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Patients with sickle cell disease (SCD) display an overactive bladder (OAB). Intravascular hemolysis in SCD is associated with various severe SCD complications. However, no experimental studies have evaluated the effect of intravascular hemolysis on bladder function. This study aimed to assess the effects of intravascular hemolysis on the micturition process and the contractile mechanisms of the detrusor smooth muscle (DSM) in a mouse model with phenylhydrazine (PHZ)-induced hemolysis; furthermore, it aimed to investigate the role of intravascular hemolysis in the dysfunction of nitric oxide (NO) signaling and in increasing oxidative stress in the bladder. Mice underwent a void spot assay, and DSM contractions were evaluated in organ baths. The PHZ group exhibited increased urinary frequency and increased void volumes. DSM contractile responses to carbachol, KCl, α-ß-methylene-ATP, and EFS were increased in the PHZ group. Protein expression of phosphorylated endothelial NO synthase (eNOS) (Ser-1177), phosphorylated neuronal NO synthase (nNOS) (Ser-1417), and phosphorylated vasodilator-stimulated phosphoprotein (VASP) (Ser-239) decreased in the bladder of the PHZ group. Protein expression of oxidative stress markers, NOX-2, 3-NT, and 4-HNE, increased in the bladder of the PHZ group. Our study shows that intravascular hemolysis promotes voiding dysfunction correlated with alterations in the NO signaling pathway in the bladder, as evidenced by reduced levels of p-eNOS (Ser-1177), nNOS (Ser-1417), and p-VASP (Ser-239). The study also showed that intravascular hemolysis increases oxidative stress in the bladder. Our study indicates that intravascular hemolysis promotes an OAB phenotype similar to those observed in patients and mice with SCD.
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BACKGROUND: Patients with sickle cell disease (SCD) experience intravascular hemolysis, leading to elevated plasma heme levels. This phenomenon has been associated with increased priapism in men with SCD. The heme group can be metabolized by heme oxygenase (HO), generating carbon monoxide (CO), which is known to promote smooth muscle relaxation via soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP). However, the effects of heme on the relaxation responses of corpus cavernosum (CC) have not been investigated. OBJECTIVES: To evaluate the functional and biochemical effects of the heme group on mouse CC smooth muscle in vitro. MATERIALS AND METHODS: Male C57BL/6 mice were used. CC tissues were mounted in organ baths. Measurement of cGMP in mice CC was evaluated. RESULTS: The cumulative addition of heme concentrations promoted the relaxation of CC. HO inhibitor (1J, 100 µM) or sGC inhibitor (ODQ, 10 µM) blocked the relaxing effect of the heme group. Pre-incubation of CC with heme (100 µM) enhanced relaxation induced by acetylcholine, sodium nitroprusside, and nitrergic relaxation (electrical field stimulation), which was abolished by 1J or ODQ. The heme group increased the cGMP production in CC, which was abolished by 1J or ODQ. cGMP levels were significantly higher in CC treated with heme, and pre-incubation with compound 1J or ODQ abolished the effect of heme in raising cGMP levels. DISCUSSION AND CONCLUSION: The HO-CO-sGC-cGMP pathway appears to play a crucial role in promoting CC relaxation. Our study provides novel insight into the role of group heme in CC relaxation and its potential contribution to priapism in SCD. Heme may serve as a pharmacological target for new therapies to prevent priapism.
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Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.
