Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial.

Androgen deprivation therapy (ADT) used for prostate cancer (PCa) management is associated with metabolic and anthropometric toxicity. Metformin given concurrent to ADT is hypothesized to counteract these changes. This planned interim analysis reports the gastrointestinal and genitourinary toxicity profiles of PCa patients receiving ADT and prostate/pelvic radiotherapy plus metformin versus placebo as part of a phase 2 randomized controlled trial. Men with intermediate or high-risk PCa were randomized 1:1 to metformin versus placebo. Both groups were given ADT for 18-36 months with minimum 2-month neoadjuvant phase prior to radiotherapy. Acute gastrointestinal and genitourinary toxicities were quantified using CTCAE v4.0. Differences in ≥ grade 2 toxicities by treatment were assessed by chi-squared test. 83 patients were enrolled with 44 patients randomized to placebo and 39 randomized to metformin. There were no significant differences at any time point in ≥ grade 2 gastrointestinal toxicities or overall gastrointestinal toxicity. Overall ≥ grade 2 gastrointestinal toxicity was low prior to radiotherapy (7.9% (placebo) vs. 3.1% (metformin), p = 0.39) and at the end of radiotherapy (2.8% (placebo) vs 3.1% (metformin), p = 0.64). There were no differences in overall ≥ grade 2 genitourinary toxicity between treatment arms (19.0% (placebo) vs. 9.4% (metformin), p = 0.30). Metformin added to radiotherapy and ADT did not increase rates of ≥ grade 2 gastrointestinal or genitourinary toxicity and is generally safe and well-tolerated.

A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens.

PURPOSE: Cystic fibrosis transmembrane conductance regulator (CFTR) and adhesion G protein-coupled receptor G2 (ADGRG2) have been identified as the main pathogenic genes in congenital bilateral absence of the vas deferens (CBAVD), which is an important cause of obstructive azoospermia. This study aimed to identify the disease-causing gene in two brothers with CBAVD from a Chinese consanguineous family and reveal the intracytoplasmic sperm injection (ICSI) outcomes in these patients. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify the candidate pathogenic genes. Real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence were used to assess the expression of the mutant gene. Moreover, the ICSI results from both patients were retrospectively reviewed. RESULTS: A novel hemizygous loss-of-function mutation (c.G118T: p.Glu40*) in ADGRG2 was identified in both patients with CBAVD. This mutation is absent from the human genome databases and causes an early translational termination in the third exon of ADGRG2. Expression analyses showed that both the ADGRG2 mRNA and the corresponding protein were undetectable in the proximal epididymal tissue of ADGRG2-mutated patients. ADGRG2 expression was restricted to the apical membranes of non-ciliated epithelia in human efferent ducts, which was consistent with a previous report in mice. Both ADGRG2-mutated patients had normal spermatogenesis and had successful clinical outcomes following ICSI. CONCLUSIONS: Our study verifies the pathogenic role of ADGRG2 in X-linked CBAVD and broadens the spectrum of ADGRG2 mutations. In addition, we found positive ICSI outcomes in the two ADGRG2-mutated CBAVD patients.

Rigorous characterization of urinary extracellular vesicles (uEVs) in the low centrifugation pellet - a neglected source for uEVs.

Urinary extracellular vesicles (uEVs) provide bio-markers for kidney and urogenital diseases. Centrifugation is the most common method used to enrich uEVs. However, a majority of studies to date have focused on the ultracentrifugation pellet, potentially losing a novel source of important biomarkers that could be obtained at lower centrifugation. Thus, the aim of this study is to rigorously characterize for the first time uEVs in the low speed pellet and determine the minimal volume of urine required for proteomic analysis (≥9.0 mL urine) and gene ontology classification identified 75% of the protein as extracellular exosomes. Cryo-Transmission Electron Microscopy (≥3.0 mL urine) provided evidence of a heterogeneous population of EVs for size and morphology independent of uromodulin filaments. Western blot detected several specific uEV kidney and EV markers (≥4.5 mL urine per lane). microRNAs quantification by qPCR was possible with urine volume as low as 0.5 mL. Particle enumeration with tunable resistive pulse sensing, nano particles tracking analysis and single EV high throughput imaging flow cytometry are possible starting from 0.5 and 3.0 mL of urine respectively. This work characterizes a neglected source of uEVs and provides guidance with regard to volume of urine necessary to carry out multi-omic studies and reveals novel aspects of uEV analysis such as autofluorescence of podocyte origin.

