Network pharmacology integrated molecular docking reveals the bioactive components and potential targets of Morinda officinalis-Lycium barbarum coupled-herbs against oligoasthenozoospermia.

Oligoasthenozoospermia (OA) is one of the most common types of male infertility affecting sperm count and sperm motility. Unfortunately, it is difficult for existing drugs to fundamentally improve the sperm quality of OA patients, because the pathological mechanism of OA has not been fully elucidated yet. Morinda officinalis-Lycium barbarum coupled-herbs (MOLBCH), as traditional Chinese Medicines, has been widely used for treating OA over thousands of years, but its molecular mechanism is still unclear. For this purpose, we adopted a comprehensive approach integrated network pharmacology and molecular docking to reveal the bioactive components and potential targets of MOLBCH against OA. The results showed that MOLBCH alleviated apoptosis, promoted male reproductive function, and reduced oxidant stress in the treatment of OA. Ohioensin-A, quercetin, beta-sitosterol and sitosterol were the key bioactive components. Androgen receptor (AR), Estrogen receptor (ESR1), Mitogen-activated protein kinase 3 (MAPK3), RAC-alpha serine/threonine-protein kinase (AKT1), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were the core potential targets. PI3K/Akt signaling pathway, prostate cancer, AGE-RAGE signaling pathway in diabetic complications were the most representative pathways. Moreover, molecular docking was performed to validate the strong binding interactions between the obtained core components and targets. These observations provide deeper insight into the pathogenesis of OA and can be used to design new drugs and develop new therapeutic instructions to treat OA.

Evaluation of genitourinary fistulas in pelvic malignancies with etiopathologic correlation: role of cross sectional imaging in detection and management.

OBJECTIVE: Genitourinary fistulas in pelvic malignancies are abnormal communications occurring due to either locally advanced tumours invading the surrounding organs or post-therapeutic complications of malignancies. In this article we review and describe the role of cross-sectional imaging findings in the management of genitourinary fistulas in pelvic malignancies. METHODS: A retrospective study, for the period January 2012 to December 2018, was undertaken in patients with pelvic malignancies having genitourinary fistulas. The cross-sectional (CT and MRI) imaging findings in various types of fistulas were reviewed and correlated with the primary malignancy and the underlying etiopathology. RESULTS: Genitourinary fistulas were observed in 71 patients (6 males, 65 females). 11 types of fistulas were identified in carcinomas of cervix, rectum, ovary, urinary bladder, sigmoid colon, vault, endometrium and prostate. The commonest were rectovaginal and vesicovaginal fistulas. 13 patients had multiple fistulas. The sensitivity, specificity, positive and negative predictive values of CT and MRI are 98%, 100%, 66%, 98% and 95%, 25%, 88% and 50% respectively. Contrast-enhanced CT with oral and rectal contrast is more sensitive and specific than MRI in the evaluation of genitourinary fistulas. CONCLUSION: Imaging findings significantly influence the management and outcome of genitourinary fistulas in pelvic malignancies. Contrast-enhanced CT is the imaging modality of choice in the evaluation of pelvic fistulas associated with malignancies and MRI is complimentary to it. ADVANCES IN KNOWLEDGE: To our knowledge, this study is the first of its kind wherein the mean duration of occurrence of fistulas in pelvic malignancies is correlated with the underlying etiopathology.

Molecular basis of antimicrobial resistance in Mycoplasma genitalium.

Mycoplasma genitalium is a sexually transmitted urogenital pathogen, and infection can result in serious symptoms. As M. genitalium is rather difficult to culture, infections are usually detected by molecular methods. Unfortunately, there has recently been a significant increase in resistance to azithromycin and moxifloxacin used for the treatment of M. genitalium infections. The increased resistance to (often empirically prescribed) M. genitalium treatments has resulted in frequent therapy failures and stresses the need for routine detection of antimicrobial resistance. In M. genitalium, antimicrobial resistance is almost always the result of DNA mutations and thus can easily be detected by molecular techniques. Regrettably, many microbiology laboratories do not use molecular techniques for the detection of bacterial antimicrobial resistance. As molecular tests are becoming available for M. genitalium, both for the establishment of infection and the detection of antimicrobial resistance, it is now more important to ensure that knowledge on the resistance mechanisms is transferred from the laboratory to the clinician. This review will provide a brief summary of the current status of antimicrobial resistance, its molecular mechanisms and the impact on the current status of M. genitalium treatment.