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Anemia Falciforme , Priapismo , Acetilcolina/farmacologia , Anemia Falciforme/complicações , Anemia Falciforme/metabolismo , Animais , Hemólise , Humanos , Masculino , Camundongos , Pênis , Priapismo/complicaçõesRESUMO
Background: In sickle cell disease (SCD), reduced bioavailability of endothelial NO and cGMP results in reduced expression of phosphodiesterase type 5 (PDE5), thus impairing the penile erection control mechanism and resulting in prolonged penile erection (priapism). In SCD, reduced NO bioavailability is associated with excess plasma hemoglobin due to intravascular hemolysis and increased oxidative stress. Haptoglobin is the plasma protein responsible for reducing plasma hemoglobin levels, but in SCD, haptoglobin levels are reduced, which favors the accumulation of hemoglobin in plasma. Therefore, we aimed to evaluate the effects of haptoglobin treatment on functional and molecular alterations of erectile function, focusing on the contractile and relaxant mechanisms of corpus cavernosum (CC), as well as oxidative stress. Methods: SCD mice were treated with haptoglobin (400 mg/kg, subcutaneous) or vehicle of Monday, Wednesday and Friday for a period of 1 month. Corpus cavernosum strips were dissected free and placed in organ baths. Cumulative concentration-response curves to the acetylcholine, sodium nitroprusside, phenylephrine and KCL, as well as to electrical field stimulation (EFS), were obtained in CC. Protein expressions of eNOS, phosphorylation of eNOS at Ser-1177, nNOS, PDE5, ROCK1, ROCK2, gp91phox, 3-nitrotyrosine, and 4-HNE were measured by western blot in CC. Results: Increased CC relaxant responses to acetylcholine, sodium nitroprusside and electrical-field stimulation were reduced by haptoglobin in SCD mice. Reduced CC contractile responses to phenylephrine and KCl were increased by haptoglobin in SCD mice. Haptoglobin prevented downregulated eNOS, p-eNOS (Ser-1177), PDE5, and ROCK2 protein expressions and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91phox, 3-nitrotyrosine and 4-HNE in penises from SCD mice. Haptoglobin treatment did not affect ROCK1 and nNOS protein expressions in penises from SCD mice. Basal cGMP production was lower in the SCD group, which was normalized by haptoglobin treatment. Conclusion: Treatment with haptoglobin improved erectile function due to up-regulation of eNOS-PDE5 expression and down-regulation of the gp91phox subunit of NADPH oxidase and oxidative/nitrosative stress in the penises of SCD mice. Treatment with haptoglobin also increased contractile activity due to up-regulation of ROCK2. Therefore, haptoglobin treatment may be an additional strategy to prevent priapism in SCD.
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BACKGROUND: Children and adult with sickle cell disease (SCD) display priapism associated with low nitric oxide (NO) bioavailability and oxidative stress in penis. AIM: This study aimed to evaluate the effects of hybrid compound RVT-FxMe, derived from resveratrol bearing a NO-donor subunit, on two murine model that display priapism phenotype, SCD transgenic mice and endothelial NO synthase gene-deficient (eNOS-/-) mice. METHODS: Wild-type, SCD, and eNOS-/- mice were treated with RVT-FxMe (25 mg/kg/d, 2 weeks). OUTCOMES: Hematological parameters, concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as to electrical field stimulation (EFS), were obtained in mice corpus cavernosum strips. RESULTS: Corpus cavernosum relaxations to SNP and EFS were increased in eNOS-/- group, which were normalized by RVT-FxMe treatment. SCD mice exhibited an excessive CC relaxant response induced by ACh, EFS and SNP RVT-FxMe treatment did not change the increased relaxant responses to ACh, EFS and SNP in corpus cavernosum from SCD group. CLINICAL TRANSLATION: Excess of plasma hemoglobin in SCD may interfere in pharmacological activity of NO donors compounds. STRENGTH/LIMITATIONS: While mechanistic data with promising potential is showed, the current study is not without limitations. RVT-FxMe effects in the mid- and long-term warrant complementary studies. CONCLUSION: Treatment with RVT-FxMe reversed the enhanced NO-cGMP-mediated CC relaxations in eNOS-/- mice, but not in SCD mice; it is likely that excess of plasma hemoglobin in SCD mice act to inactivate NO before it reaches soluble guanylyl cyclase, avoiding restoration of NO bioavailability in penis.
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Anemia Falciforme , Priapismo , Acetilcolina/farmacologia , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Animais , Hemoglobinas , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Óxido Nítrico , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Priapismo/tratamento farmacológico , Priapismo/etiologia , Resveratrol/farmacologiaRESUMO
BACKGROUND: Priapism impairs quality of life and has a predilection for males with sickle cell disease (SCD). The Priapism Impact Profile (PIP) is a novel 12-item instrument designed to measure general health-related impact of priapism. The aim of the study was to evaluate the validity and reliability of the PIP in a Jamaican cohort of SCD patients experiencing priapism. METHODS: One hundred SCD patients with a history of priapism were recruited from a sickle cell clinic in Kingston, Jamaica and administered the PIP questionnaire. Patients rated each item of the PIP for clarity and importance. Statistical testing was employed to evaluate the psychometric performance of the PIP. Content validation was assessed based on patient descriptive rating of the items based on clarity, and importance and criterion-oriented validity were assessed by evaluating the PIP's ability to distinguish between patient subgroups. Test-retest repeatability was assessed in 20 of the 100 patients. RESULTS: Patients were stratified into active (54) and remission (46) priapism groups based on their experience of priapism within the past year. Patients in the active priapism group were younger (p = 0.011), had a shorter duration of disease (p = 0.023), and had more frequent priapism episodes (p = 0.036) than the remission group. PIP questionnaire scores differed significantly with respect to priapism activity (p < 0.001) and prevalence of erectile dysfunction (p < 0.05) but not by priapism severity (p = 0.62). The PIP questionnaire had good content validity, with questions rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively. CONCLUSION: The PIP questionnaire was successfully validated in a Jamaican cohort of SCD patients and adequately discriminated patients with active priapism from those in remission. The instrument may be utilized in routine clinical management of patients with SCD-associated priapism. Further clinical investigations are warranted in other populations.
