Comparability of perioperative morbidity between abdominal myomectomy and hysterectomy for women with uterine leiomyomas.

OBJECTIVE: The aim of this study was to compare the perioperative morbidity associated with abdominal myomectomy with that of hysterectomy. STUDY DESIGN: This was a retrospective cohort study of 394 women at an academic medical center. Main outcome measured was perioperative morbidity, with the following secondary outcomes: febrile morbidity, hemorrhage, unintended major surgical procedures, life-threatening events, and rehospitalization. RESULTS: Morbidity was associated with myomectomy and hysterectomy in 39% and 40% of cases, respectively. The crude odds ratio for morbidity of myomectomy with respect to hysterectomy was 0.93 (95% confidence interval, 0.63-1.40). Women who underwent myomectomy were significantly younger, weighed less, and had a smaller preoperative uterine size. In a multivariable analysis that accounted for these differences the odds ratio increased to 1.46 (95% confidence interval, 0.77-2.77) but still was not statistically elevated. The study had >90% power to detect a clinically relevant 15% absolute difference in overall morbidity between the 2 groups. CONCLUSION: No clinically significant difference in perioperative morbidity between myomectomy and hysterectomy was detected. Myomectomy should be considered a safe alternative to hysterectomy.

Development of cholinergic neurons in rat brain regions: dose-dependent effects of propylthiouracil-induced hypothyroidism.

The effects of hypothyroidism on development of cholinergic system in brain regions (prefrontal cortex and hippocampus) were evaluated by measuring choline acetyltransferase (ChAT) activity and hemicholinium-3 binding to the high-affinity choline transporter. Various degrees of thyroid deficiency were produced by perinatal exposure to propylthiouracil (PTU) in drinking water ranging from 5 ppm (mg/l) to 25 ppm beginning at gestational day 18 until postnatal day 21. ChAT, a marker for cholinergic nerve terminals, was reduced by PTU in a dose-dependent manner. Concomitant with the enzyme deficits, hemicholinium-3 binding was elevated, suggesting an increase in neuronal impulse activity. Although similar changes were seen in both brain regions examined, the magnitude and duration of these changes were more definitive in the prefrontal cortex. Nonetheless, these neurochemical alterations appeared to be recoverable when the rats returned to a euthyroid state, and no further changes were observed as the animals reached adulthood. In comparison, data reported in a succeeding article indicate that deficits in cognitive function were first seen in weanling hypothyroid rats, but that the behavioral impairments lasted well into adulthood when thyroid status and cholinergic parameters in the brain appeared to have recovered to normal. These results suggest that alterations of cholinergic system caused by perinatal hypothyroidism are associated with neurobehavioral deficits at weaning, and these developmental deviations may cause permanent impairment of cognitive function despite recovery from the hormonal imbalance at adult ages.

The management of hydrosalpinges before in-vitro fertilization and embryo transfer.

Several recent studies have shown that the presence of hydrosalpinges adversely affects clinical pregnancy rates achieved with in-vitro fertilization and embryo transfer. Hydrosalpinx fluid may be toxic to the endometrium or embryo, or may mechanically interfere with implantation. Some authors recommend surgical correction of hydrosalpinges before in-vitro fertilization and have shown promising results with this approach. Proper patient selection for this therapy still needs to be defined.

Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management.

OBJECTIVE: To determine characteristics predictive of persistent ectopic pregnancy (EP). DESIGN: Retrospective cohort study. SETTING: Tertiary care, university hospital. PATIENT(S): All women treated surgically for an EP whose postoperative hCG levels were followed until complete resolution or determination of a persistent EP over a 54-month period. MAIN OUTCOME MEASURE(S): Final outcome defined as successful treatment or persistent EP. RESULT(S): Twenty-six (17.7%) of 147 patients were diagnosed with a persistent EP. An inverse relationship was noted between the percent decrease in hCG at postoperative day 1 and the incidence of persistent EP. A significantly greater percentage of persistent EPs were noted when the postoperative day 1 hCG fell < 50% from the initial preoperative hCG level (relative risk = 3.51 [1.25 to 6.68]). No case of persistent EP was noted if the postoperative day 1 hCG declined by > or = 77%. Surgical time differed significantly (129 minutes versus 101 minutes) between cases treated successfully as compared with cases in which conservative treatment failed. No other preoperative or intraoperative variables were found to be significantly different. CONCLUSION(S): Although no single postoperative hCG value is predictive of conservative surgical treatment for EP, a day-1 postoperative hCG value may be used as a predictor of persistent EP.

