Placental Transport of Zidovudine in the Rhesus Monkey

Objective: This study was undertaken to characterize the pharmacokinetics of zidovudine (ZDV) and ZDV-glucuronide (ZDVG) in the material and :fetal circulations of the rhesus monkey

Participant characteristics associated with withdrawal from a large randomized trial of spermicide effectiveness

BACKGROUND: In most recent large efficacy trials of barrier contraceptive methods, a high proportion of participants withdrew before the intended end of follow-up. The objective of this analysis was to explore characteristics of participants who failed to complete seven months of planned participation in a trial of spermicide efficacy. METHODS: Trial participants were expected to use the assigned spermicide for contraception for 7 months or until pregnancy occurred. In bivariable and multivariable analyses, we assessed the associations between failure to complete the trial and 17 pre-specified baseline characteristics. In addition, among women who participated for at least 6 weeks, we evaluated the relationships between failure to complete, various features of their first 6 weeks of experience with the spermicide, and characteristics of the study centers and population. RESULTS: Of the 1514 participants in this analysis, 635 (42%) failed to complete the study for reasons other than pregnancy. Women were significantly less likely to complete if they were younger or unmarried, had intercourse at least 8 times per month, or were enrolled at a university center or at a center that enrolled fewer than 4 participants per month. Noncompliance with study procedures in the first 6 weeks was also associated with subsequent early withdrawal, but dissatisfaction with the spermicide was not. However, many participants without these risk factors withdrew early. CONCLUSIONS: Failure to complete is a major problem in barrier method trials that seriously compromises the interpretation of results. Targeting retention efforts at women at high risk for early withdrawal is not likely to address the problem sufficiently

Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas

Context: Mutations in the gene encoding Mediator complex subunit MED12 are dominant drivers of uterine fibroids (UFs) in women of diverse racial and ethnic origins. Previously, we showed that UF-linked mutations in MED12 disrupt its ability to activate cyclin C-CDK8/19 in Mediator. However, validation of Mediator kinase disruption in the clinically relevant setting of MED12-mutant UFs is currently lacking. Objective: The objective of this study was twofold. First, to extend the ethnic distribution profile of MED12 mutations by establishing their frequency in UFs from Hispanic women of South Texas. Second, to examine the impact of MED12 mutations on Mediator kinase activity in patient-derived UFs. Methods: We screened 219 UFs from 76 women, including 170 tumors from 57 Hispanic patients, for MED12 exon 2 mutations, and further examined CDK8/19 activity in Mediator complexes immunoprecipitated from MED12 mutation-negative and MED12 mutation-positive UFs. Results: MED12 exon 2 mutations in UFs from Hispanic women are somatic in nature, predominantly monoallelic, and occur at high frequency (54.1%). We identified a minimal cyclin C-CDK8 activation domain on MED12 spanning amino acids 15 through 80 that includes all recorded UF-linked mutations in MED12, suggesting that disruption of Mediator kinase activity is a principal biochemical defect arising from these pathogenic alterations. Analysis of Mediator complexes recovered from patient UFs confirmed this, revealing that Mediator kinase activity is selectively impaired in MED12-mutant UFs. Conclusions: MED12 mutations are important drivers of UF formation in Hispanic women of South Texas. MED12 mutations disrupt Mediator kinase activity, implicating altered CDK8/19 function in UF pathogenesis.Peer reviewe

Bioluminescence imaging of Chlamydia muridarum ascending infection in mice.

Chlamydial pathogenicity in the upper genital tract relies on chlamydial ascending from the lower genital tract. To monitor chlamydial ascension, we engineered a luciferase-expressing C. muridarum. In cells infected with the luciferase-expressing C. muridarum, luciferase gene expression and enzymatic activity (measured as bioluminescence intensity) correlated well along the infection course, suggesting that bioluminescence can be used for monitoring chlamydial replication. Following an intravaginal inoculation with the luciferase-expressing C. muridarum, 8 of 10 mice displayed bioluminescence signal in the lower with 4 also in the upper genital tracts on day 3 after infection. By day 7, all 10 mice developed bioluminescence signal in the upper genital tracts. The bioluminescence signal was maintained in the upper genital tract in 6 and 2 mice by days 14 and 21, respectively. The bioluminescence signal was no longer detectable in any of the mice by day 28. The whole body imaging approach also revealed an unexpected airway infection following the intravaginal inoculation. Although the concomitant airway infection was transient and did not significantly alter the genital tract infection time courses, caution should be taken during data interpretation. The above observations have demonstrated that C. muridarum can not only achieve rapid ascending infection in the genital tract but also cause airway infection following a genital tract inoculation. These findings have laid a foundation for further optimizing the C. muridarum intravaginal infection murine model for understanding chlamydial pathogenic mechanisms

In vivo imaging of intravaginal infection with luciferase-expressing C. muridarum in mice.

