Maria Augusta Tezelli Bortolini

Genetics of pelvic organ prolapse: crossing the bridge between bench and bedside in urogynecologic research

An increasing number of scientists have studied the molecular and biochemical basis of pelvic organ prolapse (POP). The extracellular matrix content of the pelvic floor is the major focus of those investigations and pointed for potential molecular markers of the dysfunction. The identification of women predisposed to develop POP would help in the patients’ management and care. This article includes a critical analysis of the literature up to now; discusses implications for future research and the role of the genetics in POP.

Two-years results of native tissue versus vaginal mesh repair in the treatment of anterior prolapse according to different success criteria: A randomized controlled trial

To compare efficacy and safety of the traditional colporraphy and transvaginal polypropylene mesh for the treatment of advanced anterior vaginal prolapse according to different success criteria in two‐year follow‐up.

Influence of Ovarian Hormones Deprivation on Gene Expression in the Lower Urinary Tract of Rats

OBJECTIVE Identify the influence of ovarian hormone deprivation in expression genes on the lower urinary tract of rats. MATERIALS AND METHODS This study deals with gene screening on lower urinary tract of rats. Fifty isogenic rats divided in two groups of twenty-five animals have their lower urinary tract surgically removed: group I, ovariectomized rats 30 days prior to surgery; group II, non-ovariectomized rats. Total RNA was isolated from bladder and urethra, and differential expression of genes was analyzed quantitative, qualitative and comparatively by array technology and RT-PCR. RESULTS A total of 76 candidate genes were identified as differentially expressed between the groups, 26 being lower expressed in group II, and 50 in group I. Among them, differential expression validation was confirmed by RT-PCR for three lower expressed genes in group I: Vascular Endothelial Growth Factor (VEGF), Beta-2 Microglobulin (B2M) and Cytochrome c Oxidase subunit I (COX I). CONCLUSION Ovarian hormone deprivation influences the expression genes on lower urinary tract. We demonstrated that a 30-day period of castration down regulate the expression of VEGF, B2M and COX I in adult rats which are involved in activities of angiogenesis, immune responses and cellular metabolism respectively.

Neural control of lower urinary tract and targets for pharmacological therapy.

Studies on the physiology and pharmacology of the lower urinary tract have brought new information and concepts about the complex neural control of micturition. There are many mechanisms, some proven and others not yet completely understood, in which pharmacological agents may act facilitating the filling, storage, and emptying of the bladder. This review describes the peripheral innervation and the main pathways involved in lower urinary tract control. It also presents potential targets for the treatment of voiding dysfunctions.

Genetics of pelvic organ prolapse: reply

Dear Editor, We read with interest the comment of Dietz [1] about our review article on the biochemical, biomolecular and genetic basis of pelvic organ prolapse (POP) [2]. Besides presenting an overview of the literature, our objective was to provide the readers with a critical analysis of the recent studies in this field including a detailed discussion of the methodology, but not of the etiology of POP. We, however, totally agree that pelvic floor trauma caused by childbirth is the major risk factor for the development of pelvic floor dysfunction [3], as mentioned in our introduction [2]. Our conclusion regarding “... the most important causes of variations are still unknown...” refers to the individual genetic variations, and not to the causes of POP, thus highlighting the need for additional and large-scale genomic investigations. It is very likely that the genetic component plays a role in the pathogenesis of POP, as suggested by many epidemiological, family-based and linkage, expression and candidate gene association studies [4–11]. Our conclusion, therefore, relies on a basic biological principle: the final phenotype is the result of interaction between the individual genotype and environmental factors. Since the latter is most probably vaginal delivery in the case of POP, we should endeavor to find out more about the genotypic variations in the future. Animal models of POP, including genetic models, allow testing the mechanistic relationship between cause and effect of POP initiators by limiting the number of studied variables [12–14]. In contrast, clinical studies, by their nature, are never perfectly controlled. The problem is also aggravated when dealing with a dysfunction of multifactorial etiology as POP. This point was already addressed throughout the manuscript [2]. The biomolecular and biochemical analysis of pelvic floor tissues in women provides a golden opportunity for detecting a number of proteins and genes that are over-expressed and/or under-expressed in patients with POP versus controls. Those studies enable us to better discern the complex interplay between pelvic floor structural composition and support capacity. Although the mechanisms by which different risk factors in women including childbirth trauma lead to POP may be different, evidence suggests that all share a final common pathway involving a dysregulation in synthesis and/or assembly or degradation of the molecular components of the pelvic floor supportive tissue [15–18]. Human studies can further contribute to this field by offering some clues for the molecular etiology of POP thus providing a platform for further investigation of specific gene targets. In this context, genetic screening is the next obvious step required for understanding POP predisposition and its molecular basis. Sir William Osler (1849–1919) previously recognized that “variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions we know as disease”. Personalized medicine has rapidly advanced the prediction of disease incidence as well as achieving the goal of “the right treatment to the right person at the right time” based on the individual’s clinical, genetic and environmental information [19, 20]. Genomic data is the driving force behind personalized medicine. Since M. A. Bortolini (*) Department of Gynecology, Federal University of Sao Paulo, Sao Paulo, SP, Brazil e-mail: maria.augusta@gmail.com

Molecular and immunohistochemical analysis of the urethra of female rats after induced trauma and intravenous therapy with muscle derived stem cells

To identify the urethral migration of muscle derived stem cells (MDSCs) after intravenous (IV) injection in rats that underwent vaginal distension (VD) and to analyze the effects of MDSC in the urethra of rats after trauma in regards to: (1) mRNA expression of collagens, Vegf, Ngf, Ki67, Myh11, and Myh2; (2) expression of smooth and striated muscle proteins.