A rare frameshift variant in trans with the IVS9-5T allele of CFTR in a Chinese pedigree with congenital aplasia of vas deferens.

PURPOSE: Congenital aplasia of vas deferens (CAVD) is an atypical form of cystic fibrosis (CF) and causes obstructive azoospermia and male infertility. Compound heterozygous variants of CFTR are the main cause of CAVD. However, most evidence comes from genetic screening of sporadic cases and little is from pedigree analysis. In this study, we performed analysis in a Chinese pedigree with two CAVD patients in order to determine the genetic cause of this familial disorder. METHODS: In the present study, we performed whole-exome sequencing and co-segregation analysis in a Chinese pedigree involving two patients diagnosed with CAVD. RESULTS: We identified a rare frameshift variant (NM_000492.3: c.50dupT;p.S18Qfs*27) and a frequent CBAVD-causing variant (IVS9-TG13-5T) in both patients. The frameshift variant introduced a premature termination codon and was not found in any public databases or reported in the literature. Co-segregation analysis confirmed these two variants were in compound heterozygous state. The other male members, who harbored the frameshift variant and benign IVS9-7T allele, did not have any typical clinical manifestations of CF or CAVD. CONCLUSION: Our findings may broaden the mutation spectrum of CFTR in CAVD patients and provide more familial evidence that the combination of a mild variant and a severe variant in trans of CFTR can cause vas deferens malformation.

Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles.

BACKGROUND: Congenital absence of vas deferens (CAVD) is a major cause of obstructive azoospermia. Mutations in CFTR and ADGRG2 are responsible for this disease. However, until now the genetic spectrum of the CFTR and ADGRG2 genes in Chinese population and the reasons of the differences from Caucasian cohorts were not clear. OBJECTIVES: (i) To study the characteristic and functional consequences of CFTR and ADGRG2 mutations in Chinese CAVD patients. (ii) To describe the genetic spectrum of Chinese CAVD patients and explain the reasons of the differences from Caucasian cohorts and Chinese cystic fibrosis (CF) patients. MATERIALS AND METHODS: Patients were screened for mutations in CFTR by Sanger sequencing. Patients with only one or no mutations were further investigated by multiplex ligation-dependent probe amplification analysis and direct sequencing of ADGRG2 gene. Bioinformatic analysis and structural modeling of proteins were performed. RESULTS: A total of 28 mutations in CFTR were identified in 72 patients, of which five mutations were novel. Fifty-five patients (76.39%) had CFTR mutations but no indels, among which 80.00% CBAVD patients have at least one CFTR mutation and 66.67% CUAVD have at least one CFTR mutation. Two novel mutations (p.Lys818* and p.Arg1008Gln) in ADGRG2 were detected. These novel mutations were predicted to be damaging by bioinformatics and were absent or extremely low frequency among our controls and databases. The genetic spectrum of Chinese CAVD patients revealed that the most common mutations were c.1210-12T[5], p.Ile556Val and p.Gln1352His, the last two of which were predicted to reduce the domains' contacts and weaken adenosine triphosphate binding. DISCUSSION AND CONCLUSION: This study illustrates the significance of all exon sequencing in CFTR and ADGRG2. A picture of the genetic spectrum of Chinese CAVD patients and the most common mutations can be described, which are different from Caucasian cohorts and Chinese CF patients.

CFTR variants and renal abnormalities in males with congenital unilateral absence of the vas deferens (CUAVD): a systematic review and meta-analysis of observational studies.

