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Objective: The purpose of this study was to describe the methods of a randomized clinical trial of intra-vesical botulinum toxin for refractory urge urinary incontinence. Methods: Clinical sites of the Pelvic Floor Disorders Network (www.pfdn.org) recruited patients with refractory urge urinary incontinence and urodynamic evidence of detrusor overactivity incontinence (DOI) to a 2:1 placebo controlled cystoscopic injection of botulinum toxin A. Results: The primary outcome is time to failure after first injection, with failure defined as a Patient Global Impression of Improvement (PGI-I) score 4 or greater at least 2 months after the first injection or the commencement of any new treatment at any time after the first injection, or an increased intensity of previously established treatment for DOI. Conclusions: This trial was designed to test the efficacy of intra-detrusor botulinum toxin A for the treatment of refractory urge incontinence. Progress of the trial can be monitored on www.clinicaltrials. gov [ABSTRACT FROM AUTHOR]

Controversy surrounds the association between bacterial vaginosis (BV) and pelvic inflammatory disease (PID). Women (N = 1,140) were ascertained at five US centers, enrolled (1999-2001), and followed up for a median of 3 years. Serial vaginal swabs were obtained for Gram's stain and cultures. PID was defined as 1) histologic endometritis or 2) pelvic pain and tenderness plus oral temperature >38.8 degrees C, leukorrhea or mucopus, erythrocyte sedimentation rate >15 mm/hour, white blood cell count >10,000, or gonococcal/chlamydial lower genital infection. Exploratory factor analysis identified two discrete clusters of genital microorganisms. The first correlated with BV by Gram's stain and consisted of the absence of hydrogen peroxide-producing lactobacillus, Gardnerella vaginalis, Mycoplasma hominis, anaerobic gram-negative rods, and, to a lesser degree, Ureaplasma urealyticum. The second, unrelated to BV by Gram's stain, consisted of Enterococcus species and Escherichia coli. Being in the highest tertile in terms of growth of BV-associated microorganisms increased PID risk (adjusted rate ratio = 2.03, 95% confidence interval: 1.16, 3.53). Carriage of non-BV-associated microorganisms did not increase PID risk. Women with heavy growth of BV-associated microorganisms and a new sexual partner appeared to be at particularly high risk (adjusted rate ratio = 8.77, 95% confidence interval: 1.11, 69.2). When identified by microbial culture, a combination of BV-related microorganisms significantly elevated the risk of acquiring PID. [ABSTRACT FROM AUTHOR]

Background and Objectives: Vaginal acidification has been suggested as a means of normalizing the vaginal flora.Goal: The purpose of this study was to determine the effectiveness of an acetic acid-based vaginal gel in the treatment of bacterial vaginosis (BV).Study Design: Forty-four patients with BV were enrolled in a randomized, double-blind clinic trial. Of these, 29 were evaluable. Patients were randomized to receive either 5 mL acetic acid gel (n = 14) or placebo gel (n = 15) intravaginally twice daily for 7 days. Clinical criteria and vaginal Gram stain scores were compared between the initial visit and at 2 weeks after initiating therapy.Results: No significant differences were noted when comparing drug and placebo in terms of subjective or clinical improvement or improvement in Gram stain smears for bacterial vaginosis.Conclusion: Vaginal acidification with an acetic acid gel formulated to pH 3.9 to 4.1 was ineffective therapy for bacterial vaginosis. [ABSTRACT FROM AUTHOR]

Abstract Background Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. Methods We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. Results Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. Conclusions The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain.

Abstract Background The determination of Intraepidermal Nerve Fiber Density (IENFD) in skin biopsy is a useful method for the evaluation of different types of peripheral neuropathies. To allow a reliable use of the method it is necessary to determine interobserver reliability. Previous studies dealing with this topic used limited suitable statistical methods. Methods In the present study three observers determined the IENFD and estimated the staining quality of the basement membrane for an adequate quantity of 120 skin biopsies (stained with indirect immunofluorescence technique) from 68 patients. More adequate statistical methods like intraclass correlation coefficient and Bland Altman Plot were chosen to estimate interobserver reliability. Results We found an unexpected significant difference in IENFD between the observers (p < 0.05) and so the results of this study are not in line with the high interobserver reliability reported before (intraclass correlation coefficient: 0.73). The Bland Altmann Plot showed a variance growing with rising mean. The difference in IENFD between the observers and the resulting low interobserver reliability is likely caused by different interpretations of the standard counting rules. There was no significant difference in IENFD between observers for biopsies with a well-defined basement membrane. Thus skin biopsies with an inexactly defined basement membrane should not be used diagnostically for the determination of IENFD. Conclusion These results emphasise that standardisation of the method is extremely important and at least two observers should analyse skin biopsies with critical IENFD near the cut-off values.

