Transcriptional fingerprints of antigen-presenting cell subsets in the human vaginal mucosa and skin reflect tissue-specific immune microenvironments.

BACKGROUND: Dendritic cells localize throughout the body, where they can sense and capture invading pathogens to induce protective immunity. Hence, harnessing the biology of tissue-resident dendritic cells is fundamental for the rational design of vaccines against pathogens. METHODS: Herein, we characterized the transcriptomes of four antigen-presenting cell subsets from the human vagina (Langerhans cells, CD14(-) and CD14(+) dendritic cells, macrophages) by microarray, at both the transcript and network level, and compared them to those of three skin dendritic cell subsets and blood myeloid dendritic cells. RESULTS: We found that genomic fingerprints of antigen-presenting cells are significantly influenced by the tissue of origin as well as by individual subsets. Nonetheless, CD14(+) populations from both vagina and skin are geared towards innate immunity and pro-inflammatory responses, whereas CD14(-) populations, particularly skin and vaginal Langerhans cells, and vaginal CD14(-) dendritic cells, display both Th2-inducing and regulatory phenotypes. We also identified new phenotypic and functional biomarkers of vaginal antigen-presenting cell subsets. CONCLUSIONS: We provide a transcriptional database of 87 microarray samples spanning eight antigen-presenting cell populations in the human vagina, skin and blood. Altogether, these data provide molecular information that will further help characterize human tissue antigen-presenting cell lineages and their functions. Data from this study can guide the design of mucosal vaccines against sexually transmitted pathogens.

Dendritic cells and vaccine design for sexually-transmitted diseases.

Dendritic cells (DCs) are major antigen presenting cells (APCs) that can initiate and control host immune responses toward either immunity or tolerance. These features of DCs, as immune orchestrators, are well characterized by their tissue localizations as well as by their subset-dependent functional specialties and plasticity. Thus, the level of protective immunity to invading microbial pathogens can be dependent on the subsets of DCs taking up microbial antigens and their functional plasticity in response to microbial products, host cellular components and the cytokine milieu in the microenvironment. Vaccines are the most efficient and cost-effective preventive medicine against infectious diseases. However, major challenges still remain for the diseases caused by sexually-transmitted pathogens, including HIV, HPV, HSV and Chlamydia. We surmise that the establishment of protective immunity in the female genital mucosa, the major entry and transfer site of these pathogens, will bring significant benefit for the protection against sexually-transmitted diseases. Recent progresses made in DC biology suggest that vaccines designed to target proper DC subsets may permit us to establish protective immunity in the female genital mucosa against sexually-transmitted pathogens.

Correlation of Q-tip values and point Aa in stress-incontinent women.

OBJECTIVE: To estimate the relationship between pelvic organ prolapse quantification (POP-Q) point Aa and straining Q-tip angle. METHODS: We compared preoperative straining Q-tip angles and Aa measurements from 655 women with predominant stress incontinence and urethral hypermobility (defined as a resting or straining angle of greater than 30 masculine) using Pearson correlations and linear regression. Point Aa is 3 cm deep to the urethral meatus in the midline of the anterior vagina and corresponds to the urethrovesical crease. RESULTS: The median for point Aa was -1 cm (range -3 to +3 cm) and for straining Q-tip was 60 masculine (30-130 masculine). Twenty-nine percent of participants had an Aa at least 2 cm deep to the hymen, whereas in 69%, Aa was at or below -1 cm. The straining Q-tip angle was significantly different between these respective groups: 51.5 masculine and 64 masculine (P<.001). Linear regression analysis indicates that point Aa and straining Q-tip were moderately correlated (r=0.35, P<.001). As straining point Aa increased by 1 cm, Q-tip angle increased 4.6 masculine (P<.001). Age and prior anterior vaginal or incontinence surgery had no significant effect on the correlation (P=.08 and P=.64, respectively). CONCLUSION: Nearly a third of stress-incontinent women with urethral mobility by Q-tip test visually appeared to have a well-supported urethrovesical junction with POP-Q point Aa values of -2 cm or less. The position of the urethrovesical crease (point Aa) on POP-Q and straining angle on Q-tip test do not appear to reflect the same anatomic support and cannot be used to predict one another. No Aa value can rule out urethral hypermobility.

Factors associated with incontinence frequency in a surgical cohort of stress incontinent women.

OBJECTIVE: The aim of this study was to identify factors associated with urinary incontinence severity at baseline in women undergoing surgery for stress incontinence. STUDY DESIGN: Baseline data were obtained from 650 women (age 28 to 81 years) with stress incontinence participating in a randomized surgical trial. Severity of incontinence was defined by the mean number of incontinence episodes per day recorded in a 3-day bladder diary. The relationships between severity and several baseline variables were examined, including demographics, medical, obstetric, and gynecologic history, body mass index, smoking status, Q-tip displacement, and Pelvic Organ Prolapse Quantification stage (POP-Q). RESULTS: In a multivariable model, severity of incontinence was positively associated with body mass index (P = .0003) and current smoking (P = .01), and negatively associated with prolapse stage (P < .0001) and Q-tip displacement (P = .042). CONCLUSION: Incontinence severity in a surgical population was independently associated with 2 modifiable factors, obesity and tobacco use, as well as pelvic support.