PURPOSE: CFTR variant is the main genetic contributor to congenital (unilateral/bilateral) absence of the vas deferens (CAVD/CUAVD/CBAVD). We performed a systematic review to elucidate the genetic link between CFTR variants, CUAVD, and the associated risk of renal abnormality (RA). METHODS: We searched relevant databases for eligible articles reporting CFTR variants in CUAVD. The frequency of CFTR variants and RA, and the odds ratios (ORs) for common alleles and RA risk, were pooled under random-/fixed-effect models. Subgroup analyses and heterogeneity tests were performed. RESULTS: Twenty-three studies were included. Among CUAVD patients, 46% had at least one CFTR variant, with 27% having one and 5% having two. The allele frequency in CUAVD was 4% for F508del and 9% for 5T. The summary OR for 5T risk in CUAVD was 5.79 compared with normal controls and 2.82 compared with non-CAVD infertile males. The overall incidence of RA was 22% in CUAVD. The pooled OR for RA risk among CUAVD patients was 4.85 compared with CBAVD patients. CONCLUSION: CFTR variants are common in CUAVD, and the 5T allele may be associated with increased CUAVD risk. CUAVD patients bear a higher RA risk than CBAVD patients, but this is not associated with CFTR variants.

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees.

BACKGROUND: Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility. Mutations of CFTR caused the majority of CBAVD cases, and ADGRG2 was recently identified as a new pathogenic gene. Yet, most of the genetic evidence came from sporadic cases, and only one mutation in CFTR can be found in patients. METHODS: In present study, we collected two CBAVD pedigrees, each having two affected male siblings. We performed whole exome sequencing on all patients and validated all potential variants by Sanger sequencing. RESULTS: We excluded ADGRG2 variants but identified compound heterozygous variants of CFTR in both families (NM_000492.3:c.1210-33_1210-6GT[13]T[5] and c.4056G>C;p.Gln1352Cys in pedigree 1, c.592G>C;p.Ala198Pro and c.3717G>A;p.Arg1239= in pedigree 2), which were subsequently validated by direct sequencing. c.1210-33_1210-6GT[13]T[5] (also known as IVS8-T5-TG13) was a known disease-causing variant causing the skipping of exon 9 of CFTR and inherited from the proband's mother. p.Gln1352Cys and Ala198Pro were rare or novel in public databases and predicted to be deleterious. The p.Arg1239= was a synonymous variant but located at the end of an exon, which was predicted to alter the splicing pattern. CONCLUSION: Our study, in which compound heterozygous variants were identified in two pedigrees, provides more familial evidence that only recessive variants (homozygous or compound heterozygous) in CFTR cause CBAVD. Furthermore, whole exome sequencing may be utilized as a useful tool for mutation screening of genes causing CBAVD.

Schistosomiasis (Bilharziasis) ova: An incidental finding in testicular tissue of an obstructive azoospermic man.

Congenital bilateral absence of vas deferens (CBAVD) results in obstructive azoospermia in which testicular function, such as spermatogenesis, is preserved. Bilateral testicular biopsy is not only diagnostic but also therapeutic as retrieved spermatozoa are usually cryopreserved for assisted reproduction. In this case report, CBAVD was confirmed in a 24-year-old azoospermic man on the basis of persistent azoospermia associated with low semen volume, absent fructose and normal hormonal levels, ultrasonographically (absent seminal vesicles) and histologically (intact spermatogenesis). Interestingly and incidentally, only the right testicular biopsy showed ova of two parasitic species of Schistosoma, namely Schistosoma haematobium which infests the genitourinary tract and Schistosoma mansoni which infests the gastrointestinal tract. Both species are rare causes of azoospermia, and the case should be further managed as CBAVD in which the left testicle is considered the preferred site of sperm retrieval for assisted reproduction.

Urethral lichen sclerosus under the microscope: a survey of academic pathologists.