Background: Tissue resident memory T cells (TrM) provide an enhanced response against infection at mucosal surfaces, yet their function has not been extensively studied in humans, including the female genital tract (FGT)., Methods: Using polychromatic flow cytometry, we studied TrM cells, defined as CD62L-CCR7-CD103 + CD69 + CD4 + and CD8 + T cells in mucosa-derived T cells from healthy and HIV-positive women., Results: We demonstrate that TrM are present in the FGT of healthy and HIV-positive women. The expression of the mucosal retention receptor, CD103, from HIV-positive women was reduced compared to healthy women and was lowest in women with CD4 counts < 500 cells/mm 3 . Furthermore, CD103 expression on mucosa-derived CD8 + T cells correlated with antigen-specific IFN-γ production by mucosal CD4 + T cells and was inversely correlated with T-bet from CD8 + CD103 + mucosa-derived T cells., Conclusions: These data suggest that CD4 + T cells, known to be impaired during HIV-1 infection and necessary for the expression of CD103 in murine models, may play a role in the expression of CD103 on resident T cells from the human FGT., Competing Interests: The authors have no competing financial interests.

Objective: Epidemiological evidence suggests an association between the use of hormonal contraception and an increased risk of acquiring sexually transmitted diseases including HIV-1. We sought to elucidate the biological mechanisms underlying the effect of hormonal contraception on the immune system., Design: Cross-sectional study., Methods: To delineate the biological mechanisms underlying the effect of hormonal contraceptives on the immune system, we analyzed the functional capacity of circulating plasmacytoid dendritic cells (pDCs), the distribution of vaginal immune cell populations, and the systemic and genital levels of immune mediators in women using depot medroxyprogesterone acetate (DMPA), NuvaRing, or combined oral contraceptives (COC)., Results: The use of DMPA or NuvaRing was associated with reduced capacity of circulating pDCs to produce interferon (IFN)-α and tumor necrosis (TNF-α) in response to TLR-9 stimulation. Systemic levels of IFN-α and cervicovaginal fluid levels of IFN-α, CXCL10, monocyte chemotactic protein-1, and granulocyte-colony stimulating factor were significantly lower in DMPA users compared to control volunteers not using hormonal contraception. The density of CD207 Langerhans cells in the vaginal epithelium was reduced in NuvaRing and combined oral contraceptive users but not in DMPA users., Conclusions: The presented evidence suggests that the use of some types of hormonal contraception is associated with reduced functional capacity of circulating pDCs and altered immune environment in the female reproductive tract.

Fecal incontinence (FI) is a physically and psychosocially debilitating disorder which negatively impacts quality of life (QOL). It bears a significant burden not only on patients but also on their families, caretakers as well as society as a whole. Even though it is considered a somewhat common condition, especially as women age, the prevalence is often underestimated due to patients' reluctance to report symptoms or seek care. The evaluation and treatment of FI can be also hindered by lack of understanding of the current management options among healthcare providers and how they impact on QOL. This article provides a comprehensive review on the impact of FI and its treatment on QOL in women.

We report that primary human vaginal dendritic cells (DCs) display a myeloid phenotype and express CD4, CCR5, and CXCR4. Vaginal CD13(+) CD11c(+) DCs rapidly and efficiently bound transmitted/founder (T/F) CCR5-tropic (R5) viruses, transported them through explanted vaginal mucosa, and transmitted them in trans to vaginal and blood lymphocytes. Vaginal myeloid DCs may play a key role in capturing and disseminating T/F R5 HIV-1 in vivo and are candidate "gatekeeper" cells in HIV-1 transmission., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.