Hydrosalpinx fluid enhances human trophoblast viability and function in vitro: implications for embryonic implantation in assisted reproduction.

OBJECTIVE: To assess the effects of hydrosalpinx fluid on human cytotrophoblast viability and function in vitro. DESIGN: Human cytotrophoblasts obtained from third-trimester placentas were cultured in vitro with hydrosalpinx fluid, and cell viability and protein production were assayed. SETTING: A university hospital. PATIENT(S): Ten hydrosalpinx fluid samples obtained from seven women with clearly diagnosed hydrosalpinges. INTERVENTION(S): Recovery of hydrosalpinx fluid by transvaginal aspiration or at the time of surgery. MAIN OUTCOME MEASURE(S): Cell viability was assessed by the XTT assay. Secretion of trophoblast oncofetal fibronectin (tropho-uteronectin) and beta-hCG by cultured trophoblasts was determined by Western blot and ELISA of the culture media. RESULT(S): With increasing concentrations of hydrosalpinx fluid from 0% to 20%, there was a significant increase in trophoblast cell viability (1.63-fold increase in 20% hydrosalpinx fluid). Likewise, both Western blot and ELISA assays demonstrated a significant increase in tropho-uteronectin production by trophoblasts with increasing hydrosalpinx fluid concentrations (3.76-fold increase in 20% hydrosalpinx fluid). beta-Human chorionic gonadotropin production also increased significantly in the presence of hydrosalpinx fluid (3.31-fold increase in 20% hydrosalpinx fluid). CONCLUSION(S): These findings suggest that hydrosalpinx fluid improves human trophoblast viability in vitro and enhances the production of tropho-uteronectin and beta-hCG by these cells.

Dexamethasone and forskolin synergistically increase [Met5]enkephalin accumulation in mixed brain cell cultures.

Possible synergistic effects of the glucocorticoid dexamethasone (DEX, 10(-7) M) and the adenylate cyclase agonist forskolin (FSK, 10(-5) M) on [Met5]enkephalin (ME) accumulation were examined in enriched rat glial cultures and in mixed neuronal/glial cultures. In enriched glial cultures, DEX and FSK each stimulated the accumulation of ME 2-3-fold over basal media levels, but there was little additional stimulation when these agonists were combined. In contrast, mixed neuronal/glial cultures showed only weak responses to DEX or FSK alone, but the combination of these agonists produced a pronounced synergistic effect on media ME accumulation (6-10-fold over basal levels). The DEX effect was mediated via a classical glucocorticoid receptor, since DEX was potent (acting over a concentration range of 10(-11)-10(-7) M), mimicked by corticosterone (10(-6) M), and blocked by the glucocorticoid receptor antagonist RU486. There was a pronounced time lag (2 days) for the synergistic effects of DEX + FSK to develop. In situ hybridization and immunocytochemical studies suggested that astrocytes were the major source for the increased ME production in all mixed neuronal/glial cultures examined. Creating a mixed culture by plating fetal neurons onto confluent, enriched P7 glial cultures inhibited accumulation of ME in the media. DEX + FSK, but neither agonist alone, overcame this neuronal inhibition and increased accumulation of media ME to levels identical to levels in stimulated enriched glial cultures. The net effect was a 6-fold increase in ME accumulation in the mixed neuronal/glial cultures relative to a 2.5-fold increase in the enriched glial cultures. Neuronal inhibition of basal glial ME production could explain the similar synergistic effects of DEX + FSK observed in all mixed neuronal/glial cultures examined, and may be important in suppressing ME production by astrocytes in the brain.

