Aerosol delivery of ergotamine tartrate via a breath-synchronized plume-control inhaler in humans.

OBJECTIVE: To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET) with a sublingual ergot preparation and a commercial inhaler. METHODS: Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine) and a BSPCI delivering 258 microg of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler) delivering 2052 microg of ET and a BSPCI delivering 129 microg of ET. Gamma scintigraphy with (99m)Tc validation was used to quantify lung deposition. RESULTS: For both studies, ET C(max) was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio. CONCLUSION: Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations.

There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E2), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERalpha and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E2, PgR expression was reduced in all risk groups but significantly more so in the BRCA-mutated groups. Subsequent E2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women.

Myelination and remyelination of aggregate rat brain cell cultures enriched with macrophages.

We reported previously that accumulation of myelin basic protein (MBP) in foetal brain aggregate cultures is enhanced by supplementation with peritoneal macrophages. The present study demonstrates that the rate of MBP accumulation in macrophage-enriched cultures continues to increase over time unaccompanied by a matching increase in the oligodendrocyte marker cyclic nucleotide phosphodiesterase, while that of control cultures reaches a plateau. These observations are supported by electron microscopic evidence of cumulative numbers of myelinated axons in the aggregates over time and by enhanced expression of myelin protein genes in macrophage-enriched relative to control cultures. Aggregates demyelinate following short-term exposure to cytokines and antimyelin oligodendrocyte glycoprotein antibody, and MBP synthesis resumes following removal of demyelinating agents. Supplementation of cultures with macrophages influences the degree of myelin breakdown and remyelination, drawing attention to the role that macrophage-derived growth factors may play in myelinogenesis and myelin repair in inflammatory demyelinating disease.

Use of a DNA probe for the rapid detection of group B streptococci in obstetric patients.

OBJECTIVE: To determine the accuracy of a DNA probe as a rapid diagnostic test for detecting colonization of the female genital tract by group B streptococci during pregnancy. METHODS: Two rayon-tipped applicators were used to collect secretions from the posterior vaginal wall of 440 pregnant women. One of the applicators was inoculated into selective Todd-Hewitt broth and used as the reference standard for identification of group B streptococci. The other applicator was used for analysis with the DNA probe, preceded by either 2.5 hours of incubation for the initial 75 patients, or 3.5 hours' incubation for the remaining women. Following hybridization with an acridinium-labeled probe, chemiluminescence was measured with a luminometer. RESULTS: The prevalence of positive cultures was 20%. For the initial 75 patients whose cultures were amplified by incubation for 2.5 hours, the DNA probe had a sensitivity of 44%, specificity 94%, positive predictive value 79%, and negative predictive value 77%. For the cultures that were incubated for 3.5 hours, respective values were 71, 90, 61, and 94%. All vaginal specimens that had an average initial cell count of 1.5 x 10(3) cells/mL were accurately detected by the probe after 3.5 hours' growth amplification. False-positive results occurred primarily when the specimens were grossly contaminated with blood (26 of 39). The mean time required to perform the assay, including 3.5 hours of growth amplification, was 4.3 hours. CONCLUSIONS: The DNA probe demonstrated good overall sensitivity and gave no false-negative results when group B streptococci were present in concentrations of 1 x 10(4) cells/mL or greater. Sensitivity improved significantly with 3.5 hours' growth amplification as compared with 2.5 hours (P < .05), reflecting better identification of lightly colonized patients.

Rapid intrapartum detection of group B streptococcal colonization with an enzyme immunoassay.

OBJECTIVE: The purpose of this study was to determine the accuracy of a rapid immunoenzyme assay for detecting intrapartum colonization with group B streptococci. STUDY DESIGN: Three rayon-tipped swabs were used to collect specimens from the posterior vaginal wall of 424 preterm and term patients in labor. Three tests were performed on specimens obtained from the first 182 patients: semiquantitative culture on blood agar, culture in selective Todd-Hewitt broth, and ICON Strep B (Hybritech, San Diego) immunoconcentration assay. For the remaining 242 patients, the ICON test was performed only when the Todd-Hewitt broth culture was positive. RESULTS: The prevalence of positive cultures was 23%. For the first 182 patients, the immunoassay had a sensitivity of 11%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 78%. The overall sensitivity for all 424 patients was 9%. In eight women with heavy colonization, defined as an inoculum of > 10(5) cfu/ml the sensitivity of the assay was 100%. In the study population there were three cases of group B streptococcal sepsis in infants whose mothers were only lightly colonized. None of these cases of colonization were detected by the assay. CONCLUSION: The ICON immunoconcentration assay is very sensitive in identifying heavy group B streptococcal colonization of > 10(5) cfu/ml but quite insensitive in detecting lower levels of colonization. Thus it is not a suitable test for general screening.

