Assessing the genetic relationship between phimosis and 26 urogenital diseases: a Mendelian randomization study.

Purpose: This study aims to investigate the impacts of phimosis on the health of the genitourinary system through Mendelian random analysis. Material and method: A dual-sample Mendelian randomization (MR) analysis was conducted using the publicly available genome-wide association study (GWAS) data. The inverse variance weighted based on the random effects model (Re-IVW) method was used as the main statistical analysis. Complementary methods, including weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO), were applied to detect or correct the impact of horizontal pleiotropy. Result: Re-IVW showed a genetic predictive causal relationship of phimosis on glomerulonephritis (odds ratio [OR]: 1.37 [1.13-1.65], p = 0.00149) and IgA glomerulonephritis (OR: 1.57 [1.18-2.09), p = 0.00187). Suggestive evidence indicated that phimosis was associated with chronic nephritis syndrome (OR: 1.23 (1.00-1.51), p = 0.0481], acute nephritis syndrome (OR: 1.50 [1.13-2.01], p = 0.0058), and impotence (OR: 1.39 [1.11-1.73], p = 0.0035). Kidney and ureteral stone (OR: 1.14 [1.04-1.26], p = 0.0069), urethral strictures (OR: 1.26 [1.07-1.48], p = 0.0050), benign prostatic hyperplasia (OR: 1.07 [1.01-1.13], p = 0.0242), and decreased testicular function (OR: 0.72 [0.56-0.94], p = 0.0141) have genetically predictive causal relationships. Conclusion: In summary, we employed a series of reliable analytical methods to investigate the association between phimosis and 26 urogenital diseases. We have reported several strong associations, but more research is needed to evaluate whether this discovery is replicated in other environments and to gain a better understanding of potential mechanisms.

An Insight on the Role of Altered Function and Expression of Exosomes and MicroRNAs in Female Reproductive Diseases.

Exosomes are small bilayer-lipid membrane vesicles secreted by living cells that are able to transfer regulatory molecules and genetic information from one cell to another. These vesicles are enriched with several nucleic acids including mRNAs, microRNAs (miRNAs), other non-coding RNAs, as well as proteins and lipids. Alterations in the exosomal content and functions are observed in numerous reproductive diseases in both animals and human cases. MicroRNAs, a class of small endogenous RNA molecules, can negatively regulate gene expression at the post-transcription level. Aberrant microRNA expression has been reported in multiple human reproductive diseases such as polycystic ovary syndrome, preeclampsia, uterine leiomyomata, ovarian cancer, endometriosis, and Asherman's syndrome. This study focuses to review recent research on alterations of microRNA expression and the role of exosomes in female reproductive diseases. It has been demonstrated that exosomes may be a potential therapeutic approach in various female reproductive diseases. In addition, changes in expression of microRNAs act as molecular biomarkers for diagnosis of several reproductive diseases in women, and regulation of their expression can potentially reduce infertility.

The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing.

Background: Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists. Objective: To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Design: Secondary analysis of genetic data. Setting: A tertiary care academic medical center. Patients: A convenience sample of exome sequence data from 7974 self-declared healthy adults. Measurements: Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders. Results: Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned. Limitation: Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses. Conclusion: Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.

The gonadotropin system, lessons from animal models and clinical cases.

This review article centers upon family of gonadotropin hormones which consists of two pituitary hormones - follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as well as one non-pituitary hormone - human chorionic gonadotropin (hCG) secreted by placenta, and their receptors. Gonadotropins play an essential role in proper sexual development, puberty, gametogenesis, maintenance of pregnancy and male sexual differentiation during the fetal development. They belong to the family of glycoprotein hormones thus they constitute heterodimeric proteins built of common α subunit and hormone-specific ß-subunit. Hitherto, several mutations in genes encoding both gonadotropins and their receptors have been identified in humans. Their occurrence resulted in a number of different phenotypes including delayed puberty, primary amenorrhea, hermaphroditism, infertility and hypogonadism. In order to understand the effects of mutations on the phenotype observed in affected patients, detailed molecular studies are required to map the relationship between the structure and function of gonadotropins and their receptors. Nonetheless, in vitro assays are often insufficient to understand physiology. Therefore, several animal models have been developed to unravel the physiological roles of gonadotropins and their receptors.

Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract are genetically different from nodular fasciitis and lack USP6, ROS1 and ETV6 gene rearrangements.