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Anemia Falciforme/patologia , Priapismo/psicologia , Adulto , Anemia Falciforme/complicações , Estudos de Coortes , Humanos , Jamaica , Masculino , Avaliação de Resultados em Cuidados de Saúde , Aptidão Física , Priapismo/complicações , Qualidade de Vida , Índice de Gravidade de Doença , Disfunções Sexuais Fisiológicas/etiologia , Inquéritos e Questionários , Adulto JovemRESUMO
PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
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Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/genética , História do Século XX , Humanos , Masculino , Neoplasias da Próstata/patologiaRESUMO
PURPOSE: Urethral carcinoma in situ (CIS) is an uncommon malignancy that is poorly described in the published literature and is often under-recognized in the clinical setting. This short case series reports some challenges associated with the recognition and management of this disease. METHODS: A retrospective chart review was done over a 12-year period of patients presenting with urethral cancer to the Johns Hopkins Hospital. Four patients were identified with CIS of the anterior urethra, and their demographic and clinical data were recorded. RESULTS: Three patients presented with meatal lesions that were initially treated as infectious/inflammatory diseases before diagnoses of malignancy were determined following lesion biopsy. The fourth patient presented with painless hematuria and had a cystoscopy and biopsy of urethral polyps. All patients were treated surgically by sequential distal urethrectomy and various reconstructive procedures. Concurrent lymph node dissections were undertaken in two patients who had clinical or radiologic evidence of lymphadenopathy. One patient had persistent disease even after aggressive urethral resection, and he succumbed to his illness 2 years later. CONCLUSION: This is the largest series of urethral CIS, a disease with potentially serious consequences. A high index of suspicion should be maintained when evaluating and managing these patients.
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Carcinoma in Situ/diagnóstico , Excisão de Linfonodo , Recidiva Local de Neoplasia , Neoplasias Uretrais/diagnóstico , Idoso , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/cirurgia , Erros de Diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Uretrais/tratamento farmacológico , Neoplasias Uretrais/cirurgiaRESUMO
BACKGROUND: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. OBJECTIVE: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. METHODS: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. RESULTS: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. CONCLUSION: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.
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Anemia Falciforme/fisiopatologia , Estresse Oxidativo , Pênis/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , Acetilcolina/farmacologia , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Animais , Western Blotting , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Relação Dose-Resposta a Droga , Estimulação Elétrica , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/farmacologia , Pênis/efeitos dos fármacos , Pênis/inervação , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tirosina 3-Mono-Oxigenase/genética , Vasodilatadores/farmacologiaRESUMO
AIMS: To characterize the prevalence and impact of nocturnal enuresis and overactive bladder (OAB) symptomatology in the adult sickle-cell disease (SCD) population. METHODS: We performed a single-center, cross-sectional study of adult SCD patients from October 2012 to February 2014, using the validated Pfizer OAB short form questionnaire and brief voiding history surveys. Patient responses and scores were compared to that of controls having normal or sickle cell trait hemoglobin genotypes. RESULTS: A group of 239 SCD patients (116 males, 123 females) were compared with 104 normal and 57 sickle cell trait patients. Seven of 239 (2.9%) SCD patients compared to none of the 161 patients without SCD (P = 0.04) reported current nocturnal enuresis. The median age of nocturnal enuresis cessation was higher in SCD patients (12.0, IQR 9.0-15.0 years) compared to that of both normal (7.5, IQR 6.0-9.8 years) and sickle cell trait (7.5, IQR 6.0-8.8 years) groups (P < 0.0001). Ninety-three of 239 (38.9%) SCD patients compared to 17 of 104 (16.3%) normal and 11 of 57 (19.3%) sickle cell trait had scores indicating OAB symptomatology (P < 0.0001). Patients with SCD had higher OAB symptom severity and lower health-related quality of life (HRQL) scores compared to the normal and sickle cell trait groups (P < 0.0001 and P < 0.0001, respectively). CONCLUSIONS: We demonstrate an elevated rate of nocturnal enuresis and OAB symptoms in the adult SCD population. An OAB phenotype may be an under-recognized complication of SCD irrespective of age. Neurourol. Urodynam. 35:642-646, 2016. © 2015 Wiley Periodicals, Inc.