Reducing antibiotic prescribing in primary care in England from 2014 to 2017: population-based cohort study.

OBJECTIVE: To analyse individual-patient electronic health records to evaluate changes in antibiotic (AB) prescribing in England for different age groups, for male and female subjects, and by prescribing indications from 2014 to 2017. METHODS: Data were analysed for 102 general practices in England that contributed data to the UK Clinical Practice Research Datalink (CPRD) from 2014 to 2017. Prescriptions for all ABs and for broad-spectrum ß-lactam ABs were evaluated. Relative rate reductions (RRR) were estimated from a random-effects Poisson model, adjusting for age, gender, and general practice. RESULTS: Total AB prescribing declined from 608 prescriptions per 1000 person-years in 2014 to 489 per 1000 person-years in 2017; RRR 6.9% (95% CI 6.6% to 7.1%) per year. Broad-spectrum ß-lactam AB prescribing decreased from 221 per 1000 person-years in 2014 to 163 per 1000 person-years in 2017; RRR 9.3% (9.0% to 9.6%) per year. Declines in AB prescribing were similar for men and women but the rate of decline was lower over the age of 55 years than for younger patients. All AB prescribing declined by 9.8% (9.6% to 10.1%) per year for respiratory infections, 5.7% (5.2% to 6.2%) for genitourinary infections, but by 3.8% (3.1% to 4.5%) for no recorded indication. Overall, 38.8% of AB prescriptions were associated with codes that did not suggest specific clinical conditions, and 15.3% of AB prescriptions had no medical codes recorded. CONCLUSION: Antibiotic prescribing has reduced and become more selective but substantial unnecessary AB use may persist. Improving the quality of diagnostic coding for AB use will help to support antimicrobial stewardship efforts.

Genitourinary melioidosis: a descriptive study.

Melioidosis is the disease caused by the soil and water bacterium, Burkholderia pseudomallei. Our study aimed to delineate its genitourinary manifestations. Over a 10-year period (2006-2016), 20 adults with culture-confirmed genitourinary melioidosis were identified. The patients were all men with a mean age of 45.3 ± 12.3 years. The common risk factors were diabetes mellitus (65%) and alcoholism (25%); a majority of patients (90%) had chronic melioidosis. Most had disseminated disease (n = 17) and 55% were bacteraemic. The prostate was the organ most frequently involved (60%, n = 12), followed by the kidney, bladder and seminal vesicles. Diagnosis was established by blood and urine cultures and imaging. Patients were successfully treated with ceftazidime intensive therapy followed by eradicative therapy, with surgical debridement and guided aspiration, when deemed necessary. There was one case fatality and no relapses. Melioidosis is an important differential to be considered in chronic genitourinary infections in the appropriate setting.

Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea.

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).

Gonadotropin-releasing hormone analog therapeutics.

Dysregulation at any level of the hypothalamic-pituitary-gonadal (HPG) axis results in, or aggravates, a number of hormone-dependent diseases such as delayed or precocious puberty, infertility, prostatic and ovarian cancer, benign prostatic hyperplasia, polycystic ovarian syndrome, endometriosis, uterine fibroids, lean body mass, as well as metabolism and cognitive impairment. As gonadotropin-releasing-hormone (GnRH) is an essential regulator of the HPG axis, agonist and antagonist analogs are efficacious in the treatment of these conditions. GnRH analogs also play an important role in assisted reproductive therapies. This review highlights the current and future therapeutic potential of GnRH analogs and upstream regulators of GnRH secretion.

Utility of GeneXpert in the diagnosis, reliance on urine microscopy and clinical characteristics of genitourinary tuberculosis at a tertiary care hospital.

