Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.

Investigation of the effect of dorsal penile block to penile tissue.

BACKGROUND: Dorsal penile block (DPB) is a frequently used technique for regional anesthesia, but the effect of DPB on penile tissue has not been reported so far. OBJECTIVE: An experimental study was conducted to evaluate the acute effects of DPB on penile tissue. METHODS: Eighteen male rats were included and randomly assigned to three groups. No intervention was made in the control group (CG, n = 6). In the sham group (SG, n = 6) 1 ml normal saline, and in DPB group (PBG, n = 6) 1 ml of 0.25% bupivacaine without adrenaline (0.5 mg/kg), was infused with a 30 mm, 23 gauge needle. DPB was performed by inserting the needle in the midline when pulling down the penis and directing the needle to the 11 and 1 o'clock positions. Another puncture was done at the midline on the ventral side and the remaining drug was infused slowly. The penile tissues were harvested for biochemical (malonyldialdehyde: MDA; nitric oxide: NO; superoxide dismutase: SOD) and histopathological examination. Histopathological assessments were made of inflammation, edema and fibrosis; epithelial degradation in the urethra; vascular obliteration in periurethral tissue; and the peripheral nerve cells. RESULTS: Concentrations of NO and SOD were significantly decreased in the PBG compared with the CG and SG (p < 0.05). The concentration of MDA was significantly increased in the PBG compared with the CG and SG (p < 0.05) (Table). Histopathological examination revealed no significant difference between groups regarding edema, inflammation, or fibrosis (p > 0.05). In hematoxylin and eosin stain samples, vascular structures of the corpus cavernosa were slightly decreased in number in the SG and PBG compared with the CG, but that difference was not statistically significant (p > 0.05). The S-100 staining was significantly higher in the PBG and SG compared with the CG (p < 0.05), and significantly higher in the SG compared with the PBG (p < 0.05). DISCUSSION: DPB causes alteration in oxidative stress markers because of an unknown effect. Although the results revealed increased inflammatory reaction in penile tissue after DPB, they are not enough to suggest not using bupivacaine for DPB in clinical practice. CONCLUSION: Although DPB does not cause any major histopathological alteration, it results in an increase in inflammatory response in the penile tissue in the short term.

Necrosis peneana como síntoma debut de calcifilaxis sistémica. Análisis de 2 casos y revisión de la literatura / Penile necrosis as clinical presentation of systemic Calciphylaxis: Report of two cases and bibliographic review

OBJETIVOS: La calcifilaxia es un síndrome potencialmente letal descrito primordialmente en pacientes con insuficiencia renal crónica en diálisis. La etiopatogenia es incierta y existe controversia en cuanto al manejo diagnóstico y terapéutico. La necrosis peneana como manifestación de esta enfermedad es extremadamente infrecuente. Analizamos dos casos clínicos tratados en nuestro centro y realizamos una revisión de la literatura. MÉTODOS: Se recogió la información clínica de ambos pacientes y se realizó una búsqueda bibliográfica en Pubmed bajo los criterios de búsqueda "penile necrosis", "penile calciphylaxis", "sodium thiosulfate" y "systemic calciphylaxis". RESULTADOS: Ambos pacientes fueron sometidos a penectomía parcial debido a extensa necrosis peneana. Tras la misma, iniciaron un régimen de Tiosulfato de Sodio 20 mg i.v. durante sus sesiones de hemodiálisis. En ambos pacientes se apreció estabilización del proceso isquémico. CONCLUSIÓN: La biopsia de las lesiones en la necrosis isquémica de pene, por sospecha de calcifilaxis sistémica, es controvertido. Igualmente, el papel de la cirugía agresiva de entrada puede ser discutible; más aún con la aparición de nuevos fármacos específicos, como el Tiosulfato de sodio, que parecen ser eficaces en la estabilización de las lesiones