Synthetic transvaginal mesh has been employed in the treatment of pelvic organ prolapse for more than a decade. As the use of these devices increased during this period so did adverse event reporting. In 2008, the Food and Drug Administration (FDA) Public Health Notification informed physicians and patients of rising concerns with the use of synthetic transvaginal mesh. Shortly thereafter and in parallel to marked increases in adverse event reporting within the Manufacturer and User Device Experience (MAUDE), the FDA released a Safety Communication regarding urogynecologic surgical mesh use. Following this report and in the wake of increased medical industry product withdrawal, growing medicolegal concerns, patient safety, and clinical practice controversy, many gynecologists and pelvic reconstructive surgeons are left with limited long-term data, clinical guidance, and growing uncertainty regarding the role of synthetic transvaginal mesh use in pelvic organ prolapse. This paper reviews the reported complications of synthetic transvaginal mesh with an evidence-based approach as well as providing suggested guidance for the future role of its use amidst the controversy.

Wet/dry mapping provides a low-cost, comprehensive snapshot for monitoring flow conditions in rivers with interrupted perennial (spatially intermittent) surface flow. When used in conjunction with more traditional point-specific stream flow or groundwater measurements, it provides a better understanding of hydrologic systems at the broad landscape or watershed scale. Through use of trained volunteers, we mapped reaches with surface water during the driest time of year to track annual variation in length and location of perennial flow. Data from 12 years of wet/dry mapping on the San Pedro River in Arizona, USA, showed 62 reaches with surface flow in every year, totaling 32% of the river length through the San Pedro Riparian National Conservation Area. They also show areas with high year-to-year variation in flow length, which indicate changes in local groundwater conditions and may provide early warning of ecological changes. Data and maps from this project have been useful for a wide variety of conservation, management, and research efforts.

Studies of T cell-mediated immunity in the human female genital tract have been problematic due to difficulties associated with the collection of mucosal samples. Consequently, most studies rely on biopsies from the lower female genital tract or remnant tissue from hysterectomies. Availability of samples from healthy women is limited, as most studies are carried out in women with underlying pathologies. Menstruation is the cyclical sloughing off of endometrial tissue, and thus it should be a source of endometrial cells without the need for a biopsy. We isolated and phenotyped T cells from menstrual and peripheral blood and from endometrial biopsy-derived tissue from healthy women to determine the types of T cells present in this compartment. Our data demonstrated that T cells isolated from menstrual blood are a heterogeneous population of cells with markers reminiscent of blood and mucosal cells as well as unique phenotypes not represented in either compartment. T cells isolated from menstrual blood expressed increased levels of HLA-DR, αEβ7 and CXCR4 and reduced levels of CD62L relative to peripheral blood. Menstrual blood CD4+ T cells were enriched for cells expressing both CCR7 and CD45RA, markers identifying naïve T cells and were functional as determined by antigen-specific intracellular cytokine production assays. These data may open new avenues of investigation for cell mediated immune studies involving the female reproductive tract without the need for biopsies.

Mucosal surfaces play a major role in human immunodeficiency virus type 1 (HIV-1) transmission and pathogenesis, and yet the role of lamina propria macrophages in mucosal HIV-1 infection has received little investigative attention. We report here that vaginal and intestinal macrophages display distinct phenotype and HIV-1 permissiveness profiles. Vaginal macrophages expressed the innate response receptors CD14, CD89, CD16, CD32, and CD64 and the HIV-1 receptor/coreceptors CD4, CCR5, and CXCR4, similar to monocytes. Consistent with this phenotype, green fluorescent protein-tagged R5 HIV-1 entered macrophages in explanted vaginal mucosa as early as 30 min after inoculation of virus onto the epithelium, and purified vaginal macrophages supported substantial levels of HIV-1 replication by a panel of highly macrophage-tropic R5 viruses. In sharp contrast, intestinal macrophages expressed no detectable, or very low levels of, innate response receptors and HIV-1 receptor/coreceptors and did not support HIV-1 replication, although virus occasionally entered macrophages in intestinal tissue explants. Thus, vaginal, but not intestinal, macrophages are monocyte-like and permissive to R5 HIV-1 after the virus has translocated across the epithelium. These findings suggest that genital and gut macrophages have different roles in mucosal HIV-1 pathogenesis and that vaginal macrophages play a previously underappreciated but potentially important role in mucosal HIV-1 infection in the female genital tract.