AIMS: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract have a debatable relationship with inflammatory myofibroblastic tumour (generally lacking ALK rearrangement); however, they share several overlapping features with nodular fasciitis of soft tissue. As rearrangement of the USP6 gene has been recently recognised as a recurrent alteration in soft tissue nodular fasciitis, and several other alternative gene fusions have been recently recognised in inflammatory myofibroblastic tumour, the aim of this study was to investigate whether USP6, ROS1 or ETV6 rearrangements were present in these lesions (12 cases). METHODS AND RESULTS: Fluorescence in-situ hybridisation analysis was performed by the use of bacterial artificial chromosome-derived break-apart probes against USP6, ROS1, and ETV6. Two cases with adequate genetic material from recent paraffin tissue blocks were also tested by use of a solid tumour gene fusion detection assay via next-generation sequencing, targeting >50 known genes involved in recurrent fusions. None of the genitourinary pseudosarcomatous myofibroblastic proliferations was found to harbour USP6 (0/12), ROS1 (0/8) or ETV6 (0/7) rearrangements, and no gene fusions were detected in two cases studied by sequencing. CONCLUSIONS: Despite overlap in histological and immunohistochemical features between pseudosarcomatous myofibroblastic proliferation and nodular fasciitis, these tumours lack the recently recognised USP6 rearrangements that occur in nodular fasciitis, as well as alternative fusions found in ALK-negative inflammatory myofibroblastic tumours. At present, this diagnosis remains based primarily on clinical, histological and immunohistochemical features.

Microbiota composition of the koala (Phascolarctos cinereus) ocular and urogenital sites, and their association with Chlamydia infection and disease.

Disease caused by Chlamydia pecorum is characterised by ocular and urogenital infections that can lead to blindness and infertility in koalas. However, koalas that are infected with C. pecorum do not always progress to disease. In other host systems, the influence of the microbiota has been implicated in either accelerating or preventing infections progressing to disease. This study investigates the contribution of koala urogenital and ocular microbiota to Chlamydia infection and disease in a free ranging koala population. Using univariate and multivariate analysis, it was found that reproductive status in females and sexual maturation in males, were defining features in the koala urogenital microbiota. Changes in the urogenital microbiota of koalas is correlated with infection by the common pathogen, C. pecorum. The correlation of microbiota composition and C. pecorum infection is suggestive of members of the microbiota being involved in the acceleration or prevention of infections progressing to disease. The analysis also suggests that multiple microbes are likely to be associated with this process of disease progression, rather than a single organism. While other Chlamydia-like organisms were also detected, they are unlikely to contribute to chlamydial disease as they are rare members of the urogenital and ocular microbiota communities.

Global gene expression distribution in non-cancerous complex diseases.

For gene expression in non-cancerous complex diseases, we systemically evaluated the sensitivities of biological discoveries to violation of the common normalization assumption. Our results indicated that gene expression may be widely up-regulated in digestive system and musculoskeletal diseases. However, global signal intensities showed little difference in other four disease types.

Microarray analysis in gynaecology and its findings: a systematic review.

Microarray technology is a promising method for investigating gynaecological benign pathology. This systematic review examined various parameters of the design of these studies, the methods used and the gene outcome in these diseases. Electronic searches were performed in Medline (up to April 2009). An overall representation of important genes for each disease detected was performed. The results showed genes were up-regulated or down-regulated. However, studies suffer from several flaws in their design, the sample size employed and the reporting method. In conclusion, a significant amount of work has been performed on benign gynaecological diseases using microarray technology. New trial designs need to be employed that incorporate microarray reporting standards. New research directions should evolve based on these results.

Significant linkage evidence for a predisposition gene for pelvic floor disorders on chromosome 9q21.

Predisposition factors for pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress urinary incontinence (SUI), urge urinary incontinence (UUI), and hernias, are not well understood. We assessed linkage evidence for PFDs in mostly sister pairs who received treatment for moderate-to-severe POP. We genotyped 70 affected women of European descent from 32 eligible families with at least two affected cases by using the Illumina 1 million single-nucleotide polymorphism (SNP) marker set. Parametric linkage analysis with general dominant and recessive models was performed by the Markov chain Monte Carlo linkage analysis method, MCLINK, and a set of SNPs was formed, from which those in high linkage disequilibrium were eliminated. Significant genome-wide evidence for linkage was identified on chromosome 9q21 with a HLOD score of 3.41 under a recessive model. Seventeen pedigrees (53%) had at least nominal evidence for linkage on a by-pedigree basis at this region. These results provide evidence for a predisposition gene for PFDs on chromosome 9q.