<p>The 10 female Balb/cJ mice labeled “a” to “j” as indicated on top of the figure were intravaginally infected with luciferase-expressing <i>C. muridarum</i> as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101634#pone-0101634-g002" target="_blank">Fig.2</a> legend. At each time point after infection (when vaginal swabs were taken, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101634#pone-0101634-g002" target="_blank">Fig. 2</a> legend) as indicated along left side of the figure, all mice were subjected to whole body in vivo imaging. The relative bioluminescence intensity was shown in the form of color heat map as indicated along the right side of the figure. The intensity of bioluminescence was also quantitatively measured from the pre-defined lower and upper genital tract areas. Significant bioluminescence signals first becoming detectable in the lower (green) or upper (red) genital tract areas were marked with thin arrows. Peak bioluminescence signals in the upper genital tract of each mouse were marked with thick red arrows. Bioluminescence signals remained detectable in the genital tract areas on day 21 after infection were indicated with think green arrows while those in the chest areas with thick yellow arrows. Note that most mice achieved a maximal ascending infection by days 7 or 10 after intravaginal infection while some mice have also acquired airway infection.</p

Enlarged bioluminescence images from mice with or without airway signals and mice infected with wild type C. muridarum.

<p>The bioluminescence images from mice c and h shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101634#pone-0101634-g003" target="_blank">Fig. 3</a> were enlarged and shown in the same order of infection time as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101634#pone-0101634-g003" target="_blank">Fig. 3</a>. Airway bioluminescence signal in mouse h was marked with a yellow arrow. Mice k and l were infected with wild type <i>C. muridarum</i> and 7 days after infection, bioluminescence imaging was taken after injection with luciferin. Note a similar genital tract infection time course between mice c and h and lack of any significant bioluminescence signals in mice k and l.</p

Live C. muridarum organism recovery from vaginal swabs along the infection time course.

<p>After the intravaginal infection with the luciferase-expressing <i>C. muridarum</i> organisms, vaginal swabs were taken at different time points as indicated along the X-axis for monitoring live chlamydial organism shedding from the lower genital tract. The number of live organisms recovered from the vagina/cervix swabs expressed as log₁₀ IFUs per swab (top panel) and percent of mice that remained positive for shedding live organisms (bottom panel) were displayed along the Y-axis. Note that high levels of live organisms were recovered from the lower genital tract during the first 10 days after infection and the shedding dropped significantly by day 14 after infection, which is consistent with the time courses of genital tract infection with wild type <i>C. muridarum</i>.</p

Unilateral Labial Hypertrophy in Adolescents: when should we Interfere? Two Case Reports

Synopsis: Adolescent and pre-menarchal patients with symptomatic unilateral labial hypertrophy should be counselled extensively prior to surgical management regarding risks of recurrence or contralateral occurrence. Purpose: Present the management of two unique cases of adolescent girls with unilateral labial hypertrophy. Case 1: 9 year-old pre-menarchal patient with a five-month history of unilateral labial hypertrophy causing discomfort that limited daily activities. External pelvic examination revealed grossly asymmetric labia minora. The left labia minora measured 5 cm in length. After counseling, the patient underwent unilateral labioplasty with resolution of symptoms. Patient returned after two years complaining of contralateral labial hypertrophy.The patient again underwent surgical management due to discomfort and interference with normal daily activities. Case 2: 12 year-old post-menarchal patient with a history of unilateral labial hypertrophy causing irritation and discomfort starting prior to menarche. External pelvic exam revealed grossly asymmetric labia minora. The right labia minora measured 4.5cm in length. The patient underwent unilateral labioplasty with resolution of her symptoms. After 2 years of follow up, patient remained asymptomatic. Conclusion: Adolescence unilateral labial hypertrophy may represent a normal variant and surgery should be delayed until achieving full puberty. However, when it causes significant discomfort or interferes with normal daily activities, surgical management should be considered after counseling regarding recurrence or contralateral occurrence