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Anemia Falciforme/epidemiologia , Enurese Noturna/epidemiologia , Bexiga Urinária Hiperativa/epidemiologia , Adulto , Anemia Falciforme/complicações , Comorbidade , Estudos Transversais , Feminino , Humanos , Jamaica/epidemiologia , Masculino , Enurese Noturna/etiologia , Prevalência , Inquéritos e Questionários , Bexiga Urinária Hiperativa/etiologia , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to determine the association of testosterone deficiency and priapism in adult men with sickle cell disease (SCD). METHODS: A cross-sectional study of 50 adult men with SCD (hemoglobin SS) was performed. All patients had early morning blood taken for total and free testosterone, FSH, LH, prolactin, lipid levels, LDH and hematological indices. Patients completed an interviewer-administered questionnaire regarding priapism frequency, duration and treatment. Testosterone deficiency was defined as a serum total testosterone<12 nmol/L (346 ng/dL). RESULTS: The mean age of the study population was 34.2±8.9 years. Priapism was noted in 24 (48%) patients and was most frequently seen in men between ages 18-25 years. Testosterone deficiency was observed in 11 of the 50 (22%) patients, particularly in 6 of 24 (25%) patients with histories of priapism. There was no difference in mean total testosterone levels in patients with and without a history of priapism (16.7±4.9 nmol/L and 15.4±5.9 nmol/L, respectively) (p=0.43). Similarly, there was no difference in serum LH and FSH levels based on history of priapism. CONCLUSION: Testosterone deficiency is prevalent in patients with SCD; however, we did not identify an association based on a history of priapism. Larger, prospectively gathered data are needed to define the priapism profile of SCD patients with testosterone deficiency.
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Anemia Falciforme/sangue , Priapismo/sangue , Testosterona/deficiência , Adolescente , Adulto , Anemia Falciforme/complicações , Contagem de Células Sanguíneas , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Hormônio Foliculoestimulante/sangue , Humanos , L-Lactato Desidrogenase/sangue , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Priapismo/complicações , Fatores de Risco , Testosterona/sangue , Triglicerídeos/sangue , Adulto JovemRESUMO
AIMS: The aim of this study was to evaluate the immunohistochemical expression of mammalian target of rapamycin (mTOR) pathway-related biomarkers in penile carcinomas, and to assess associations with histological type, histological grade, and human papillomavirus (HPV) infection. METHODS AND RESULTS: We built four tissue microarrays from 112 invasive penile squamous cell carcinomas, and evaluated the immunohistochemical expression of PTEN, phospho-AKT, phospho-mTOR, and phospho-S6. We found decreased or loss of PTEN expression in 87% of cases. Warty and/or basaloid carcinomas had a higher proportion of PTEN loss (P = 0.02), whereas keratinizing tumours showed higher levels of phospho-S6 (P = 0.009); phospho-AKT and phospho-mTOR levels were not significantly different between warty/basaloid and keratinizing carcinomas (P = 0.75 and P = 0.77, respectively). PTEN was not associated with histological grade (P = 0.18). Expression levels of phospho-S6 were significantly higher in low-grade tumours (P = 0.001), whereas expression levels of phospho-AKT and phospho-mTOR were slightly higher in high-grade tumours (P = 0.01 and P = 0.35, respectively). We did not find any association between HPV infection and mTOR markers (P ≥ 0.2 in all cases). CONCLUSIONS: Our results provide evidence of dysregulation of the mTOR pathway in penile carcinomas independently of HPV infection. Future clinical studies should further evaluate the prognostic and predictive usefulness of these markers in patients with penile cancer.