Surgical intervention for both emergency and elective surgeries will increase as women live longer and maintain active lifestyles. Older women with operable conditions tolerate elective gynecologic and other nonvascular surgery with acceptable morbidity and mortality. However, increased medical comorbidities, with their associated increase in polypharmacy and perioperative risks as women age, make it important to a priori optimize perioperative medical conditions and medication management. Other considerations include assessing functional and cognitive status, since these may be impaired acutely with increased prevalence of drug use during surgical hospitalization. With aging and postmenopausal status, changes associated with aging appear to play a greater role than gender in pharmacologic responses. Surgical outcomes should be optimized to maintain and even improve women's quality of life.

Objectives: To examine variability in bacterial vaginosis (BV) over 6- to 12-month intervals., Study Design: One thousand one hundred ninety-three women were followed for a median of 3 years with serial vaginal swab Gram stains for BV. Discrete time hazard models were fit to identify independent risk factors for BV., Results: Women with BV at study entry were categorized as having normal flora at the next visit 20% of the time, and women with normal flora at study entry were categorized as having BV at the next visit 20% of the time. Among women with initially normal flora, factors associated with BV were black race, lower education, a history of BV, a history of chlamydial/gonococcal cervicitis, and lack of monogamy., Conclusion: About one fifth of women with normal flora develop BV over a given 6- to 12-month interval, and the modifiable risk factors of cervicitis and lack of monogamy contribute to the development of BV.

Objective: The objective of this study was to assess in prospective data whether bacterial vaginosis (BV) is associated with gonococcal/chlamydial cervicitis., Study: A total of 1179 women at high risk for sexually transmitted infections was followed for a median of 3 years. Every 6 to 12 months, vaginal swabs were obtained for Gram stain, culture of microflora, and Neisseria gonorrhoeae and Chlamydia trachomatis. A Gram stain score of 7 to 10 based on the Nugent criteria categorized BV., Results: Baseline BV was associated with concurrent gonococcal/chlamydial infection (adjusted odds ratio, 2.83; 95% confidence interval [CI], 1.81-4.42). However, the association between BV and subsequent, incident gonococcal/chlamydial genital infection was not significant (adjusted relative risk [RR], 1.52; 95% CI, 0.74-3.13). Dense growth of pigmented, anaerobic Gram-negative rods (adjusted RR, 1.93; 95% CI, 0.97-3.83) appeared to elevate the risk for newly acquired gonococcal/chlamydial genital infection., Conclusions: BV was common among a predominantly black group of women with concurrent gonococcal/chlamydial infection but did not elevate the risk for incident infection.

Douching has been linked to gonococcal or chlamydial cervicitis and pelvic inflammatory disease (PID) in retrospective studies. The authors conducted a 1999-2004 prospective observational study of 1,199 US women who were at high risk of acquiring chlamydia and were followed for up to 4 years. Cervical Neisseria gonorrhoeae and Chlamydia trachomatis were detected from vaginal swabs by nucleic acid amplification. PID was characterized by histologic endometritis or pelvic pain and tenderness plus one of the following: oral temperature >38.3 degrees C, leukorrhea or mucopus, erythrocyte sedimentation rate >15 mm/hour, white blood cell count >10,000, or gonococcal/chlamydial lower genital tract infection. Associations between douching and PID or gonococcal/chlamydial genital infections were assessed by proportional hazards models. The 4-year incidence rate of PID was 10.9% and of gonococcal and/or chlamydial cervicitis was 21.9%. After adjustment for confounding factors, douching two or more times per month at baseline was associated with neither PID (adjusted hazard ratio = 0.76, 95% confidence interval: 0.42, 1.38) nor gonococcal/chlamydial genital infection (adjusted hazard ratio = 1.16, 95% confidence interval: 0.76, 1.78). Frequency of douching immediately preceding PID or gonococcal/chlamydial genital infection was not different between women who developed versus did not develop outcomes. These data do not support an association between douching and development of PID or gonococcal/chlamydial genital infection among predominantly young, African-American women.