BACKGROUND: One-third of the world's population is infected with tuberculosis (TB) with new infection occurring every second. In humans, TB is primarily caused by Mycobacterium tuberculosis(MTB). Genitourinary TB (GUTB) is still a major health problem in many developing countries including India and had been declared by the World Health Organisation as 'public health emergency' in 1993. MATERIALS AND METHODS: This is a prospective study conducted at a tertiary care hospital involving 46 patients who presented with clinical feature suggestive of GUTB - urine specimens of these 46 patients were analysed for acid-fast bacilli (AFB), AFB culture, GeneXpert, and other relevant investigations were done to reach the diagnosis. Majority of patients were female (65.25%). This is especially relevant to rural and low socioeconomic areas in developing countries where women's health is worse than men's (in terms of nutrition); women's risk of disease may be increased. Most of our patients were above 30 years of age and exhibited nonspecific symptoms such as dysuria, haematuria and frequency. All patients were put on antitubercular drugs and followed as per the guidelines. CONCLUSION: The sample size in the present study is small to arrive at a brisk inference, but it may safely be postulated that yield of detection for GeneXpert may be improved using multiple sampling, especially the early morning ones. It is also pertinent to mention here that GeneXpert may not be able to pick up mutant genomes.

Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation.

Background: In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea. Methods: Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin. Results: The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose. Conclusions: This study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea. Clinical Trials Registration: NCT02294682.

ß3-Adrenoceptor Control of Lower Genitourinary Tract Organs and Function in Male: An Overview.

The sympathetic nervous system is one component of the nervous regulatory system of the physiological function of the lower genitourinary tract. Our knowledge on the role of this sympathetic system has advanced during the last decade due to the characterization of ß3-adrenoceptors (ß3-ARs) in the urogenital system. This review focuses on the pharmacological and molecular evidence supporting the functional roles of ß3-AR in male genitourinary tissues of various species. An electronic search in two different databases was performed including MEDLINE (PubMed) and EMBASE from 2010 to 2016. ß3-agonists may be a promising alternative to antimuscarinics in the treatment of overactive bladder (OAB) based on available evidence. Although more recent studies have evaluated the involvement of ß3-ARs in the physiological control and regulation of various tissues of the lower genitourinary tract mainly urinary bladder, penis, urethra, ureter, there are few innovations in the pipe-line. Among the ß3-agonists, mirabegron is a unique drug licensed for the treatment of patients with OAB. Many drugs classified as ß3-agonists are still under investigations for the treatment of OAB, lower urinary tract symptoms, ureteral stones, benign prostate hyperplasia, prostate cancer and erectile dysfunction. This review discusses the potential roles of ß3-AR as new therapeutic targets by evaluating the results of preclinical and clinical studies related to male lower genitourinary tract function. Looking into the future, the potential benefits of ß3- AR agonists from experimental and clinical investigations may provide an attractive therapeutic option.

Male Urogenital Disorders and Metabolic Syndrome: Possible Links, Characteristics and Potential Treatment Strategies.

BACKGROUND: Metabolic syndrome (MetS), as a cluster of metabolic derangements which are major risk factors for vascular disease is one of the most important threats to public health. Although the epidemiological and limited amount of basic science and clinical evidence link MetS to several male urogenital disorders, a holistic approach aiming to define common mechanistic pathways and new possible therapeutic targets are lacking. OBJECTIVE: The current review has focused on providing scientific evidence on the role of MetS and its components on male urogenital disorders and the definition of new therapeutic targets. METHOD: In this review, current clinical and basic science literature were assessed examining the role of MetS in etiology and pathogenesis of male urogenital disorders and performed through PubMed from 2000 to May 2017. RESULTS AND CONCLUSION: MetS shows an important association with common male urogenital disorders such as benign prostatic enlargement, lower urinary tract symptoms, erectile dysfunction, infertility and renal disease. MetS affects male urogenital system mainly through endocrine and vascular mechanisms. Obesity, hypogonadism, obesity-induced androgen deficiency, hyperinsulinemia and inflammation are the mechanisms commonly involved and may act as potential targets for MetS-male urogenital system interrelations. Future studies are needed to evaluate the therapeutic approaches for intervention in MetS-male urogenital disease relations.

Mycoplasma genitalium Infection in Men.