OBJECTIVE: Calciphylaxis is a potentially lethal syndrome reported mainly in patients with ESRD on hemodialysis. Etiopathogenesis remains unclear and there is much controversy regarding optimal diagnostic and therapeutic approach. Penile necrosis as a disease presentation is extremely rare. We report two clinical cases treated in our center and perform an evidence review. METHODS: Clinical data was obtained from both patients and an evidence review was performed on PubMed under the criteria "penile necrosis" and "Calciphylaxis". RESULTS: Both patients underwent partial penectomy due to severe penile necrosis. After surgery both patients received treatment with sodium thiosulfate (STS) 20mg in every hemodialysis session. Both patients showed stabilization of necrotic lesions. DISCUSSION: The same way that biopsying the ischemic lesions produced by Calciphylaxis is discussed and even misadvised, the role of aggressive surgery as first line therapy might be uncertain specially with the raising of new specific drugs such as sodium thiosulfate (STS) that have shown efficacy stopping disease progression

Granuloma annulare of the penis: a uncommon location for an usual disease.

The subcutaneous clinical variant of granuloma annulare (GA) is rare and tends to present more frequently in children, in locations unusual for conventional GA. Involvement of the penis is exceptional and has been rarely reported. Most cases are located in the shaft of the penis and tend to persist without spontaneous remission. Diagnosis is done only after biopsy, and surgical resection of the lesions is not unusual. We report a new case of subcutaneous GA of the penis in a 13-year-old boy with lesions persistent for the past year. Surgical excision of one of them allowed the correct diagnosis. No further treatment was done, and the condition has not remitted 1 year later. We stress the importance of clinical recognition of unusual presentations of GA to avoid overtreatment of lesions that do not need an aggressive approach.

Mechanisms of penile fibrosis.

INTRODUCTION: Penile fibrosis has been conceptually identified with the plaque that develops in the tunica albuginea in Peyronie's disease (PD), or with localized processes induced in the corpora cavernosa by ischemic or traumatic events. Recently, it has been proposed that a diffuse, progressive, and milder intracorporal fibrosis, which affects also the media of the penile arteries, is responsible for vasculogenic erectile dysfunction (ED) associated with aging, smoking, diabetes, hypertension, and post-radical prostatectomy. These processes differ in etiology, time course, target cells, and treatment, but have many features in common. AIM: To review the literature pertaining to fibrosis in the penis, related to PD and ED. METHODS: PubMed search for pertinent publications mainly during 2001-2008. RESULTS: This review focuses initially on PD and then deals with studies on ED in animal and cell culture models, discussing some of the pathophysiological similarities between tunical fibrosis in PD and corporal fibrosis in corporal veno-occlusive dysfunction (CVOD), and emerging therapeutic strategies. The role of profibrotic factors, the excessive deposit of collagen fibers and other extracellular matrix, the appearance of a synthetic cell phenotype in smooth muscle cells or the onset of a fibroblast-myofibroblast transition, and in the case of the corporal or penile arterial tissue the reduction of the smooth muscle cellular compartment, are discussed. This histopathology leads either to localized plaques or nodules in penile tissues, or to the diffuse fibrosis causing impairment of tissue compliance that underlies CVOD and arteriogenic ED. The antifibrotic role of the sustained stimulation of the nitric oxide/cyclic guanosine monophosphate pathway in the penis and its possible relevance to exogenous and endogenous stem cell differentiation is also briefly presented. CONCLUSIONS: Fibrotic processes in penile tissues share a similar cellular and molecular pathophysiology and common endogenous mechanisms of defense that have inspired novel pharmacological experimental approaches.

Immunohistochemical and ultrastructural features of Langerhans cells in condyloma acuminatum.

BACKGROUND: There are few studies on the abnormal morphology of Langerhans cells (LCs) in condyloma acuminatum (CA) lesions and the essence of the abnormal morphology of LCs in CA lesions is still not well elucidated. The aim of this study was to further investigate the morphological features of LCs in CA lesions. METHODS: CD1a(+) LCs in 13 CA lesions and in 13 normal controls were labeled using immunohistochemistry and examined by light microscopy. Ultrastructural investigation on LCs in six CA lesions and in six normal controls was performed by electron microscopy. RESULTS: Compared with those in normal controls, most CD1a(+) LCs in CA lesions exhibited dysplastic dendrities and abnormal distribution. The number of CD1a(+) LCs in CA lesions (26.31 +/- 18.84) was statistically lower (p < 0.001) than that in normal controls (72.00 +/- 27.40). Electron microscopy showed that the number of Birbeck granules within lesional LCs (4.00 +/- 2.94) was significantly decreased (p < 0.001) than that within normal LCs (10.80 +/- 4.78). The ultrastructures of most lesional LCs displayed degenerative changes. CONCLUSIONS: The morphology of most LCs in CA lesions shows degenerative changes, which suggest that these LCs have been functionally impaired.

Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health.

The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3', 5'-cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). New investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying existing and emerging therapeutic strategies for erectile disorders.

Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma.

BACKGROUND: Human papillomaviruses (HPVs) are sexually transmitted human carcinogens that may play a role in the oncogenesis of penile cancer. OBJECTIVES: To investigate the role of HPV infection and expression of the tumour suppressor protein p16INK4A in the pathogenesis of penile cancer. METHODS: By means of polymerase chain reaction amplification and reverse hybridization line probe assay to detect HPV infection, and immunohistochemical staining for p16INK4A and Ki67, we analysed 26 penile squamous cell carcinomas (SCCs) and 20 independent penile lichen sclerosus (LS) lesions from 46 patients. RESULTS: HPV DNA was found in 54% of penile SCCs and 33% of penile LS cases in single and multiple infections. High-risk HPV 16 was the predominant HPV type detected. No relationship between Ki67 expression and HPV infection was observed. Strong immunostaining for p16INK4A correlated with HPV 16/18 infection in both penile LS and penile SCC. In our penile SCC series the cancer margins were also associated with penile LS in 13 of 26 lesions, and HPV was detected in seven of the 13 SCC cases associated with LS and in six of the 11 SCC lesions not involving LS. CONCLUSIONS: Our study shows a high prevalence of HPV 16 and p16INK4A expression in penile lesions, consistent with an active role for HPV in interfering with the retinoblastoma pathway. High-risk HPV infection could be involved in the tumorigenic process in 50% of penile cancers, and the use of prophylactic HPV vaccines has the potential to prevent these cancers.

Ectopic modified sebaceous glands in human penis.

The balanopreputial sulcus is believed to be the most frequent site of the so-called Tyson's glands. The intriguing feature of these anatomical structures is their mere existence, which has been doubted. Herein, the authors present a case of a 24-year-old man who underwent surgical treatment of his phimosis. On microscopic examination of the specimen, glands with morphological features similar to those described by Tyson were noted.

Nitric oxide/redox-based signalling as a therapeutic target for penile disorders.

Oxidative and/or nitrosative stress is implicated in the pathogeneses of assorted penile disorders of clinical significance, notably erectile dysfunction, priapism and penile fibrosis. It is becoming increasingly recognised that the generation and activity of reactive oxygen and nitrogen species in the penis influence vascular homeostasis of this organ, with adverse effects exerted at cellular and molecular levels. Furthermore, these elements may interact with molecular signalling pathways operating in the penis, modulating their functional roles. This interaction in particular suggests that by accessing molecular targets associated with oxidative/nitrosative stress in the penis, new pharmacotherapeutic approaches may be developed to promote normal erectile ability and preserve erectile tissue health. This notion pertains to, but also extends beyond, interventions which predictably target components of the nitric oxide-based signal transduction pathway for the on-demand treatment of erectile dysfunction. The next line of pharmaceuticals for disorders of the penis, in general, may well spawn from an integrative understanding of the complex regulatory interactions influenced by, as well as influencing nitric oxide signalling in this organ.

[Predicting cancerization of condyloma acuminatum by testing expression of p16].

BACKGROUND & OBJECTIVE: About 3%-10% of condyloma acuminatum (CA) may develop into cancer. Some studies indicated that homologous deletion of p16 gene is a major factor that causes cancerization of CA. This study was to detect expression of P16 protein in CA tissues and its cancerization tissues, and to investigate relationship of abnormal expression of P16 and cancerization of CA. METHODS: A total of 75 skin biopsy specimens were collected, including 30 normal skin samples (control group), 35 CA samples, and 10 cancerized CA samples. Expression of P16 was tested by LSAB immunohistochemistry, and relationship of P16 and cancerization of CA was statistically analyzed. RESULTS: CA and normal skin tissues showed weakly positive expression of P16, no significant difference exist (P< 0.05). Cancerized CA tissues showed positive or strongly positive expression of P16, significantly stronger than CA and normal skin tissues (P< 0.05). CONCLUSIONS: Positive and strongly positive expression of P16 in CA tissue implied risk of cancerization of CA. P16 may be a useful predictor for cancerization of CA.