Among 684 sexually active women with pelvic inflammatory disease (PID) followed up for a mean of 35 months, we related contraceptive use to self-reported PID recurrence, chronic pelvic pain, and infertility. Persistent use of condoms during the study reduced the risk of recurrent PID, chronic pelvic pain, and infertility. Consistent condom use (about 60% of encounters) at baseline also reduced these risks, after adjustment for confounders, by 30% to 60%. Self-reported persistent and consistent condom use was associated with lower rates of PID sequelae.

Signal transducer and activator of transcription 5 (STAT5) activation plays a central role in GH- and prolactin-mediated signal transduction in the pancreatic beta-cells. In previous experiments we demonstrated that STAT5 activation is necessary for human (h)GH-stimulated proliferation of INS-1 cells and hGH-induced increase of mRNA-levels of the cell cycle regulator cyclin D2. In this study we have further characterized the role of STAT5 in the regulation of cyclin D expression and beta-cell proliferation by hGH. Cyclin D2 mRNA and protein levels (but not cyclin D1 and D3) were induced in a time-dependent manner by hGH in INS-1 cells. Inhibition of protein synthesis by coincubation with cycloheximide did not affect the hGH-induced increase of cyclin D2 mRNA levels at 4 h. Expression of a dominant negative STAT5 mutant, STAT5aDelta749, partially inhibited cyclin D2 protein levels. INS-1 cells transiently transfected with a cyclin D2 promoter-reporter construct revealed a 3- to 5-fold increase of transcriptional activity in response to hGH stimulation. Furthermore, coexpression of a constitutive active STAT5 mutant (either CA-STAT5a or CA-STAT5b) was sufficient to drive transactivation of the promoter. CA-STAT5b was stably expressed in INS-1 cells under the control of a doxycycline-inducible promoter. Gel retardation experiments using a probe representing a putative STAT5 binding site in the cyclin D2 promoter revealed binding of the doxycycline-induced CA-STAT5b. Furthermore, induction of CA-STAT5b stimulated transcriptional activation of the cyclin D2 promoter and induced hGH-independent proliferation in these cells. In primary beta-cells, adenovirus-mediated expression of CA-STAT5b profoundly stimulated DNA-synthesis (5.3-fold over control) in the absence of hGH. Our studies indicate that STAT5 activation is sufficient to drive proliferation of the beta-cells and that cyclin D2 may be a critical target gene for STAT5 in this process.

Background: Black women are more likely to have bacterial vaginosis (BV) than are non-Hispanic white women. We examined whether this disparity can be explained by racial differences in known BV risk factors., Methods: Nine hundred black and 235 white women were enrolled from five US sites. At baseline, structured interviews were conducted and vaginal swabs self-collected for Gram-stain and culture., Results: Black women were more likely than white women to have BV/intermediate vaginal flora. They also were more likely to be older, have lower educational attainment and family incomes, have a history of a sexually transmitted disease, and douche. After adjustment for demographic and lifestyle factors, blacks remained at elevated risk for BV/intermediate flora (OR 2.2, 95% CI 1.5-3.1). Blacks also were more likely to have specific BV-related vaginal microflora, as well as gonococcal or chlamydial cervicitis (OR 2.2, 95% CI 1.2-3.8) after adjustment for known BV risk factors., Conclusion: Risk factor differences did not explain the observed racial disparity in the occurrence of BV, BV-related microflora, or gonococcal or chlamydial cervicitis. These findings highlight our limited understanding of the factors accounting for the occurrence of bacterial vaginosis and cervicitis among black and white women.

Background: Although douching is common, it is a potentially harmful habit., Goal: We studied attitudes and knowledge around the behavior of douching., Study Design: Of 1,200 women enrolled in this multisite study, 532 douched and answered questions on a structured interview regarding douching behaviors., Results: Over half had douched for 5 or more years. Douching was most often initiated on the recommendation of female relatives and practiced for reasons of hygiene. Half of women considered douching to be healthy. Those who considered douching to be unhealthy reported that douching may disrupt vaginal flora but did not cite more serious risks. Nonetheless, women who had been advised by a health professional to stop douching were less likely to consider douching healthful and were more likely to have tried to stop., Conclusion: Women had a limited understanding of potential adverse health consequences associated with douching. Targeted health messages may influence women to initiate douching cessation.

DNA from 129 paired thyroid tumorous and non-tumorous tissue samples of Belarussian children (102 patients; age at surgery