injection was significantly higher in the multiple conception group, but the number of follicles was not. The total sperm count, total motile sperm count, and sperm motility after washing did not differ between the groups. However, couples with multiple pregnancies had sperm with a significantly higher amplitude of lateral head movement than couples with single pregnancies. A peak E2 level of >583 pg/mL on the day of hCG injection and sperm with an ALH of >4 microm after washing predicted the occurrence of multiple pregnancy. CONCLUSION(S): Sperm with an amplitude of lateral head movement of >4 microm and a peak E2 level of >583 pg/mL are significant risk factors for multiple pregnancy in patients undergoing IUI.

Evaluation of Langerhans' cells in the cervical epithelium of women with cervical intraepithelial neoplasia.

OBJECTIVE: Cervical infection with human papillomavirus (HPV) results in a more permissive environment for malignant transformation. In squamous epithelia the Langerhans' cell (LC) is responsible for antigen presentation. Studies that use S-100 immunostaining demonstrate low LCs in cervical intraepithelial neoplasia (CIN) while those that use other methods have shown normal numbers of LCs. This observation led us to postulate that a defect in S-100 proteins, not a simple decrease in LC number, may be the cause of immune suppression. To evaluate this we identified LCs in the cervix of women with HPV/CIN in a prospective fashion using two antibodies, S-100 and CD1, each targeting a different element of the LC. METHODS: Paired biopsies of the cervix were taken, one paraffin embedded for S-100 and the other snap frozen for CD1 staining. LCs were counted and expressed as the number of cells per millimeter of epithelium. Analysis of variance was used to assess differences between counts in normal, low-grade, and high-grade lesions. HPV was tested by hybrid capture. RESULTS: S-100 LCs were significantly reduced in dysplasia, LG 8.6 and HG 6.0, compared to normal at 16.7 cells/mm (P = 0.04). S-100 LCs were reduced in HPV-infected cases at 5.9 vs 12.8 cells/mm in HPV negatives (P = 0.02). Acute inflammatory infiltrates were associated with increased S-100 LCs independent of pathology. CD1 LCs were not significantly altered by any parameters tested. CONCLUSIONS: HPV/CIN may exert an immunosuppressive effect by decreasing the S-100 LCs. The association of S-100-positive LCs coupled with cervical inflammatory changes suggests an important function of the S-100 proteins in the development of an anti-HPV response.