Dating of pregnancy by trimesters: a review and reappraisal.

Many patients and obstetricians divide the events of human pregnancy into three intervals traditionally termed "trimesters." This system presumably arose from an equal division of the "9 months of pregnancy" into 3-month intervals. There are several problems with this system that follows pregnancy by months or trimesters. First, the average human pregnancy lasting 280 days or 40 weeks is not evenly divisible by three, leaving one to wonder how long each trimester is. Second, conversion from "weeks pregnant" to "months pregnant" is often an estimate that can foster misunderstanding between the patient and her obstetrician. Last, following pregnancy by the Gregorian calendar does not reflect embryonic or fetal developmental milestones. We propose a revision of this system to one in which natural embryonic and fetal developmental landmarks are used instead of trimesters to define the progressive stages of pregnancy. These landmarks occur approximately at 5-week intervals allowing a more simple division of pregnancy into four 10-week quartiles, each with two 5-week intervals. This article reviews many of these important landmarks within this framework. This system emphasizes a developmentally based way of understanding the events of pregnancy for both the patient and the obstetrician.

Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures.

Dopaminergic neurotoxicities of 6-hydroxydopamine (6-OHDA) and the lipopolysaccharide (LPS) were compared in rat mesencephalic cultures plated on poly-L-lysine or on glial monolayers. In the neuron-enriched cultures plated on polylysine, 6-OHDA killed 89% of the tyrosine hydroxylase (TH)-immunopositive neurons, but LPS was not neurotoxic. Conversely, in mixed neuron/glial cultures, 6-OHDA killed only 27% of the TH-immunopositive neurons while LPS killed 70%. The mixed neuronal/glial mesencephalic culture offers a better in vitro model for studying possible mechanisms involved in Parkinson's disease.

Selective killing of cholinergic neurons by microglial activation in basal forebrain mixed neuronal/glial cultures.

Microglia activation by lipopolysaccharides (LPS) significantly decreased choline acetyltransferase-immunopositive (ChAT+) neuron number and ChAT activity in rat primary basal forebrain mixed neuronal/glial cultures. The number of non-cholinergic (ChAT(-)) neurons was unaffected. LPS induced nitric oxide synthase (NOS) in microglia, increased the media level of the NO metabolite nitrite, and the NOS inhibitor Ng-nitro-L-arginine methylester (NAME) protected the ChAT+ neurons from LPS. The combination of beta-amyloid peptide (1-42) and interferon-gamma (INF-gamma) also increased the media nitrite level and decreased ChAT+ neuron number. Cholinergic neurons are lost early in the course of Alzheimer's disease, and the enhanced sensitivity of these neurons to microglial activation in mixed neuronal/glial culture may be useful for modeling Alzheimer's disease and developing therapeutic strategies to combat this disease.

Endometrial integrin expression in women exposed to diethylstilbestrol in utero.

OBJECTIVE: To determine if the endometrium of women exposed in utero to diethylstilbestrol (DES) demonstrates altered integrin expression compared with normal fertile controls. DESIGN: Case control study. Expression of eight integrins in 15 luteal phase endometrial biopsies from DES-exposed women were compared with 17 biopsies from age- and cycle day-matched controls. All patients were ovulatory. Endometrial biopsies were performed in the luteal phase, and all were histologically "in phase." SETTING: Infertility practice of an academic teaching hospital. PATIENTS: Women exposed in utero to DES and matched fertile controls. MAIN OUTCOME MEASURES: Intensity of endometrial integrin immunohistochemical staining by the semiquantitative HSCORE technique. RESULTS: Endometrial stroma of DES-exposed women demonstrated greater expression of the integrin subunits alpha 5 and alpha v. No differences were noted between DES-exposed women and fertile controls in the glandular epithelial expression of integrin subunits alpha 1, alpha 2, alpha 3, alpha 6, and alpha v nor the stromal staining of subunits of alpha 6 and beta 3. Epithelial expression of integrin subunits beta 3 and alpha 4, reliable luteal markers of uterine receptivity, were similar in DES and control patients. CONCLUSIONS: Markers of uterine receptivity are similar in the endometrium of women exposed in utero to DES compared with normal fertile controls. Interesting differences exist in stromal integrin expression between groups, though the significance of this finding is uncertain at present. It is unlikely that DES-exposed women have significantly altered endometrial function as a cause of infertility.