Mycoplasmagenitalium is one of the major causes of nongonococcal urethritis (NGU) worldwide but an uncommon sexually transmitted infection (STI) in the general population. The risk of sexual transmission is probably lower than for Chlamydia trachomatis. Infection in men is usually asymptomatic and it is likely that most men resolve infection without developing disease. The incubation period for NGU caused by Mycoplasma genitalium is probably longer than for NGU caused by C. trachomatis. The clinical characteristics of symptomatic NGU have not been shown to identify the pathogen specific etiology. Effective treatment of men and their sexual partner(s) is complicated as macrolide antimicrobial resistance is now common in many countries, conceivably due to the widespread use of azithromycin 1 g to treat STIs and the limited availability of diagnostic tests for M. genitalium. Improved outcomes in men with NGU and better antimicrobial stewardship are likely to arise from the introduction of diagnostic M. genitalium nucleic acid amplification testing including antimicrobial resistance testing in men with symptoms of NGU as well as in their current sexual partner(s). The cost effectiveness of these approaches needs further evaluation. The evidence that M. genitalium causes epididymo-orchitis, proctitis, and reactive arthritis and facilitates human immunodeficiency virus transmission in men is weak, although biologically plausible. In the absence of randomized controlled trials demonstrating cost effectiveness, screening of asymptomatic men cannot be recommended.

Genitourinary involvement and management in children with Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are devastating hypersensitivity disorders that cause epidermal cell death and can affect all epidermal surfaces, including the urethra, vagina, labial and scrotal skin. Despite the well-described ocular and orofacial manifestations of SJS/TEN, there is a paucity of reports on the genitourinary (GU) symptoms and their management. Specifically, consulting services often ask the pediatric urology team if it is safe to place a urethral catheter, but there is no data in the literature to help guide management. The present study sought to review all pediatric cases of SJS/TEN in a tertiary care hospital to determine the incidence and optimal management of GU manifestations, including the use of urethral catheters. METHODS: With IRB approval, cases of SJS and TEN that were managed as an inpatient between January 2008 and June 2015 were retrospectively reviewed in order to identify the extent of GU involvement/manifestations, the treatment provided, use of urethral catheterization and long-term follow-up or complications. RESULTS: Thirty-one patients (15 female, 16 male; age range 2-18 years) presented with SJS or TEN over the study period. Etiologies for SJS/TEN included mycoplasma infection (48%) and medications (45%). Incidences of GU manifestations at presentation and their management are shown in Summary Table. Overall, 74% of patients had genital involvement of skin lesions. In 12 cases (39%), urology consultation was obtained. Twenty patients (61%) complained of dysuria and one child had gross hematuria in the setting of meatal lesion. Petroleum jelly was used in the majority of patients. A urethral catheter was placed in eight patients (25.8%, four female, four male) with a range of duration of 7-23 days. No patient developed hematuria or any other complications (i.e. strictures or urinary symptoms) after catheter removal. One boy required lysis of penile adhesions in the short-term. One of each gender developed penile and labial adhesions on long-term follow-up that self-resolved. CONCLUSIONS: GU involvement in SJS/TEN occurred in almost three-quarters of patients and was managed conservatively like other skin/mucosal manifestations. Long-term sequelae were rare and urethral catheterization appeared to be safe, without any short-term or long-term complications.

Gonorrhea in Indonesia: High Prevalence of Asymptomatic Urogenital Gonorrhea but No Circulating Extended Spectrum Cephalosporins-Resistant Neisseria gonorrhoeae Strains in Jakarta, Yogyakarta, and Denpasar, Indonesia.

