Urogenital Tissue Research Articles

The cell fates of intermediate cell population in prostate development

Organ development, regeneration and cancer initiation are typically influenced by the proliferation and lineage plasticity of tissue-specific stem cells. Prostate intermediate cells, which exhibit characteristics of both basal and luminal cells, are prevalent in pathological states and during organ development. However, the identity, fate and function of these intermediate cells in prostate development are not well understood. Through single-cell RNA-seq analysis on neonatal urogenital sinus tissue, we identified intermediate cells exhibiting stem cell potential. A notable decline in the population of intermediate cells was observed during prostate development. Prostate intermediate cells were specifically labeled in early and late postnatal development by the enhanced dual-recombinase-mediated genetic tracing systems. Our findings revealed that these cells possess significant stem cell capabilities as demonstrated in organoid formation and cell fate mapping assays. These intermediate cells also exhibited intrinsic bipotential properties, enabling them to differentiate into both basal and luminal cells. Additionally, we discovered a novel transition from intermediate cell expressing neuroendocrine markers to neuroendocrine cell during prostate development. This study highlights intermediate cells as a crucial stem cell population and enhances our understanding of their role in prostate development and the plasticity of prostate cancer lineage.

(011) Beneficial Effects of Vaginal Prasterone (DHEA) on the Vaginal Histology of Women with GSM Beyond the Epithelium

Abstract Introduction There is mounting evidence that androgens play an important role, together with estrogens, in the maintenance of genitourinary health. Objective Vaginal prasterone was used to characterize the histological changes associated with the dual androgen - estrogen stimulation of the vaginal wall in the treatment of the genitourinary syndrome of menopause (GSM). Since prasterone is converted to androgens which are subsequently aromatised in estrogens, a group of patients on aromatase inhibitors (AI) was included to isolate changes attributable to androgens. Methods Vaginal biopsies and vulvar pictures were collected before and after 12 weeks of treatment with 6.5 mg intravaginal prasterone daily (Intrarosa®). Eight women with GSM were recruited, including two breast cancer survivors on AI. Results Following treatment, the epithelium showed striking histological improvements, regaining thickness, ridges, active proliferation and glycogen synthesis. In the lamina propria, treatment led to increases in elastin content and nerve endings density. Visual evaluation of the vulva showed reduction of the redness and inflammation in the vestibule and the urethral meatus as well as a relaxation of the vaginal entrance. All observations were consistent between the groups with and without AI. Conclusions Data presented here are believed to be the first demonstration of the beneficial effects of androgens deep into the lamina propria of GSM patients both together with or independently from estrogens. Tissue changes observed could help understand some of the GSM symptomatology improvements observed before on dyspareunia and other sexual function parameters. While further studies are warranted to better understand how androgens and estrogens work synergistically in the treatment of GSM, the data presented here strongly suggest that prasterone has deep beneficial impacts on the urogenital tissue. Disclosure Yes, this is sponsored by industry/sponsor: Endoceutics Clarification: Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Endoceutics

Hypereosinophilic Syndrome Complicated by Ischemia of the Lower Limb Clinical Case with Review of the Literature

Hyper eosinophilia is the result of a disorder, which can be of central origin, with an excessive production of polymorphonuclear eosinophils (PNE), or of a peripheral dysfunction with an abundant recruitment of polynuclear neutrophils from the marrow by the tissues. peripheral more frequently the digestive and urogenital respiratory tissue. The diagnostics must be early to avoid complications. Any case of hypereosinophilia requires a very precise etiological investigation, with a balance sheet of visceral repercussions of eosinophilia. Some genetic abnormalities of the eosinophil line or a dysfunction of the lymphoid line, can be discovered, the targeted therapy trials have revolutionized the prognosis, sometimes pejorative of these diseases, we report here the case of hypereosinophilia complicated by ischemia of the lower limbs.