INTRODUCTION: Given the poor understanding of the pathophysiology of genital lichen sclerosus (GLS) and a lack of accepted definitive diagnostic criteria, we proposed to survey pathologists regarding their understanding of GLS. We hypothesized that significant disagreement about GLS will exist. MATERIALS AND METHODS: All urologists participating in the Trauma and Urologic Reconstruction Network of Surgeons identified genitourinary (GUP) and dermatopathologists (DP) at their respective institutions who were then invited to participate in an online survey regarding their experience with diagnosing GLS, GLS pathophysiology and its relationship to urethral stricture disease. RESULTS: There were 23 (12 DP, 11 GUP) pathologists that completed the survey. The most agreed upon criteria for diagnosis were dermal collagen homogenization (85.7%), loss of the normal rete pattern (33.3%) and atrophic epidermis (28.5%). No pathologists believed GLS had an infectious etiology (19% maybe, 42% unknown) and 19% believed GLS to be an autoimmune disorder (42% maybe, 38% unknown); 19% believed LS to be premalignant, but 52% believed it was associated with cancer; 80% believed that LS could involve the urethra (DP (92%) versus GUP (67%); p = 0.272). Of those diagnosing urethral GLS, 80% of DUP believed that GLS must first involve the glans/prepuce before involving the urethra, while all GUP believed that urethral disease could exist in isolation (p = 0.007). CONCLUSIONS: There was significant disagreement in this specialized cohort of pathologists when diagnosing GLS. A logical first step appears to be improving agreement on how to best describe and classify the disease. This may lead to improve treatments.

Papel de los espermatozoides en la transmisión de bacterias uropatógenas: Escherichia coli y Enterococcus faecalis / Role of sperm in the transmission of uropathogenic bacteria: Escherichia coli and Enterococcus faecalis

Introducción: Los espermatozoides viajan por el tracto reproductivo femenino en búsqueda del oocito con el fin de fecundarlo. En su recorrido interactúan con diferentes sustancias y microorganismos que alteran la biología espermática, interfiriendo con el éxito reproductivo. El objetivo de este trabajo fue evaluar la capacidad que tienen los espermatozoides humanos de interactuar y transportar las bacterias Escherichia coli (E. coli) y Enterococcus faecalis (E. faecalis). Materiales y métodos: Se incubaron espermatozoides humanos seleccionados de muestras de semen de voluntarios aparentemente sanos con concentraciones crecientes de E. coli y E. faecalis durante una hora. Posteriormente se realizaron cultivos cuantitativos en los agares MacConckey y chocolate de la mezcla bacterias-espermatozoides con y sin lavados o tratamiento postinfección con tripsina. Resultados: Los espermatozoides interactúan y transportan las bacterias. En conjunto, los lavados y el tratamiento con tripsina causan una disminución estadísticamente significativa de unidades formadoras de colonia para E. faecalis ATCC 29212, E. faecalis ATCC 51299 y E. coli ATCC 25922. Conclusión: Los espermatozoides humanos crean interacciones fuertes con las bacterias E. coli y E. faecalis favoreciendo su difusión en el tracto reproductivo femenino

Introduction: Sperm travel through female reproductive tract seeking an oocyte to fertilise. During this journey, the sperm may interact with various substances and microorganisms that change its biology, interfering with reproductive success. The aim of this study was to evaluate the ability of human sperm to interact with and carry the bacteria Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis). Materials and methods: Human sperm selected from semen samples of apparently healthy volunteers were incubated with increasing concentrations of E. coli and E. faecalis for one hour. Subsequently, quantitative cultures of the bacteria-sperm mixture were grown in MacConckey and chocolate agars with and without washing or post-infection treatment with trypsin. Results: Sperm interact and carry bacteria. Washes and trypsin treatment together cause a statistically significant reduction in colony-forming units for E. faecalis ATCC 29212, E. faecalis ATCC 51299 and E. coli ATCC 25922. Conclusion: Human sperm create strong interactions with E. coli and E. faecalis bacteria, promoting their dissemination in the female reproductive tract

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.

Demographic and behavioural risk factors associated with Trichomonas vaginalis among South African HIV-positive men with genital ulcer disease: a cross-sectional study.