FPMRSChallenges on behalf of the Collaborative Research in Pelvic Surgery Consortium (CoRPS): managing complicated cases: Series 1: Adverse events after a sacrocolpopexy: management and recommendations on treatment of a vesicovaginal fistula

This case presents the work-up and management of a spina bifida patient with recurrent prolapse. Four international experts also provide their evaluation of and approach to this complex case. According to the literature, little is known regarding the approach to the management of this specific patient population.

Collagen XVIII and LOXL-4 polymorphisms in women with and without advanced pelvic organ prolapse

Introduction and hypothesisWe verified the presence of single nucleotide polymorphisms (SNP) rs2236479 of the collagen 18 (COL18A1) and rs2862296 of the lysyl oxidase-like 4 (LOXL-4) genes and the association with pelvic organ prolapse (POP) in Brazilian women and determined risk factors for POP development.MethodsWe assessed 532 postmenopausal women divided into POP (stages III and IV) and control (stages 0 and I) groups by examination and peripheral blood sample collection. DNA sequences of interest were analyzed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). We used logistic regression models for the analyses, with p < 0.005 for significance.ResultsThe frequency of homozygous polymorphic alleles (AA) in COL18A1 and (GG) in LOXL-4 were similar in both groups (17.5% and 15.4% for COL18A1 and 18.9% and 20.6% for LOXL-4, respectively). There were no associations between those polymorphisms or other genotypes and POP. Multiple logistic regression analysis identified age [odds ratio (OR) = 1.10, confidence interval (CI) 95% = 1.07; 1.14), number of vaginal births (OR = 1.66, CI 95% = 1.36; 2.03), and family history (OR = 2.55 CI 95% = 1.43; 4.55) as independent risk factors for POP.ConclusionOur study suggests lack of association between DNA polymorphisms rs2236479 of COL18A1 and rs2862296 of LOXL-4 with advanced POP in this population.

Outpatient biofeedback in addition to home pelvic floor muscle training for stress urinary incontinence: a randomized controlled trial

To test if biofeedback (BF) added to pelvic floor muscle training (PFMT) increases the frequency of home exercises performed by women with stress urinary incontinence (SUI).

Registering a clinical trial

The results of clinical trials are a basic source of information used in clinical practice, in the development of clinical guidelines and evidence-based patient information, in systematic reviews and health technology assessments, in the work of institutional review boards, and within medical education [1]. The research community relies on the unrestricted flow of data from these trials, but some remain unpublished and hidden, particularly if they do not serve the interests of the sponsors or the authors, leading to selective publication. Since 2004, there has been a push from governments and international organizations including the International Committee of Medical Journal Editors (ICMJE) [2] and the World Health Organization (WHO) to make clinical trial information more widely available and to standardize registries and processes of registering. Trial registration is currently the best strategy for countering selective publication, making it suitably transparent, and strengthening the validity and value of the scientific evidence base [1, 2] (http://www.who.int/ictrp/en/). Registration of clinical trials in a comprehensive, computerized database should reduce publication bias by improving the ability to identify trials on an intervention and decreasing the likelihood of studies being missed. The registries are supposed to provide credible and comprehensive information on medical interventions, and to ensure that a complete view of research is accessible to all those involved in healthcare decision making. Selective publication or reporting means that not all trials are disclosed. Selective publishing in favor of a positive trial or statistically significant results, together with a reduced willingness to publish negative or inconclusive studies, may lead to imbalance in the scientific literature, overestimation of potential benefits and underestimation of the harm of a treatment [1, 3]. Systematic reviews of the literature further magnify this bias and distortion in medical literature by combining these favorable studies to obtain greater statistical power at the clinical level, and such reviews are often the source for clinical guidelines [4]. Thus, selective publication has a negative impact on patient health and may interfere in the decisions of ethics research boards and funding agencies which are based on the available data [1]. Currently, the International Urogynecology Journal encourages the registration of randomized and controlled clinical trials with a public clinical trials registry prior to commencing patient recruitment. The IUJ editors have decided to move the journal forward by taking another step on the road to full transparency of all relevant information about a particular trial. From now on, the IUJ will require registration of all prospective interventional clinical trials that are to be considered for publication. BOngoing^ studies for which the investigators are still collecting, cleaning or organizing data also require registration (even retrospectively) before submission to the IUJ. The IUJ will defer the application of the policy of mandatory prospective registration (registration of clinical trials with a public trials registry made at or before the time of first patient enrollment as recommended by the ICMJE) for 2 years to allow investigators, trial sponsors, and regulatory bodies time to plan for their implementation. We believe anyone should be able to learn of any trial’s existence and its important characteristics, irrespective of its outcomes, or the benefit and potential harm of the intervention under investigation. Following the criteria of the ICMJE andWHO, the IUJ will accept registrations with any one of the registries listed below. They are accessible to the public at no charge, open to all prospective registrants, managed by a not-for-profit * Maria Augusta T. Bortolini maria.augusta@gmail.com