Appearance of the levator ani muscle in pregnancy as assessed by 3-D MRI.

OBJECTIVE: The purpose of this study was to describe levator ani (LA) anatomy in postterm nulliparas using 3-dimensional (3-D) magnetic resonance (MR). STUDY DESIGN: Nulliparas (n = 84) with uncomplicated, postterm pregnancies underwent an MR (4 mm slices, 0 gap) of the uterus and pelvis. LA volume and morphometry were assessed using 3-D post-processing software. RESULTS: LA insertion into the symphysis was visible in 93%, and the iliococcygeus muscle assumed a convex shape (arch) in the 92% of the 84 women. The LA shape was characterized as "U" in 53% and "V" in 47%. Mean LA volume was 13.5 (3.7) cm3. There was a positive association between LA volume and higher fetal station (P = .02) and increasing BMI (P < .001). However, no relationship between LA volume and station was found after adjusting for BMI. CONCLUSION: BMI was correlated with LA volume in postterm nulliparas. LA insertion into the symphysis and the iliococcygeus arch were well-preserved overall and morphometry was variable.

Vascular anatomy over the superior pubic rami in female cadavers.

OBJECTIVE: The objective of the study was to characterize the vascular anatomy over the superior pubic ramus. STUDY DESIGN: Detailed dissections of the retropubic space were performed in 15 fresh female cadavers. Vessels crossing the superior pubic rami were inspected for width, course, communications, and relationship to the midline of the pubic symphysis and the obturator canal. RESULTS: Vessels 1 mm or greater in width connecting the obturator vessels and inferior epigastric or external iliac vessels were noted in 10 of 15 (66.7%) cadavers: 9 (60%) had veins, 5 (33.3 %) had arteries, and 4 (26.7%) had both. In all specimens, the vessels crossed over the superior pubic rami lateral to or at the level of the obturator canal, which was on average 5.4 cm from the midline of the pubic symphysis. CONCLUSION: Communicating vessels crossing the superior pubic rami were present in the majority of specimens. Understanding this anatomy should aid the surgeon in avoiding vascular complications.

Predicting bacteriuria in urogynecology patients.

OBJECTIVE: This study was undertaken to determine whether reagent strip testing can predict bacteriuria in urogynecology patients. STUDY DESIGN: All women undergoing urodynamic evaluations from June 1997 to October 2001 were identified by using a computerized database. Urine culture results were compared with reagent strip testing. Significant bacteriuria was defined as greater than 10(5) colony-forming units per milliliter. RESULTS: Bacteriuria prevalence was 8.6% (n = 51). Sensitivity and specificity of nitrites were 0.51, (95% CI, 0.31-0.66) and 0.991, (95% CI, 0.974-0.998), respectively. Blood had a lower sensitivity (0.35, 95% CI, 0.20-0.54) and specificity (0.80, 95% CI, 0.75-0.84). Leukocyte esterase was similar to blood with a sensitivity of 0.28 (95% CI, 0.14-0.45) and specificity of 0.83 (95% CI, 0.78-0.87). No combination of tests offered improved sensitivity or specificity over nitrites alone. CONCLUSION: Nitrite dipstick testing has excellent specificity for bacteriuria in urogynecologic patients. These results support the treatment of women with positive nitrites who are preparing to undergo urodynamics without obtaining culture.

Anal incontinence in women presenting for gynecologic care: prevalence, risk factors, and impact upon quality of life.

OBJECTIVE: The purpose of this study was to estimate the prevalence and impact upon quality of life of anal incontinence (AI) in women aged 18 to 65. STUDY DESIGN: Consecutive women presenting for general gynecologic care were given a bowel function questionnaire. Women with AI were prompted to complete the Fecal Incontinence Severity Index (FISI) and Fecal Incontinence Quality of Life Scale (FIQL). RESULTS: The cohort was composed of 457 women with a mean age of 39.9 +/- 11 years. AI prevalence was 28.4% (95% CI 24.4-32.8). After logistic regression, IBS (OR 3.22, 1.75-5.93), constipation (OR 2.11, 1.22-3.63), age (OR 1.05, 1.03-1.07), and BMI (OR 1.04, 1.01-1.08) remained significant risk factors. The mean FISI score was 20.4 +/- 12.4. Women with only flatal incontinence scored higher, and women with liquid loss scored lower on all 4 scales of the FIQL. CONCLUSION: AI is prevalent in women seeking benign gynecologic care, and liquid stool incontinence has the greatest impact upon quality of life.

Effect of periurethral denervation on smooth muscles of the lower urinary tract.