OBJECTIVES: Demographic and risky sexual behaviours may increase the risk for Trichomonas vaginalis (TV) infection and, thus, enhance HIV transmission to uninfected partners. We assessed the demographic and behavioural risk factors associated with TV among South African HIV-positive men with genital ulcer disease. METHODS: We conducted a cross-sectional study with data from a randomised controlled trial conducted by the Centers for Disease Control and Prevention and the London School of Hygiene and Tropical Medicine. The data were obtained from three primary healthcare clinics in South Africa. At baseline (n=387), participants reported on demographics, sexual behaviour, history of sexually transmitted infections and clinical ulcers. The outcome TV was measured using real-time multiplex PCR assays and a Rotor-gene 3000 platform from the first and past urine samples of all participants. Logistic regression model estimated ORs and 95% CIs adjusted for demographics, sexual risk behaviours and ulcer conditions. RESULTS: An estimated 11.4% of TV was detected among the men. The odds of TV infection were significantly associated with high blister counts (OR 4.0, 95% CI 1.6 to 28, p=0.01), ulcer pain (OR 0.4, 95% CI 0.2 to 0.7, p=0.003), number of days with ulcers (OR 0.4, 95% CI 0.2 to 0.8, p=0.006), sought treatment before coming into clinics (OR 0.07, 95% CI 0.002 to 0.7, p=0.005) and being unqualified worker (OR 2.5, 95% CI 0.9 to 6.7 p=0.05). Multivariate analyses revealed that increased days with ulcers (OR 0.1, 95% CI 0.04 to 0.5, p=0.002) and ulcer pain intensity (OR 0.08, 95% CI 0.007 to 1.1, p=0.05) remained significantly associated with decreased odds of TV infection. Men from the Sotho ethnic group were eight times more likely to have TV infection (OR 8.6, 95% CI 1.3 to 55.7, p<0.02) than men from the other ethnic groups. CONCLUSION: HIV-positive men with severe ulceration should be screened and treated for TV to minimise HIV transmission to uninfected partners.

Braquiterapia de alta tasa de dosis como monoterapia en cáncer de próstata: una revisión sistemática sobre eficacia y seguridad / High-dose rate brachytherapy as monotherapy in prostate cancer: a systematic review of its safety and efficacy

Contesxto: La braquiterapia con alta tasa de dosis (HDR-BT) es un tratamiento de uso creciente en pacientes con cáncer de próstata (CP) localizado. Objetivo: Evaluar la eficacia y seguridad de HDR-BT como monoterapia en CP. Adquisición de evidencia: Revisión sistemática de la literatura mediante búsqueda en MEDLINE (PubMed), Cochrane Library, CDR, Clinicaltrials y EuroScan. Se evaluaron indicadores de eficacia y de seguridad. Síntesis de evidencia: Fueron seleccionadas 2 revisiones y 12 estudios no controlados, incluidos en estas 2revisiones. En términos de eficacia, el control local en 6 estudios es 97-100%. La supervivencia libre de progresión bioquímica varía: 85-100% en riesgo bajo y 79-92% en riesgo alto. La supervivencia libre de metástasis es >95% a 8 años, salvo en un estudio que es 87% a 5 años. La supervivencia global es ≥95% en 8 estudios. En relación con la seguridad, la mayoría de los estudios recogen complicaciones genitourinarias y gastrointestinales agudas y a largo plazo, especialmente de grado ≥ 2. Solo 3 estudios encuentran complicaciones grado 4. Excepto uno (sin complicaciones), en los 11 restantes las complicaciones complicaciones genitourinarias son más frecuentes y más graves que las gastrointestinales. Dos estudios evalúan la calidad de vida y muestran un descenso inicial en distintos dominios y posterior recuperación parcial o total, salvo en la esfera sexual. Conclusiones: La HDR-RT como monoterapia es eficaz, especialmente en riesgo bajo e intermedio. No existe suficiente información en pacientes de riesgo alto. La toxicidad a corto-medio plazo es aceptable. Consideramos necesario potenciar la investigación que aporte más información sobre eficacia y seguridad a largo plazo de este tratamiento