Treatment of Epstein-Barr Virus-Related Post-Renal Transplantation Development of Diffuse Large B Cell Lymphoma of the Distal Ureter: A Case Report

Posttransplant lymphoproliferative disorder with involvement of the donor urogenital tissue is a rare and serious complication of solid organ transplant. We report an adult kidney transplant recipient who developed the diffuse large B cell lymphoma of the distal ureter in the setting of new allograft nephropathy. Early intervention, reduction of immunosuppression, surgical reconstruction and chemotherapy salvaged the allograft kidney and averted a fatal outcome. The renal function recovered to the baseline with creatinine ranging between 1.3 and 1.5. The patient did not require dialysis at any point after ureteral stent placement and reconstructive surgery. In addition, the case highlights the importance of multidisciplinary management involving transplant nephrology, oncology, transplant surgery, and urology in such a complicated disease process.

Consensus statement - Urogenital atrophy.

This guidance refers to urogenital atrophy, a chronic and progressive condition due to estrogen deficiency, most commonly associated with the menopause. There is a potential negative impact on all urogenital tissue quality including the vulva, vagina, bladder and urethra. Symptoms may not become apparent for several years after the menopause and therefore any association is lost, with women accepting symptoms as a normal part of the aging process. There may be reluctance to discuss symptoms with a clinician and this is likely to be linked with under diagnosis and under treatment. Urogenital atrophy has been described as a silent epidemic with lack of awareness affecting an accurate diagnosis and access to treatment. Whilst vaginal estrogen (also referred to as local estrogen) therapy is the best-known treatment, newer drugs and interventions are now available.

Methotrexate-induced toxic effects and the ameliorating effects of astaxanthin on genitourinary tissues in a female rat model.

The purpose of the study was to explore the possible deleterious effects of Methotrexate (MTX) treatment on the urogenital tissues and the potential protective effects of Astaxanthin (AXA). Twenty-four female Wistar Albino rats (12months old) were divided into 3 groups as follows: Group I (Control group): rats received a single dose of 0.1ml saline by gavage and intraperitoneal injection. Group II (MTX group): rats received a single dose of 20mg/kg MTX, i.p, on the 2nd day. Group III (MTX + AXA group): rats received 100mg/kg AXA orally for 7days in addition to a single dose of MTX. The levels of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and histopathological and immunohistochemical markers (Caspase-3, iNOS, CRP, G-CSF) were evaluated in urogenital tissues. In ovarian tissues, a statistically significant increase in TOS levels (p = 0.001) and OSI index (p = 0.028) were observed in Group II compared to Group I. TAS level was significantly higher in Group III compared to Group II and I (p = 0.009 and 0.002, respectively). However, a significant decrease in OSI level was observed in Group III compared to Group II (p = 0.035). In fallopian tube tissues, TAS level was significantly decreased in Group II compared to Group I (p = 0.047). Histopathologically, marked hyperemia was observed in MTX group. AXA treatment ameliorated all the pathological findings. Immunohistochemically, all the studied markers were considerably increased in Group II, however, they were decreased by AXA. These findings revealed that MTX treatment caused oxidative stress, apoptosis, and inflammation in the urogenital tissue. We found that AXA significantly ameliorated the damage caused by MTX in the urogenital tissue. The results of the study have indicated that AXA may be a promising nutritional support substance against the damage caused by chemotherapeutic and cytotoxic agents, such as MTX, to the urogenital tissue.

Male Sexual Disorders of Patients with Cancer in Medical Oncology Service in University Hospital of Brazzaville

Considered as taboo, sexual difficulties and couple intimacy remain rarely tackled by patients and again less by the oncologist practicians. It might seem that faced with the vital stake of disease, this kind of worries seem to be frivolous, indeed shameful to be tackled. The current study had an objective to assess the impacts of cancer on male sexuality followed and treated in medical service in University Hospital of Brazzaville. Studying male sexual disorder of patients with cancer in medical oncology service in university hospital of Brazzaville. It was a retrospective study, from April 1^st to July 31^st 2018. All patients with cancer aged at least 18 years old with a performance of WHO between 0-2 were included. About one hundred (100) patients we examined whose eighty four (84) men, it appears that the most sexual disorder found is the one of craving, then the one of orgasm. Certain troubles had a link with the onset of cancer (p<5). The men presented a great number of sexual disorder had a cancer of digestive type (47.6%), urogenital (22.6%) and soft tissue (19%). In terms of received treatments: surgery-chemotherapy (men 22%), chemotherapy only (21.4%), surgery only (19%). The global frequency of sexual disorders to all patients is 98.4% in medical oncology service. It is important to consider those sexual disorders at the time of the care of those patients according to their repercussion on life quality during and after all treatment even in the absence of all progressive nature of disease. The most sexual disorder found is the one of craving.