[Experimental and clinical research of "Keyouling" on treatment of condyloma acuminata].

OBJECTIVE: To investigate the effects of traditional Chinese medicine "Keyouling" in treatment of condyloma acuminata (CA). METHODS: The effects of "Keyouling" at different concentrations on growth and proliferation of rabbits' prepuce epithelial cells and CA warts tissue were assessed by means of cellular primary culture and subculture, and the effects of "Keyouling" at different concentrations on the expression level of HPV6.11 DNA and expression level of HPV6.11 DNA of different area of CA patient's penis were quantitatively detected by means of FQ-PCR. RESULTS: "Keyouling" had no effect on growth and proliferation of rabbits' prepuce cuticle cells, but it had significant inhibition on CA warts tissue cells and expression of HPV6.11 DNA. Concentrations of "Keyouling" assumed negative correlated with cell proliferation rate of CA warts tissue and expression level of HPV6.11 DNA, and also had significant inhibition on expression of HPV6.11 DNA of negative cutaneous lesion area and cutaneous lesion area of CA patients. CONCLUSION: "Keyouling" had significant anti HPV6.11 effect, could significantly restrain growth and proliferation of CA warts tissue cells, while it had no damaging effect on normal organic cuticle cells. It was suggested that "Keyouling" was safe in clinical use and had good therapeutic effect on CA and subclinical infection.

In vivo fluorescence kinetics and photodynamic therapy in condylomata acuminata.

BACKGROUND: Topical application of 5-aminolaevulinic acid (ALA) to condylomata acuminata leads to accumulation of protoporphyrin IX (PpIX); therefore ALA-induced photodynamic therapy (ALA-PDT) appears to be a potential treatment. OBJECTIVES: To investigate in vivo the PpIX fluorescence time course after topical application of ALA in order to determine the optimal time for irradiation, and to assess the efficacy of subsequently performed ALA-PDT. METHODS: Fluorescence kinetics was studied in 12 male patients with condylomata acuminata. Confirmation of diagnosis was established with conventional histology and polymerase chain reaction. Lesions were treated with 20% ALA and irradiated at the optimal time with a dose of 70 J cm-2 or 100 J cm-2 light. An additional session with 100 J cm-2 was administered 1 week later to lesions that persisted. RESULTS: The in vivo study of fluorescence kinetics indicated that the optimal time for irradiation varied among patients from 6 to 11 h. The overall cure rate was 72.9%, 12 months after treatment. CONCLUSIONS: Topical ALA-PDT is a potentially effective treatment for condylomata acuminata.

Mucinous metaplasia of the penis.

AIMS: To determine the incidence of mucinous metaplasia occurring in the foreskin or glans penis and any associated clinical or histopathological features. METHODS AND RESULTS: Following the recognition of two index cases, 100 other foreskin specimens were retrieved from the histopathology archives at Southampton General Hospital. The haematoxylin and eosin-stained slides were examined by a single observer to detect the presence of mucin-producing cells in the surface epithelium. The absence of mucinous metaplasia in negative cases was confirmed with mucin histochemistry. In total, four cases of mucinous metaplasia were identified, three involving the foreskin and one involving the glans penis. The age range was 51-80 years. Three cases were associated with Zoon's balanitis and the fourth showed mild non-specific balanitis. All four cases showed positive staining with both diastase periodic acid-Schiff and alcian blue. No mucin-producing cells were identified in non-inflamed or minimally inflamed specimens. CONCLUSIONS: Mucinous metaplasia of the penis is an uncommon but under-recognized condition. It is seen in the elderly and appears to be a metaplastic change associated with severe chronic inflammation, and possibly more specifically with Zoon's balanitis. Our study identified a case affecting the glans penis, a site not previously recorded.