Context: High-dose rate brachytherapy (HDR-BT) is an increasingly popular treatment for patients with localised prostate cancer (PC). Objective: To assess the safety and efficacy of HDR-BT as monotherapy in PC. Acquisition of evidence: A systematic literature review was conducted through searches on MEDLINE (PubMed), Cochrane Library, CDR, ClinicalTrials and EuroScan. We assessed safety and efficacy indicators. Summary of the evidence: We selected 2 reviews and 12 uncontrolled studies, included in these 2 reviews. In terms of efficacy, local control in 6 studies was 97-100%. The biochemical progression-free survival varied as follows: 85-100% for low risk and 79-92% for high risk. Survival free of metastases was >95% at 8 years, except in one study where the survival rate was 87% at 5 years. The overall survival was ≥95% in 8 studies. In terms of safety, most of the studies recorded acute and long-term genitourinary and gastrointestinal complications, especially grade ≥2. Only 3 studies found grade 4 complications. All studies, except for one without complications, observed genitourinary complications that were more frequent and severe than the gastrointestinal complications. Two studies assessed the quality of life and showed an initial reduction in various domains and subsequent partial or total recovery, except in the sexual domain. Conclusions: HDR-BT is effective as monotherapy, especially in cases of low to intermediate risk. There is insufficient information on high-risk patients. The short to medium-term toxicity was acceptable. Further research needs to be funded to provide more information on the long-term safety and efficacy of this treatment

[Pathogenesis of urological complications after radiation therapy]. / Pathogenese urologischer Komplikationen nach Strahlentherapie.

Radiation therapy is a treatment modality that is often used in the uro-oncological setting. The common indication for the radiation therapy in the urological sphere is prostate cancer, whether it is used primarily as a radical approach, or postoperatively as adjuvant or salvage therapy. All urological organs are sensitive to radiation injury with the urinary bladder being the most susceptible with a typical cascade including acute and late changes, arising in the dose-dependent manner. The common indication for radiation therapy in urology is prostate cancer, which collaterally affects the urinary bladder and rarely urethra (especially the bulbo-membranous urethra). Ureteral damage and stricture formation is almost always restricted to the cases of intraoperative therapy and external beam radiation therapy for other urological malignancies (gynecological organs, rectum, retroperitoneal soft tissue tumors) and should not be underestimated. Postradiotherapeutic tissue changes, especially of the prostate, can cause difficulties for pathologists and urologists with regard to diagnosis of prostate cancer recurrence and salvage therapy.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies.

BACKGROUND & OBJECTIVES: The role of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in congenital bilateral absence of vas deferens and unilateral renal agenesis (CBAVD-URA) has been controversial. Here, we report the cases of five Indian males with CBAVD-URA. The objective was to evaluate the presence or absence of CFTR gene mutations and variants in CBAVD-URA. The female partners of these males were also screened for cystic fibrosis (CF) carrier status. METHODS: Direct DNA sequencing of CFTR gene was carried out in five Indian infertile males having CBAVD-URA. Female partners (n=5) and healthy controls (n=32) were also screened. RESULTS: Three potential regulatory CFTR gene variants (c.1540A>G, c.2694T>G and c.4521G>A) were detected along with IVS8-5T mutation in three infertile males with CBAVD-URA. Five novel CFTR gene variants (c.621+91A>G, c.2752+106A>T, c.2751+85_88delTA, c.3120+529InsC and c.4375-69C>T), four potential regulatory CFTR gene variants (M470V, T854T, P1290P, Q1463Q) and seven previously reported CFTR gene variants (c.196+12T>C, c.875+40A>G, c.3041-71G>C, c.3271+42A>T, c.3272-93T>C, c.3500-140A>C and c.3601-65C>A) were detected in infertile men having CBAVD and renal anomalies Interpretation & conclusions: Based on our findings, we speculate that CBAVD-URA may also be attributed to CFTR gene mutations and can be considered as CFTR-related disorder (CFTR-RD). The CFTR gene mutation screening may be offered to CBAVD-URA men and their female partners undergoing ICSI. Further studies need to be done in a large sample to confirm the findings.