Adipocytes protect fibroblasts from radiation-induced damage by adiponectin secretion

Prostate and colon cancers are among the most common cancers diagnosed annually, and both often require treatment with radiation therapy. Advancement in radiation delivery techniques has led to highly accurate targeting of tumor and sparing of normal tissue; however, in the pelvic region it is anatomically difficult to avoid off-target radiation exposure to other organs. Chronically the effects of normal urogenital tissue exposure can lead to urinary frequency, urinary incontinence, proctitis, and erectile dysfunction. Most of these symptoms are caused by radiation-induced fibrosis and reduce the quality of life for cancer survivors. We have observed in animal models that the severity of radiation-induced fibrosis in normal tissue correlates to damaged fat reservoirs in the pelvic region. We hypothesize that adipocytes may secrete a factor that prevents the induction of radiation-associated fibrosis in normal tissues. In these studies we show that the adipokine, adiponectin, is secreted by primary mouse adipocytes and protects fibroblasts from radiation-induced cell death, myofibroblast formation, and senescence. Further, we demonstrated that adiponectin does not protect colorectal or prostate cancer cells from radiation-induced death. Thus, we propose that adiponectin, or its downstream pathway, would provide a novel target for adjuvant therapy when treating pelvic cancers with radiation therapy.

Effect of the Sodium-Glucose Cotransporter 2 Inhibitor, Dapagliflozin, on Genitourinary Infection in an Animal Model of Type 2 Diabetes

PurposeTo investigate the effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, on inflammatory cytokines of urogenital tissue in a rat model of type 2 diabetes (T2DM) to infer pharmaceutical influence of dapagliflozin on genitourinary infection or inflammation.MethodsStudy animals were divided into the following 4 groups of 10 animals each: (1) the Otsuka Long-Evans Tokushima Fatty (OLETF)-DA group treated with dapagliflozin at 1.0 mg/kg/day, (2) the OLETF-VO group treated with voglibose at 0.6 mg/kg/day, (3) the control group (OLETF-CO) given water, and (4) the Long-Evans Tokushima Otsuka (LETO) rats were included as nondiabetic control group. Changes in blood glucose, 24-hour urine volume, and urine glucose were measured. The interleukin-1β (IL-1β) and interleukin-18 (IL-18) levels in the bladder and the urethra were quantified, respectively.ResultsThe urine glucose level and the 24-hour urine volume at 12 weeks of treatment were significantly higher in the OLETF-DA group than that in any other group (P<0.05). The cytokine analysis of the bladder and urethra showed higher IL-18 and IL-1β in the OLETF-DA and the OLETF-CO groups than that in the OLETF-VO and LETO groups (P<0.05). The cytokine levels did not differ between the OLETF-DA and the OLETF-CO groups, and the level of IL-18 in the OLETF-DA group was higher in the urethra than in the bladder.ConclusionsThis study revealed that dapagliflozin increased the urine glucose concentration, resulting in an inflammatory response remain in the urogenital tract as the untreated diabetic rats. Therefore, when treating patients with T2DM with dapagliflozin, careful attention should be paid to genitourinary infection or inflammation.

Characterization of Clinical and Histological Rejection of Male Genital Tissues Using a Novel Microsurgical Rat Penile Transplantation Model.