Integrins as markers of uterine receptivity in women with primary unexplained infertility.

OBJECTIVE: To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. DESIGN: Prospective, controlled study design. PATIENTS: Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. MAIN OUTCOME MEASURE: Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. RESULTS: All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. CONCLUSIONS: Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.

Recurrent squamous cell carcinoma of the cervix with pulmonary lymphangitic metastasis.

A case report and review of the world literature are presented to examine all the reported cases of cervical carcinoma manifesting as pulmonary lymphangitic carcinomatosis in order to better understand this rare condition. The clinical and pathologic features of this disease process are reviewed, as are potential treatment options. We present the first reported case of an immunocompromised patient with cervical carcinoma and pulmonary lymphangitic metastasis with a prospective diagnosis made by transbronchial biopsy. Given that this condition carries a uniformly fatal prognosis, unwanted therapy may result from a missed diagnosis. A prospective pathologic diagnosis by transbronchial biopsy may guide appropriate therapy in these patients.

A multiple-dose safety trial of eptastigmine in Alzheimer's disease, with pharmacodynamic observations of red blood cell cholinesterase.

A placebo-controlled multiple dose study was conducted to evaluate the safety, tolerability, and pharmacodynamics of multiple dose levels of eptastigmine in 25 patients with probable Alzheimer's disease (AD). Twenty patients (12 M, 8 F; mean age 74, range 57-84) were randomized to receive 12mg (N = 3), 20mg (N = 6), 28mg (N = 6) or placebo (N = 5) tid on a double-blind basis for 14 days, followed by seven days of single blind placebo, in successively rising dose groups. All patients completed the study without intolerable or severe adverse events. All doses significantly (p < 0.001) reduced peak and trough RBC cholinesterase (AChE) activity as compared to baseline. Percent inhibition for Day 14 peak and trough RBC AChE peak and trough values, respectively, appeared proportional to dose: 18% and 21% (12mg); 36% and 35% (20mg); 40% and 44% (28mg). In order to determine the maximum tolerated dose of eptastigmine, an additional single-blind study was performed in five patients (2 M, 3 F; mean age 78, range 72-80) utilizing a rising dose schedule of eptastigmine (N = 4) or placebo (N = 1), starting with the previously tolerated 28mg tid dose and increasing by 4mg tid up to a potential maximum of 56mg tid. Dose-limiting adverse events occurred requiring discontinuation of medication in one patient at 48mg tid and two patients at 52mg tid; RBC AChE inhibition was proportional to dose, with peak values up to 70% inhibition at 48mg tid. The maximum tolerated dose of 48mg tid was identified as a basis for potential Phase II multicenter efficacy trials.

Safety and tolerance of intravenous nimodipine.