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Carcinoma de Células Escamosas/metabolismo , Infecções por Papillomavirus/metabolismo , Neoplasias Penianas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Infecções por Papillomavirus/patologia , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Fosforilação , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Análise Serial de TecidosRESUMO
OBJECTIVE: To characterize transforming growth factor beta 1 (TGFß1) and related signaling pathway proteins in a large cohort of human penile tissue (HPT) samples. METHODS: HPT was collected from patients undergoing penile prosthesis implantation for erectile dysfunction (ED) and divided into the following 2 groups: postradical prostatectomy ED (RP-ED; n = 57) and organic ED (O-ED; n = 30). HPT from patients undergoing partial penectomy without ED was used as controls (CON; n = 6). Western blot analysis was performed to investigate the protein expressions of TGFß1, thrombospondin 1 (TSP1; an activator of TGFß1), fibronectin (an extracellular matrix glycoprotein induced by TGFß1), and a family of transcriptional factors activated by TGFß1 (Smad2, phospho-Smad2-serine-465/467 [pSmad2], Smad3, phospho-Smad3-serine-423/425 [pSmad3]). RESULTS: Expressions of TGFß1 and TSP1 were significantly higher in RP-ED (P <.05) and O-ED (P <.05) groups compared with that of the CON group and were not different between either ED groups. Expressions of Smad2, pSmad2, Smad3, pSmad3, and fibronectin were similar among all groups. Within the RP-ED group, a subgroup analysis showed that time from RP to penile prosthesis implantation was related to increased expression of pSmad2 (P <.05), and previous history of intracavernosal injection was related to increased expression of TGFß1 (P <.05). CONCLUSION: Our results demonstrate that TSP1- and TGFß1-dependent fibrotic changes occur in penile tissue in patients with ED regardless of etiology. The unchanged expression of the Smad transcriptional factors may be reconciled by a Smad-independent downstream signaling pathway transmitting TGFß1 signals.
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Disfunção Erétil/metabolismo , Pênis/metabolismo , Proteínas Smad Reguladas por Receptor/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Idoso , Disfunção Erétil/patologia , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de SinaisRESUMO
Priapism is defined as a persistent, painful erection that continues beyond, or is unrelated to, sexual stimulation. It may be categorized as either ischemic (low/absent flow) or nonischemic (high flow). Stuttering priapism is a variant of the ischemic type that is characterized by repetitive, transient, painful, self-limiting episodes of priapism. It is associated with various hematological disorders, including sickle cell disease and pharmacological treatments. The consequences of ineffective treatment of priapism are erectile dysfunction and impaired quality of life due to chronic pain and physical disfigurement. Many of the existing medical therapeutic options for treatment of stuttering priapism are nonmechanistic and associated with significant adverse effects. However, the scientific knowledge of stuttering priapism has transitioned in the past few years, from a condition that is poorly understood to one that has borne a burst of evolving molecular science. In this review, the pathophysiology of priapism is discussed, with particular emphasis on new molecular effectors and mechanisms. Novel treatment methods, as well as potential future agents, based on the emerging molecular evidence are discussed.
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Isquemia/fisiopatologia , Priapismo/fisiopatologia , Anemia Falciforme/complicações , Disfunção Erétil/etiologia , Humanos , Isquemia/complicações , Isquemia/terapia , Masculino , Priapismo/etiologia , Priapismo/terapiaRESUMO
UNLABELLED: Study Type - Aetiology (case control) Level of Evidence 3b. What's known on the subject? and What does the study add? Penile rehabilitation is still controversial regarding good results. Our study shows a non-invasive treatment option to recovery after cavernous nervous damage. The assessment of changes in the intracavernous pressure and karyometry demonstrates the protective effect of annexin-A1 in an animal model of cavernous nerve injury. We found that annexin-A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis. OBJECTIVE: ⢠To evaluate the protective effect of annexin-A1 against irreversible damage to cavernous tissue after cavernous nerve injury. PATIENTS AND METHODS: ⢠Thirty Sprague-Dawley male rats were divided into 3 groups; sham-operated rats (n= 10), bilateral cavernous nerve injury treated intravenously with 100 µg/kg annexin-A1 (n= 10), and a crush group of rats submitted to bilateral cavernous nerve injury and vehicle (n= 10). Groups were compared in respect to intracavernous pressure and karyometric parameters. RESULTS: ⢠After annexin-A1 treatment, the maximum changes in intracavernous pressure responses were significantly higher in the annexin-A1 group compared to the vehicle-only group on the 7(th) postoperative day (p-value <0.05). Hematoxylin-eosin staining showed that the percentage of cavernosal smooth muscle was higher in the annexin-A1 group. Karyometry showed that the nuclear volume was greater in the annexin-A1 group, as was the major/minor smooth muscle cell diameter ratio compared to the vehicle-only group on the 7(th) postoperative day (p-value <0.05). CONCLUSION: ⢠This is the first report that, by assessing changes in the intracavernous pressure and karyometry, demonstrates the protective effect of annexin-A1 in an animal model of cavernous nerve injury. We found that annexin-A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis.