Penis transplantation represents an exciting new avenue for restoration of male urogenitalia. However, little is known about the specific immunological features of penile transplants, limiting their application in complex urogenital reconstruction. To properly study this emerging form of transplantation, adequate preclinical models are a necessity. The purpose of this study is to establish a clinical and histological rejection classification of urogenital tissue transplants using a new rat heterotopic penile transplant model that includes preputial skin. Syngeneic and allogeneic heterotopic penile transplantations were performed on Lewis and Brown Norway rats using a new model designed by our group. Grafts were clinically and histologically monitored at postoperative days (POD) 3-30. Six syngeneic and 25 allogeneic transplants were performed. All syngeneic and tacrolimus-treated grafts survived until endpoint. Allogeneic graft rejection is shown to follow a 4-stage clinical progression with all untreated allografts developing epidermal sloughing at POD7 and full rejecting between POD14 and POD16. Histological samples were used to develop a specific 4-grade rejection classification analogous to the 2007 Banff Criteria for skin-containing allografts. Graft skin and urethral lining tissue are first rejection targets followed by tunica albuginea and corpora cavernosa in a distal to proximal pattern. We established a robust and reproducible murine model to study the immunobiology of male genital tissue in the context of transplantation and developed a novel 4-grade clinical and histological rejection scale based on graft skin and urethral lining as the main targets of rejection.

The impact of the sepsis on female urogenital system: the role of pregabalin.

The aim of the study was to investigate the oxidative damage and inflammatory effects of sepsis on the urogenital system in the Lipopolysaccharide (LPS)-induced sepsis model and ameliorating role of Pregabalin (PGB). Twenty-four female Wistar Albino rats (12months old) were divided into 3 groups as follows: Sepsis group (Group S) (5mg/kg LPS, i.p, single dose); Sepsis+ PGB group (Group SP) (5mg/kg LPS, i.p, single dose and 30mg/kg PGB); Control group (Group C) (0.1ml/oral and i.p. saline, single dose), 6h after LPS administration, the animals were killed. Subsequently, analyses of urogenital tissue oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed. Total oxidative status (TOS) and oxidative stress index (OSI) values in the urogenital tissues were increased in Group S (Total anti-oxidative status (TAS) decreased) compared to the Control group (p < 0.05). PGB improved these values (p < 0.05). The immunohistochemical markers [Caspase-3, granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), Serum Amyloid A (SAA) and inducible nitric oxide synthase (iNOS)] were significantly increased in Group S except for bladder (p < 0.001). Statistically significant immunohistochemical positiveness was found only for IL-6 in urinary bladder, though all the others values were negative. With the administration of PGB (Group SP), the expressions of these immunoreactions were markedly decreased (p < 0.001). These findings demonstrated that sepsis caused oxidative stress and inflammation in the urogenital tissues. We have revealed that PGB ameliorated tissue damage caused by sepsis.

Overall systematic approach to sepsis damages on urogenital tissues: protective power of lacosamide.

The aim of the study was to evaluate the harmful effects of sepsis on the urogynecological tissues and the ability of Lacosamide (LCM) on Lipopolysaccharide (LPS)-induced cytokine production, oxidative stress and apoptotic pathways, in the experimental rat sepsis model. Twenty-four female Wistar albino rats (12months old) were divided into 3 groups as follows: control group (Group I) (0.1ml/oral and i.p. saline, single dose), sepsis group (Group II) (5mg/kg LPS, i.p. single dose) and sepsis + LCM group (Group III) (5mg/kg LPS, i.p. single dose and 40mg/kg LCM). Six hours after the last LPS administration, the animals were sacrificed. Subsequently, the analyses of urogenital tissues total oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed. Total oxidant capacity (TOC) and oxidative stress index (OSI) values in the urogenital tissues were increased in the urogenital tissues in Group II [Total antioxidant capacity (TAC) was decreased] compared to group I (p < 0.05). LCM improved these values (p < 0.05). The immunohistochemical markers (Tumor Necrosis Factor-alpha (TNF-α), interleukin-1 beta (IL-1β), heat shock protein 70 (HSP-70), C-reactive protein (CRP), Malondialdehyde (MDA) were significantly increased in Group II (p < 0.001). With the administration of LCM (Group III), the expressions of above-mentioned markers were markedly decreased (p < 0.001). Marked hyperemia and slight hemorrhages with neutrophil leukocyte infiltrations were seen histopathologically in Group II. LCM treatment ameliorated the pathological findings. These findings demonstrated that sepsis caused oxidative stress, apoptosis and inflammation in the urogenital tissues. We revealed that LCM ameliorated the damage caused by sepsis in urogenital tissue.