BACKGROUND: Little is known about the epidemiology of asymptomatic urogenital gonorrhea and antimicrobial susceptibility of Neisseria gonorrhoeae (NG) strains circulating in Indonesia. We studied these issues in 3 large Indonesian cities. METHODS: In 2014, participants were recruited from sexually transmitted infection clinics and through outreach in Jakarta, Yogyakarta, and Denpasar. Neisseria gonorrhoeae detection in genital specimens was performed with NG-qPCR at the Public Health Service in Amsterdam. Antimicrobial susceptibility was investigated using the Etest. RESULTS: Among 992 participants, 781 were asymptomatic and included in the risk factors analysis: 439 (56.2%) men, 258 (33.0%) women, and 84 (10.8%) transwomen. They differed significantly in age and were mostly men who have sex with men (35.2%) and female sex workers (29.3%).Overall, 175 (22.4%) asymptomatic participants had a positive NG-qPCR result. Factors positively associated with asymptomatic urogenital gonorrhea were being recruited through outreach (vs clinic-based), inconsistent condom use, and being divorced/widowed (vs single).Among 79 urogenital cultured isolates derived from 27 symptomatic and 52 asymptomatic participants, all isolates were susceptible to ceftriaxone and cefixime, and 98.7% of isolates were susceptible to azithromycin. In contrast, resistance to doxycycline (98.7%) and ciprofloxacin (97.4%) was common. CONCLUSIONS: Prevalence of asymptomatic urogenital gonorrhea among Indonesian key populations is very high. Little to no resistance against extended spectrum cephalosporins and azithromycin was observed. However, almost all isolates were resistant to doxycycline and ciprofloxacin. Strengthening outreach sexually transmitted infections services, composing guidelines to screen asymptomatic individuals, and implementing periodical antimicrobial resistance surveillance are recommended.

[Interferon in combined therapy of human papillomavirus infections associated with sexually transmitted infections. linical observation].

To investigate the effectiveness of Ingaron (interferon-) in the treatment of HPV infection associated with sexually transmitted infections, the authors analyzed the scientific literature on the association of human papillomavirus infection with other viral and microbial pathogens. A clinical case of the association of human papillomavirus infection, urogenital infections (urogenital chlamydia and genital herpes) and localized scleroderma penis is described. The results of integrated therapy of diseases with the help of Interferon-gamma have been presented. According to the literature, up to 70-80% of HPV infections are associated with microbial (opportunistic, obligate pathogens) and viral infectious agents. Chronic inflammation caused by bacterial and viral associations destroys the immune system and it leads to the ineffectiveness of the therapy. Pathogenic therapy of sexually transmitted infections in combination with interferon-gamma (Ingaron) contributes to the eradication of bacterial pathogens, prevention of viral STI recurrence and elimination of high oncogenic risk types of HPV. Thus, we can reasonably infer that Ingaron (interferon-) alleviates the initial immune disturbances, improves the effectiveness of the treatment and may be recommended for treating HPV infection associated with sexually transmitted infections.

[AN EVIDENCE BASED UPDATE ON THE INVESTIGATION AND MANAGEMENT OF MALE LOWER URINARY TRACT SYMPTOMS].

In this review, we aim to summarise the evidence regarding the diagnosis and management of male Lower urinary tract symptoms (LUTS). It is inevitable that with an ageing population the prevalence of male LUTS is likely to increase. Thus symptom prevention and preservation of quality oflife (QoL) feature as high priorities for clinicians and patients alike. There are now a number of different pharmacological options available to men with LUTS which lead to significant improvements in symptom scores, flow rate and QoL. Meta-analyses have shown the benefits for 5-α reductase inhibitors, antimuscarinics, alpha blockers and more recently the phosphodiesterase-5 inhibitors. High level evidence also exists for combinations of all of the above agents with alpha blockers except phosphodiesterase-5 inhibitors and so men with concomitant storage symptoms, prostate volume >30ml/ PSA>1.4 or erectile dysfunction may be considered for combination treatment. The last few years have seen an increase in the data regarding less invasive methods of cystometry. Although these do not provide the same information as cystometry, they may have a role in answering specific questions and counselling men with BPH/LUTS. The key to incorporating these newer techniques in the assessment of men will lie with standardisation and use for specific indications. In an era of personalised medicine, appropriate patient selection is likely to provide the key to the most effective clinical investigative and management strategy.

[Fosfomycin for urogenital tract infections: Advances in studies].

Fosfomycin (FOM) is an antibiotic with a small relative molecular weight (138.1) and a long half-life, and has a unique chemical structure and antibacterial mechanisms. It exerts a bactericidal activity by inhibiting the early synthesis of bacterial cell walls. It is also a broad-spectrum antibiotic with a good drug tolerance and compliance and a low pressure to bacterial resistance, but no cross-resistance with other antibiotics. Recent studies show the effectiveness of FOM in the treatment of acute uncomplicated urinary tract infections and urogenital tract infections as well, such as prostatitis and epididymitis. This review focuses on the clinical application of FOM in the treatment of infectious diseases of the urogenital tract.