OBJECTIVE: To evaluate the safety and tolerance of intravenous nimodipine administered via a peripheral vein in healthy male volunteers. DESIGN: Double-blind, placebo- and vehicle-controlled trial with three fixed-dose panels. SETTING: Inpatient infusion and observation periods. SUBJECTS: 61 healthy male volunteers, aged 18-40 years. METHODS: Subjects in panel 1 received nimodipine 0.4 mg/h, vehicle 2 mL/h, or placebo 2 mL/h; subjects in panel 2 received nimodipine 1 mg/h, vehicle 5 mL/h, or placebo 5 mL/h; subjects in panel 3 received nimodipine 2 mg/h, vehicle 10 mL/h, or placebo 10 mL/h. All infusions were administered intravenously for 48 hours and volunteers were observed for 48 hours after cessation of the infusion. In addition to standard safety assessments (physical examination, electrocardiogram, laboratory studies, and adverse event reporting), supine and standing blood pressures and pulse rates were measured frequently. Plasma samples were also analyzed for nimodipine and its two demethylated metabolites. RESULTS: Of 61 subjects, 55 completed the 48-hour infusion and 6 discontinued the study because of adverse events. Intravenous nimodipine was well tolerated at 0.4 and 1 mg/h. However, all six subjects who received nimodipine 2 mg/h experienced moderate-to-severe adverse events, and one subject was discontinued because of dizziness, diaphoresis, and postural hypotension. The matched vehicle (10 mL/h) also was not well tolerated, with three subjects who discontinued because of phlebitis. Two subjects who received placebo were also discontinued during the study. Small (2 mm Hg) decreases in mean supine diastolic blood pressure were observed in the 0.4- and 1-mg/h nimodipine groups, but the 2-mg/h group showed a slight (5 mm Hg) increase in blood pressure. These changes were not clinically significant. Clearance and half-life of nimodipine and its metabolites were similar at all three dosages. CONCLUSIONS: Using peripheral vein administration, nimodipine 2 mg/h and matched vehicle at 10 mL/h were not well tolerated in this healthy normal population. The maximum tolerated dose of nimodipine was found to be 1 mg/h.

Aberrant integrin expression in the endometrium of women with endometriosis.

Integrins are ubiquitous cell adhesion molecules that undergo dynamic alterations during the normal menstrual cycle in the human endometrium. The alpha v beta 3 vitronectin receptor integrin is expressed in endometrium at the time of implantation, but its presence is delayed in endometrium that is assessed to be out of phase using classical histological features. To investigate the expression of this integrin in women with endometriosis, we assessed the presence of the beta 3-subunit throughout the menstrual cycle in 268 "in-phase" endometrial biopsies, using immunohistochemistry. The beta 3-subunit was expressed on endometrial epithelium after days 19-20 of the menstrual cycle. In 241 women whose biopsies were obtained after day 19, a lack of beta 3 expression was found to be closely related to the diagnosis of endometriosis (by Wilcoxon test, P = 0.02). This defect in integrin expression was associated with nulliparity, inversely related to the stage of disease, and occurred despite the presence of in-phase histological features. In a prospective double blind assessment of this integrin, we found endometrial beta 3 analysis to have a high specificity and positive predictive value as a nonsurgical diagnostic test for minimal and mild endometriosis. In conclusion, aberrant integrin expression in the native endometrium is associated with the finding of endometriosis and may identify some women with decreased cycle fecundity due to defects in uterine receptivity.

Idioventricular rhythm: hypervagotonia associated with placebo.

We report a case of hypervagotonia manifested by idioventricular rhythm in a healthy, athletic man who participated in a Phase I study of an investigational calcium-channel blocker. Upon breaking the study's double-blind study code, it was discovered that the subject had received placebo. We discuss this unusual finding and the implications of including athletic subjects in safety/tolerance studies.

Arsenazo III and its analogues-V Complex formation of niobium with o,o'-dihydroxyazo compounds.

A new group of reagents-the 2,7-bisazo derivatives of chromotropic acid-has been synthesized and the reaction of these compounds with niobium studied. Reaction with niobium occurs in strongly acidic medium (1-3N) and is characterized by high sensitivity ( = 30-50 x 10(3)). The functional grouping responsible for the reaction was shown to be the o,o'-dihydroxyazo group. The analytical usefulness of the reagents is determined by the presence of the electron-withdrawing substituents and the nature of the diazo coupling component. Niobium reacts in partially hydrolysed form with these reagents, to give 1:1 complexes.