Cellular origin of microRNA-371a-3p in healthy males based on systematic urogenital tract tissue evaluation.

BackgroundThe microRNA‐371a‐3p (miR‐371a‐3p) has been reported to be an informative liquid biopsy (serum and plasma) molecular biomarker for both diagnosis and follow‐up of patients with a malignant (testicular) germ cell tumor ((T)GCT). It is expressed in all histological cancer elements, with the exception of mature teratoma. However, normal testis, semen, and serum of males with a disrupted testicular integrity without a TGCT may contain miR‐371a‐3p levels above threshold, of which the cellular origin is unknown.ObjectivesTherefore, a series of relevant tissues (frozen and formalin‐fixed paraffin‐embedded (FFPE), when available) from the complete male urogenital tract (i.e., kidney to urethra and testis to urethra) and semen was investigated for miR‐371a‐3p levels using targeted quantitative RT‐PCR (qRT‐PCR).Materials and methodsIn total, semen of males with normospermia (n = 11) and oligospermia (n = 3) was investigated, as well as 88 samples derived from 32 different patients. The samples represented one set of tissues related to the entire male urogenital tract (11 anatomical locations), three sets for 10 locations, and four sets for six locations.ResultsAll testis parenchyma (n = 17) cases showed low miR‐371a‐3p levels. Eight out of 14 (57%) semen samples showed detectable miR‐371a‐3p levels, irrespective of the amount of motile spermatozoa, but related to sperm concentration and matched Johnsen score (Spearman's rho correlation coefficient 0.849 and 0.871, p = 0.000, respectively). In all other tissues investigated, miR‐371a‐3p could not be detected.DiscussionThis study demonstrates that the miR‐371a‐3p in healthy adult males is solely derived from the germ cell compartment.ConclusionsThe observation is important in the context of applying miR‐371a‐3p as molecular liquid biopsy biomarker for diagnosis and follow‐up of patients with malignant (T)GCT. Moreover, miR‐371a‐3p might be an informative seminal biomarker for testicular germ cell composition.

Local oestrogen therapy modulates extracellular matrix and immune response in the vaginal tissue of post‐menopausal women with severe pelvic organ prolapse

This study investigates the effect of local oestrogen therapy (LET) on the expression of proteins participating in collagen/elastin biogenesis and immune markers in vaginal tissues of post‐menopausal women with severe pelvic organ prolapse (POP). Vaginal biopsies were collected from the anterior vaginal wall of informed and consented 52 post‐menopausal women with severe POP undergoing total hysterectomy. Twenty‐nine of the 52 women were treated with LET (in the form of vaginal oestrogen cream or tablet), while the remaining 23 untreated patients served as the controls. This study was approved by Sinai Health System REB. Vaginal tissue specimens were analysed for gene and protein expression using real‐time RT‐PCR and Luminex assays, protein localization and immune cell infiltration were assessed by immunohistochemistry. Forty‐four cytokines were detected. We found that LET application: (a) significantly increased (P < 0.05) gene and protein expression levels of extracellular matrix (ECM) structural proteins, collagen and elastin, as well as the expression of ECM maturation enzyme BMP1; (b) decreased protein expression level of ECM degradation enzymes MMP1, MMP2 and MMP3 accompanied by an increase in their tissue inhibitors, TIMP1 and TIMP4; (c) significantly increased (P < 0.05) the gene and protein expression levels of 14 vaginal cytokines involved in leucocyte infiltration, which was confirmed by immunohistochemistry. Our results indicate that LET plays an important role in the activation of immune system within the local vaginal environment, limiting the undesirable ECM degradation, which supports the strengthening of vaginal ECM in post‐menopausal women, therefore resisting menopause/age‐related changes and inducing urogenital tract tissue regeneration.

Regulation of masculinization: androgen signalling for external genitalia development.