OBJECTIVE: This study was undertaken to determine the effect of periurethral denervation on contractile function of the smooth muscle of the lower urinary tract of the female rat. STUDY DESIGN: Periurethral nerve transection or sham operation was performed in 35 young female rats. Contractile function of the bladder dome and base was determined as a function of time after surgery. Statistical analysis was conducted by Student t test. RESULTS: Periurethral denervation resulted in impaired contractile responses to electrical field stimulation in the bladder base (nerve-transected 45 +/- 11 g/cm 2 ; sham 84 +/- 10 g/cm 2 , P < .05) and dome (nerve-transected 179 +/- 16 g/cm 2 ; sham 334 +/- 29 g/cm 2 , P < .05) 2 weeks after nerve transection. The ability to respond to potassium chloride and the muscarinic agonist, carbachol, and the rates of contraction and relaxation, however, remained intact. Baseline phasic contractile activity was increased significantly in bladders from nerve-transected animals. Maximal field-stimulated contractions of the longitudinal urethra smooth muscle were not altered by periurethral denervation (sham 21 +/- 6 g/cm 2 , nerve-transected 19 +/- 5 g/cm 2 , P = .4). Compromised nerve-mediated contractions of the bladder dome and base improved significantly by 21 days. CONCLUSION: Periurethral nerve transection results in transient impairment of neurogenic contractile responses in the bladder base and dome, though the intrinsic ability of the bladder to contract remains intact. This compromised response of the dome, in conjunction with previous results demonstrating impaired urethral smooth muscle relaxation, suggests that transection of periurethral neurons may have complex effects on the entire lower urinary tract.

A comprehensive pelvic dissection course improves obstetrics and gynecology resident proficiency in surgical anatomy.

OBJECTIVE: This study was undertaken to evaluate the impact of a pelvic dissection course on resident proficiency in surgical anatomy. STUDY DESIGN: Over a 1-year period, residents attended a course consisting of pretesting and posttesting, lectures, and pelvic dissection. Tests results were analyzed using paired Student t test, analysis of variance, and Kruskal-Wallis statistics. RESULTS: Of 42 residents, 24 completed all testing (study cohort). On written and practical examinations, resident scores improved a median of 42% and 29% (both P<.0001). Postgraduate year (PGY) 2 demonstrated the greatest improvement on the practical and PGY-3s demonstrated the greatest improvement on the written. Baseline written and practical results discriminated PGY level (construct validity): PGY-2=PGY-3

Morphometric properties of the posterior vaginal wall in women with pelvic organ prolapse.

OBJECTIVE: Our purpose was to analyze the morphometric properties of the posterior vaginal wall and compare the smooth muscle distribution in the posterior vaginal muscularis in women with and without pelvic organ prolapse. STUDY DESIGN: Specimens were taken from the apex of the posterior vaginal wall after hysterectomy from 15 women with pelvic organ prolapse and from 8 healthy control subjects. Smooth muscle cells of the posterior vaginal wall were identified by immunohistochemistry with antibodies to smooth muscle alpha-actin. Morphometric analysis was performed on histologic cross-sections of the posterior vaginal wall to determine the fractional area of nonvascular smooth muscle in the muscularis. The innervation pattern of the vaginal wall was determined by use of S100 immunostaining. Statistical comparisons between two groups were conducted by a Student t test. Comparisons between multiple groups were conducted with a one-way analysis of variance followed by a post-hoc Student-Neuman-Keuls test. RESULTS: The fractional area of nonvascular vaginal smooth muscle in the muscularis of women with posterior wall prolapse was significantly decreased compared with that of healthy control subjects. Nerve bundles were located in the deep vaginal muscularis and adventitia of the posterior vaginal wall. In women with posterior wall prolapse, nerve bundles were smaller and fewer in number. CONCLUSION: Morphologic features of the posterior vaginal wall are significantly altered in women with posterior wall prolapse compared with asymptomatic control subjects.

Morphometric analysis of smooth muscle in the anterior vaginal wall of women with pelvic organ prolapse.

OBJECTIVE: The purpose of this study was to compare the smooth muscle content of the anterior vaginal wall in normal women and women with pelvic organ prolapse. STUDY DESIGN: Specimens were taken from the apex of the anterior vaginal cuff after abdominal hysterectomy from 28 women with pelvic organ prolapse and 12 control subjects. Smooth muscle cells of the anterior vaginal wall were identified by immunohistochemistry with antibodies to smooth muscle alpha-actin. Morphometric analysis was used to determine the fractional area of nonvascular smooth muscle in the muscularis in histologic cross-sections of the anterior vaginal wall. RESULTS: The fractional area of nonvascular vaginal smooth muscle in the muscularis of women with prolapse was significantly decreased compared with that of control subjects. This decreased fraction of smooth muscle in the anterior vaginal wall was not related to age, race, or stage of prolapse. In women with prolapse, vaginal smooth muscle content was most diminished in specimens from postmenopausal women with no estrogen replacement. The fractional area of muscularis smooth muscle was also decreased significantly in premenopausal women with prolapse. CONCLUSION: The fraction of smooth muscle in the muscularis of the anterior vaginal wall is significantly decreased in women with pelvic organ prolapse compared with normal control subjects.