Assessment of rapid identification tests for genital carriage of group B streptococci.

OBJECTIVE: The purpose of this study was to assess the relative value of reported methods for rapid identification of group B streptococcal colonization of the female genital tract. DATA SOURCES: Trials of group B streptococcal identification techniques published in peer-reviewed journals were located using a computerized literature search and cited references from relevant articles or text chapters. METHODS OF STUDY SELECTION: Reports were included in the analysis if the methodology fulfilled the following criteria: 1) A reference culture method was used for comparison; 2) performance characteristics were presented or could be calculated; 3) the method could be performed in a standard laboratory on a 24-hour-a-day basis; and 4) results could be routinely available within 12 hours. DATA EXTRACTION AND SYNTHESIS: Performance characteristics such as sensitivity, specificity, and predictive values for the various methods were evaluated and compared. Factors such as colonization rates and methods for identifying carriers were included in the overall assessment of test performance. CONCLUSIONS: The overall sensitivity of current methods for the rapid detection of group B streptococcal colonization is low. However, some rapid antigen detection tests are highly sensitive in identifying heavily colonized patients, and therefore may be useful for selecting high-risk patients for intrapartum antibiotic prophylaxis.

Assessment of a rapid latex agglutination test for group B streptococcal colonization of the genital tract.

OBJECTIVE: The purpose of this study was to determine the reliability of a rapid enzyme extraction-latex agglutination test in detecting intrapartum colonization of the maternal genital tract by group B streptococci. METHODS: Swabs of vaginal secretions were obtained from 314 patients in labor with either ruptured or intact membranes. Four tests were performed on each specimen: 1) qualitative culture on blood agar, 2) semiquantitative culture on blood agar, 3) culture in selective Todd-Hewitt broth, and 4) latex agglutination preceded by enzyme extraction. RESULTS: The prevalence of positive cultures was 29%. When compared with culture in Todd-Hewitt broth, the latex agglutination test had a sensitivity of 30%, specificity 93%, positive predictive value 64%, and negative predictive value 76%. In patients with heavy colonization the test had a sensitivity of 76%, compared with 17% in patients with light growth (P less than .001). The lower limit of sensitivity of the test was 4 x 10(5) cfu/mL. The performance of the test was not affected by rupture of the membranes. CONCLUSION: Although the latex agglutination test is reasonably sensitive in detecting heavy colonization, low overall performance combined with technical difficulties in assessment of particle agglutination make the test unsuitable for general screening.

Intraamniotic infection in patients with intact membranes and preterm labor.

The purpose of this review was to determine the frequency of intraamniotic infection in women with preterm labor and intact membranes and to assess the need for amniocentesis in these patients. We reviewed reports in the English language literature from the past 10 years in which the frequency of intraamniotic infection was determined by transabdominal amniocentesis. The 16 studies reviewed demonstrated frequencies of positive cultures that varied from 0 to 61 per cent. This extreme variability seems to be the result of diverse patient populations, dissimilar microbiologic techniques, and different definitions of preterm labor. Advanced cervical dilation and poor response to tocolytic agents were two factors associated with a higher frequency of intraamniotic infection. We conclude that each institution must determine the frequency of intraamniotic infection associated with preterm labor in their patient population. In populations with a high frequency of infection, amniocentesis for microbiologic evaluation is recommended for management of preterm labor, especially in patients who have advanced cervical dilatation or who are unresponsive to tocolytic therapy.

Grafted synthetic sorbents for enhanced removal of toxic chemical agents from plasma.

A series of porous polymeric sorbents and activated carbon were used to remove diisopropyl methylphosphonate (DIMP) from human plasma and normal saline. The sorptive capacities of the commercially available sorbents Amberlite XAD-4, XAD-2, XN1010, and XE348, and Calgon 400 were determined. Butyl- and palmityl-grafted XAD-4 were prepared with graft efficiencies of 32 and 6%, respectively, and tested for sorptive capacities. DIMP removal efficiencies were compared to dialysis with a 1.8 m2 Cordis-Dow hollow fiber artificial kidneY (HFAK). Butyl-grafted XAD-4 and active carbon outperformed the other sorbents in removing DIMP from both saline and plasma. An order of magnitude reduction in removal ability was noted for all the adsorbents when the mobile media was plasma. Pronounced plasma precipitation was elicited by activated carbon, an effect not observed with any of the polymeric resins tested. The removal efficiencies on a 18.0 g basis of XAD-4, butyl-grafted XAD-4, and active carbon were comparable to that of the HFAK used in this study. These sorbents, however, possess a macroscopic surface area of approximately 0.1 m2, an order of magnitude lower than that of the HFAK. This reduction in contact area is believed to reduce substantially the possibility of undesirable molecular and cellular effects.