The biology of masculinization is fundamentally important for understanding the embryonic developmental processes that are involved in the development of the male reproductive tract, external genitalia, and also the tumorigenesis of prostate cancer. The molecular mechanisms of masculinization are of interest to many researchers and clinicians involved in varied fields, including molecular developmental biology, cancer research, endocrinology, and urology. Androgen signalling is mediated by the nuclear androgen receptor, which has fundamental roles in masculinization during development. Various modes of androgen signalling, including 5α-dihydrotestosterone-induced regulation of mesenchymal cell proliferation, have been observed in masculinization. Such regulation is essential for regulating urogenital tissue development, including external genitalia development. Androgen-induced genes, such as MAFB, which belongs to the activator protein 1 (AP-1) superfamily of genes, have essential roles in male urethral formation, and disruption of its signalling can interfere with urethral formation, which often results in hypospadias. Another AP-1 superfamily gene, ATF3, could be responsible for some instances of hypospadias in humans. These androgen-dependent signals and downstream events are crucial for not only developmental processes but also processes of diseases such as hypospadias and prostate cancer.

Visible-Near Infrared Spectroscopic Assessment of Urogenital Tissue in Premenopausal and Postmenopausal Women.

Background:A clinical study was conducted to evaluate the feasibility of using visible and near-infrared (NIR) spectroscopy as a potential noninvasive measure of genital skin health in premenopausal and postmenopausal women.Methods:A total of 45 female subjects (aged 21-70 years), all of whom gave fully informed consent to participate, were enrolled in the study and assigned to 1 of 3 groups: 15 premenopausal (Pre-M), 15 postmenopausal receiving hormone replacement therapy (Post-M HRT), and 15 postmenopausal receiving no form of hormone replacement therapy (Post-M non-HRT). Spectral measurements were taken at the vaginal mucosa, and spectral data were evaluated for the erythema index (EI), hemoglobin index (HI), bilirubin/β-carotene, and melanin. The color index (CI; calculated as the ratio of absorbance at 480 nm/540 nm) was also determined. Results were compared with previously published results on biomarkers and physical characteristic of genital tissue measured on the same groups of women.Results:Spectral measurements from the Post-M Non-HRT subjects indicated a significant reduction in HI compared with the Pre-M group (P = .0003) and to the Post-M HRT group (P < .0001). Similarly, EI was reduced in the Post-M Non-HRT (P < .0001 and P = .0041 for the Pre-M and Post-M HRT groups, respectively). In contrast, the Post-M Non-HRT subjects exhibited a significant increase in β-carotene compared with the Pre-M subjects (P = .0098). Bilirubin and melanin were not significantly affected. The Post-M Non-HRT group exhibited a significant increase in CI, indicating a shift away from the hemoglobin absorption region (510-620 nm wavelength) and toward the bilirubin/β-carotene absorption region (450-490 nm wavelength). This change was significant when compared with both the Pre-M group (P < .0001) and the Post-M HRT group (P = .0048). The changes in spectral measurements were consistent with previously reported changes in physical parameters (vaginal atrophy, increased pH, decreased skin temperature) and with decreased concentrations of the biomarkers histamine and histidine.Conclusions:Hemodynamic spectral characteristics differ in postmenopausal vaginal tissue compared with tissue in premenopausal women, with decreased absorbance in the hemoglobin absorption region (510-620 nm wavelength) and an increased absorbance in the bilirubin/β-carotene absorption region (450-490 nm wavelength). A change in absorbance in the visible and NIR wavelengths is a promising, additional measure of genital skin health related to menopause and vulvovaginal atrophy.

Genitourinary vascularized composite allotransplantation.

Genitourinary vascularized allotransplantation (GUVCA) is gaining interest as a treatment option for patients with functional and aesthetic urogenital tissue loss. Only three cases have been done worldwide and research on the implementation and feasibility of this procedure is in an elementary state. The psychosocial impact and ethical considerations with GUVCA are remote, particularly because of the intimate and personal nature of genital tissue. Though two of the three penile transplantation cases are considered successful, various unexpected factors and complications have been described alongside these successes. Treatment outcome depends on a complex combination of immunological, technical, and psychosocial components that will be different per individual case. Multidisciplinary evaluation and treatment protocols should be established to ensure that the quality of life in GUVCA recipients can be increased in a safe and ethical way. Penile transplantation represents challenging new potential to improve phallus reconstruction in patients with severe genital tissue defects, but worldwide experience with GUVCA is limited. Controlled multicenter research is required to better define the risk/benefit ratio of this experimental yet promising treatment option.