Papular acantholytic dyskeratosis of the anogenital and genitocrural area: case series and review of the literature.

BACKGROUND: Papular acantholytic dyskeratosis (PAD) of the anogenital/genitocrural area is described as a rare distinct clinicopathological entity known to dermatopathologists, although its characteristic histopathologic pattern resembles both Hailey-Hailey disease and Darier disease. The objective of this study is to describe the clinical characteristics, histopathologic features and response to treatment of PAD. METHODS: We report in detail six cases of PAD. A literature search of the keyword 'papular acantholytic dyskeratosis' was performed on Google scholar and PubMed, 21 cases of this entity were found. A total of 27 patients including our six cases are reviewed in this study. RESULTS: The mean age at diagnosis was 38.8 years with a male to female ratio of 0.8 : 1. Clinically, papular lesions (55.6%) are the typical manifestation of PAD, and the anogenital area (63%) is the most commonly involved site. Lesions were resistant to topical steroids, subcutaneous interferon and antibiotics while one case showed complete resolution of the lesions after retinoid therapy. Laser therapy showed good results in one case. None of the patients had spontaneous remission. CONCLUSION: Awareness of the clinicopathological hallmarks herein may be important to avoid underdiagnosis of PAD and may contribute to understanding the pathogenesis of this rare disease.

Combined Therapy With Adipose-Derived Mesenchymal Stem Cells and Ciprofloxacin Against Acute Urogenital Organ Damage in Rat Sepsis Syndrome Induced by Intrapelvic Injection of Cecal Bacteria.

UNLABELLED: We hypothesized that combined treatment with autologous adipose-derived mesenchymal stem cell (ADMSC) and ciprofloxacin is superior to ciprofloxacin only in reducing sepsis-induced urogenital organ damage and mortality in rat sepsis syndrome (SS) caused by intrapelvic injection of cecal bacteria (1.0 × 10(4) cells per milliliter; total, 5.0 ml). Male Sprague-Dawley rats (n = 60) equally divided into group 1 (sham-control), group 2 (SS), group 3 (SS-ADMSC [5.0 × 10(5) intravenously at 0.5, 6, and 18 hours after sepsis induction]), group 4 (SS-ciprofloxacin [3.0 mg/kg, b.i.d.] for 5 days), and group 5 (SS-ADMSC-ciprofloxacin) were sacrificed by day 5. Mortality rate and creatinine level were highest in group 2 and lowest in group 1 and significantly higher in groups 3 and 4 than those in group 5, but there was no difference between groups 3 and 4 (all p < .005). The kidney injury score, inflammatory biomarker expressions at protein (tumor necrosis factor-1α, nuclear factor-κB, matrix metallopeptidase-9, regulated on activation, normal T-cell expressed and secreted, interleukin-1ß) and cellular (CD14+, migratory inhibitor factor positive, CD68+) levels in kidneys and urinary bladder were lowest in group 1 and highest in group 2, higher in group 4 than in groups 3 and 5, and higher in group 3 than in group 5 (all p < .001). Protein expressions of apoptosis (Bax, cleaved caspase 3 and poly[ADP-ribose] polymerase 1, p21 protein [Cdc42/Rac]-activated kinase 2) and oxidative stress (oxidized protein, NADPH oxidase (NOX)-1, NOX-2) in these organs showed an identical pattern compared with that of inflammation in all groups (all p < .001). In conclusion, ADMSC-assisted ciprofloxacin therapy offered an additional benefit by reducing acute urogenital organ damage in rat. SIGNIFICANCE: Autologous adipose-derived mesenchymal stem cell-assisted ciprofloxacin therapy offered an additional benefit by reducing acute urogenital organ damage in rats.