Lymphohistiocytic and granulomatous phlebitis in penile lichen sclerosus.

Lichen sclerosus (LS) is a chronic inflammatory disease of unknown etiology that may affect the genital and/or extragenital skin of individuals of either sex at all ages. In boys, the prepuce is the most common site of involvement. The diagnostic criteria of LS include the presence of inflammatory infiltrates mainly composed of T lymphocytes. We report on two cases of LS of the prepuce because of the unusual feature of lymphocytic (CD45RO+ and CD20+), histiocytic (CD68+), and granulomatous phlebitis. This lesion was not present in a group of another 18 cases of childhood penile LS. We have not been able to find any references describing and illustrating inflammatory involvement of the dermal vein walls in LS. Unlike the data reported in the literature, the dermal inflammatory infiltrates of these two cases showed a similar proportion of B and T lymphocytes in addition to frequent CD68+ histiocytes.

Annular lichen planus showing a change in metallothionein expression on immunohistochemistry.

The immunohistochemical localization of metallothioneins (MTs), low-molecular-weight metal-binding proteins, was investigated in a case of annular lichen planus (LP) that enlarged centrifugally with healing in the centre after a month. The annular lesion was found to exhibit the early, developed and late stages of LP, as judged by the clinical and histopathological findings. Immunostaining for MTs was increased around the lesion, discontinuous around the rim of the erythema and undetectable in the centre of the lesion. MT expression was examined in eight specimens of idiopathic LP. Discontinuous immunostaining for MTs was observed in six specimens and increased staining around the lesion was observed in two specimens. These results suggest that MT expression changes depending on the inflammatory stage of LP. Although the role of MTs in dermatological disease is still unknown, their expression might be related to the pathological process of LP.

Immunohistochemical expression of glucose transporter-1 in human penile proliferative lesions.

Glucose transporters (GLUTs) are a family of membrane proteins responsible for the transport of glucose across cellular membranes. In terms of their mRNA levels, they have been reported to be expressed in some human tumours. However, the immunohistochemical localization of GLUTs in human urogenital lesions has rarely been studied. This study was performed to evaluate the expression of GLUT1 in penile proliferative lesions (18 cases of penile carcinoma and 13 cases of condyloma acuminatum). Using an isoform-specific anti-GLUT1 antibody, formalin-fixed paraffin-embedded sections were stained by the avidin-biotin complex method. In all cases of penile carcinoma, GLUT1 staining was diffusely recognized on the cell membrane of the carcinoma cells in the mainly infiltrating areas. However, the inner areas of the tumour were more weakly and focally stained. The intensity of staining for the penile carcinoma (staining score = 2.8 +/- 0.6) was stronger than that for condyloma acuminatum and that for adjacent non-proliferative areas. All cases of condyloma acuminatum showed a diffuse staining on the cell membrane in the basal and intermediate layers (staining score = 2.4 +/- 0.5). Non-proliferative (histologically normal) glans areas adjacent to the above lesions expressed the weakest GLUT1 staining only in the stratum basale (staining score = 1.8 +/- 0.5). These three areas showed significantly different staining scores from each other (p < 0.01). In conclusion, GLUT1 is expressed dominantly in penile proliferative lesions, especially in infiltrating areas of penile carcinoma.

Immunohistochemical detection of p53 protein expression in HPV-induced condyloma acuminatum.

Immunohistochemical peroxidase staining for p53 protein was performed on 22 condyloma acuminatum tissue samples from patients infected with human papillomavirus (HPV). The purpose of our study was to understand the benign character of this syndrome. The patients studied were infected by HPV type 6 and 11. Two monoclonal antibodies, PAbs DO-1 and 240, were used to detect the p53 protein. Overexpression of wild-type p53 was found in the nuclei of the basal cell layers. In healthy tissues and non-infected patients no p53 protein expression was detected. We would like to speculate that infection with HPVs and their viral protein E7, which is implicated in disruption of normal growth, may regulate the induction of wild-type p53 over-expression, as is known for DNA-damaging agents such as UV- or X-radiation.