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Anexina A1/farmacologia , Disfunção Erétil/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Pênis/lesões , Pênis/inervação , Animais , Masculino , Pressão , Ratos , Ratos Sprague-Dawley , Traumatismos do Sistema NervosoRESUMO
Priapism is a true urological emergency that is typified by a persistent and painful erection. High-risk groups include patients with hematological or coagulative disorders; for example, those with sickle cell disease, leukemia or glucose-6-phosphate dehydrogenase deficiency. The diagnosis for priapism must be made urgently using patient history, physical examination and blood gas findings on corporal aspiration. Emergency treatment is needed to avoid erectile dysfunction. However, in high-risk groups, prophylaxis must be encouraged. A number of prophylactic measures are emerging based on progress in the understanding of the pathophysiology of priapism in these particular patients. In this Review, priapism as it relates to hematological disorders is discussed, focusing on treatment and prophylaxis.
Assuntos
Doenças Hematológicas/complicações , Doenças Hematológicas/diagnóstico , Priapismo/diagnóstico , Priapismo/etiologia , Animais , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/terapia , Doenças Hematológicas/terapia , Humanos , Masculino , Priapismo/terapiaRESUMO
PURPOSE: To investigate the effects of alpha-1 adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia (BPH) regarding potential risks of complications in the setting of cataract surgery. AIM: To address recommendations, optimal control therapy, voiding symptoms and safety within the setting of cataract surgery. MATERIALS AND METHODS: A comprehensive literature review was performed using MEDLINE with MeSH terms and keywords "benign prostatic hyperplasia", "intraoperative floppy iris syndrome", "adrenergic alpha-antagonist" and "cataract surgery". In addition, reference lists from identified publications were reviewed to identify reports and studies of interest from 2001 to 2009. RESULTS: The first report of intraoperative floppy iris syndrome (IFIS) was observed during cataract surgery in patients taking systemic alpha-1 AR antagonists in 2005. It has been most commonly seen related to use of tamsulosin. Changes of medication and washout periods of up to 2 weeks have been attempted to reduce the risk of complications in the setting of cataract surgery. CONCLUSION: Patients under clinical treatment for BPH should be informed about potential risks of this drug class so that it can be discuss with their healthcare providers, in particular urologist and ophthalmologist, prior to cataract surgery.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Extração de Catarata , Doenças da Íris/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Extração de Catarata/efeitos adversos , Humanos , Iris/efeitos dos fármacos , Masculino , Fatores de RiscoRESUMO
PURPOSE: To investigate the effects of alpha-1 adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia (BPH) regarding potential risks of complications in the setting of cataract surgery. AIM: To address recommendations, optimal control therapy, voiding symptoms and safety within the setting of cataract surgery. MATERIALS AND METHODS: A comprehensive literature review was performed using MEDLINE with MeSH terms and keywords "benign prostatic hyperplasia", "intraoperative floppy iris syndrome", "adrenergic alpha-antagonist" and "cataract surgery". In addition, reference lists from identified publications were reviewed to identify reports and studies of interest from 2001 to 2009. RESULTS: The first report of intraoperative floppy iris syndrome (IFIS) was observed during cataract surgery in patients taking systemic alpha-1 AR antagonists in 2005. It has been most commonly seen related to use of tamsulosin. Changes of medication and washout periods of up to 2 weeks have been attempted to reduce the risk of complications in the setting of cataract surgery. CONCLUSION: Patients under clinical treatment for BPH should be informed about potential risks of this drug class so that it can be discuss with their healthcare providers, in particular urologist and ophthalmologist, prior to cataract surgery.