The pelvic floor dysfunction associated lower urinary tract diseases

The pelvic floor dysfunction associated lower urinary tract disease. It is women who often multiple diseases, is closely related to the perineum and urogenital diaphragm tissue of old injury and chronic inflammation caused by pregnancy, childbirth, surgical delivery, injection of pelvic trigger point and interventional treatment for the pelvic floor dysfunction associated lower urinary tract diseases is significance. Key words: Pelvic floor; Urethral diseases; Editorial

P08.33 Azithromycin pharmacokinetics and implications for extended doses forchlamydia trachomatisand other sexually transmitted infections

Introduction Chlamydia treatment failure remains concerning with high repeat positive diagnoses of up to 14% in women and 22% for rectal infections in men. Meta-analysis estimates of rectal chlamydia treatment efficacy suggests azithromycin may be 20% less efficacious than doxycycline, but this is based on observational data only – with no RCTs evaluating rectal chlamydia treatment nor any pharmacokinetic data for azithromycin in rectal mucosa. This systematic review will examine the dose-related pharmacokinetics of azithromycin in blood and tissues with discussions on possible considerations of extended regimens to improve efficacy for anorectal infections should a 1 g dose prove suboptimal from RCTs. Methods Medline and Embase were searched from 1946 to February 2015. Inclusion criteria were: English language, adults and reported pharmacokinetics after any oral dose of azithromycin. Studies of urogenital and rectal tissue were the primary focus but other tissues (excluding eyes) were included. Dose administered and pharmacokinetic parameters such as peak concentration and area under the concentration-time curve (AUC) were extracted. Results Studies reported high concentrations of azithromycin in cervical, urological, gynaecological, pulmonary, prostatic and oral tissue/fluid after total doses of 500 mg to >2 g. No studies of rectal tissue were reported, however studies of gastric tissue/fluid (a proxy for rectal tissue) showed high concentrations being rapidly attained and sustained for >7 days. Increasing doses results in greater tissue concentrations, which are sustained longer above chlamydia minimum inhibitory concentration (MIC) but with only modest increases in peak blood levels between high and low doses. Similar tissue concentrations were obtained whether the total dose was given over short versus longer duration, suggesting regimens beyond (e.g. >3 days) do not have absorption advantages. Conclusion Azithromycin concentrations above the MIC are rapidly attained and sustained following treatment. While no data are available in rectal tissue, studies in gastric tissue/fluid suggest adequate rectal concentrations should be obtained. Azithromycin pharmacokinetics also suggest that total doses >1 g given over a few days can be effective in delivering high concentrations to tissues susceptible to chlamydia infections. Disclosure of interest statement None.

Em Algorithm for MLE of a Probit Model for Multiple Ordinal Outcomes

The correlated probit model is frequently used for multiple ordered data since it allows to incorporate seamlessly different correlation structures. The estimation of the probit model parameters based on direct maximization of the limited information maximum likelihood is a numerically intensive procedure. We propose an extension of the EM algorithm for obtaining maximum likelihood estimates for a correlated probit model for multiple ordinal outcomes. The algorithm is implemented in the free software environment for statistical computing and graphics R. We present two simulation studies to examine the performance of the developed algorithm. We apply the model to data on 121 women with cervical or endometrial cancer. Patients developed normal tissue reactions as a result of post-operative external beam pelvic radiotherapy. In this work we focused on modeling the effects of a genetic factor on early skin and early urogenital tissue reactions and on assessing the strength of association between the two types of reactions. We established that there was an association between skin reactions and polymorphism XRCC3 codon 241 (C&gt;T) (rs861539) and that skin and urogenital reactions were positively correlated.ACM Computing Classification System (1998): G.3.