Evaluation of an automated extraction method for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae by Cobas Amplicor PCR from different sample materials.

A commercially available automated device (MagNA Pure LC) was adapted for nucleic acid extraction of urogenital specimen for subsequent PCR detection of Chlamydia trachomatis and Neisseria gonorrhoeae in a clinical laboratory. Results were compared to the standard manual extraction procedure and showed excellent correlation, with even slightly increased sensitivity.

Outcome of urogenital infection with Chlamydia muridarum in CD14 gene knockout mice.

BACKGROUND: CD14 has been postulated to play a role in chlamydial immunity and immunopathology. There is evidence to support this role in human infections but its function in a mouse model has not been investigated. METHODS: Female CD14 gene knockout and C57BL/6J wild type mice were infected intravaginally with Chlamydia muridarum. The infection course was monitored by detection of viable chlamydiae from serially collected cervical-vaginal swabs. The sequela of tubal factor infertility was assessed using hydrosalpinx formation as a surrogate marker. RESULTS: A significantly abbreviated infection course was observed in the CD14 gene knockout mice but hydrosalpinx formation occurred at similar rates between the two groups. CONCLUSION: Involvement of CD14 during chlamydial infection impedes infection resolution but this does not affect the sequela of infertility as assessed by hydrosalpinx formation.

Urologic manifestations of genetic diseases.

Many genetic disorders have genitourinary manifestations in childhood. In order to care for these children, the physician should be aware of such potential manifestations. A succinct overview of the pediatric genetic disorders that have urologic manifestations is presented to assist in the evaluation of patients, counseling of parents and treatment of urologic manifestations of childhood genetic diseases.

Getting rid of caveolins: phenotypes of caveolin-deficient animals.

The elucidation of the role of caveolae has been the topic of many investigations which were greatly enhanced after the discovery of caveolin, the protein marker of these flask-shaped plasma membrane invaginations. The generation of mice deficient in the various caveolin genes (cav-1, cav-2 and cav-3) has provided physiological models to unravel the role of caveolins or caveolae at the whole organism level. Remarkably, despite the essential role of caveolins in caveolae biogenesis, all knockout mice are viable and fertile. However, lack of caveolae or caveolins leads to a wide range of phenotypes including muscle, pulmonary or lipid disorders, suggesting their implication in many cellular processes. The aim of this review is to give a broad overview of the phenotypes described for the caveolin-deficient mice and to link them to the numerous functions so far assigned to caveolins/caveolae.

The Caveolin genes: from cell biology to medicine.

Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. Caveolins 1 and 2 are co-expressed in most cell types, while the expression of caveolin-3 is muscle-specific. Thus, endothelial cells and fibroblasts are rich in caveolins 1 and 2, while cardiac myocytes and skeletal muscle fibers express caveolin-3. In contrast, smooth muscle cells express all three caveolins (Cav-1, -2, and -3). Mechanistically, caveolins interact with a variety of downstream signaling molecules, including Src-family tyrosine kinases, p42/44 mitogen activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS), and hold these signal transducers in the inactive conformation until activation by an appropriate stimulus. In many ways, caveolins serve both to compartmentalize and regulate signaling. Recent studies using caveolin-deficient mouse models dramatically show that caveolae and caveolins play a prominent role in various human patho-biological conditions, especially those related to the cardiovascular system. These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and caveolins in the pathogenesis of human diseases.

[Modern diagnostics for urological infections]. / Moderne Diagnostik urologischer Infektionen.

This paper provides a short overview of modern, molecular-based diagnostic procedures of urogenital tract infections. Although gaining importance, molecular methods have not yet become a reliable substitution for the classic procedures in terms of costs and quality standards. As an example of a new molecular approach in microbiology, a method for the detection of the most relevant uropathogens in a single PCR is presented. Furthermore, the development of a real time PCR is described.

Genetic diseases in adults.

Genetic diseases that do not primarily affect the genitourinary tract may have urologic manifestations. These urologic manifestations range from benign and malignant renal disease to infertility. Thus, the practicing urologist may be involved in the care of these patients and should have knowledge of these diseases. Continued improvements in the diagnosis and treatment of these genetic diseases will likely result in improved survival and will increase the number of patients who may develop urologic manifestations of these diseases.

Genetic diseases pediatrics.

The field of genetics will continue to grow because of advances in molecular biology. These advances will lead to further understanding of genetic conditions, which will enhance the urologist's knowledge of the urologic manifestations of these conditions. This will enable improved parental counseling and patient care.