Collagenase clostridium histolyticum for the treatment of Peyronie's disease: a prospective Italian multicentric study.

Peyronie's disease (PD) is a common condition which results in penile curvature making sexual intercourse difficult or impossible. Collagenase clostridium histolyticum (CCH) is the first licensed drug for the treatment of PD and is indicated in patients with palpable plaque and curvature deformity of at least 30° of curvature. However, only few monocentric studies are available in the current literature and this is the first national multicentric study focusing on this new treatment. In five Italian centres, 135 patients have completed the treatment with three injections of CCH using Ralph's shortened modified protocol. The protocol consisted of three intralesional injections of CCH (0.9 mg) given at 4-weekly intervals in addiction to a combination of home modelling, stretching and a vacuum device on a daily basis. An improvement in the angle of curvature was recorded in 128/135 patients (94.8%) by a mean (range) of 19.1 (0-40)° or 42.9 (0-67)% from baseline (p < 0.001). There was also a statistically significant improvement in all IIEF and PDQ questionnaires subdomains (p < 0.001 in all subdomains). This prospective multicentric study confirms that the three-injection protocol is effective enough to achieve a good result and to minimize the cost of the treatment.

El manejo del priapismo isquémico agudo: una revisión actualizada / The management of the acute ischemic priapism: A state of the art review

Objetivo: Revisar la literatura actual sobre implantación de prótesis peneana temprana en pacientes con priapismo isquémico (PI) refractario. Adquisición de la evidencia: Se ha realizado una búsqueda sistemática de los términos «prótesis peneana», «priapismo», «impotencia», «fibrosis», «cilindros de prótesis reducidos» y «satisfacción del paciente» en bases de datos PubMed, EMBASE, Cochrane, SCOPUS y Science Citation Index. Síntesis de la evidencia: El daño del tejido cavernoso en PI está relacionado con el tiempo. Las medidas conservadoras y la aspiración con o sin instilación intracorpórea de agonistas alfa-adrenérgicos suelen tener éxito en las primeras etapas. La cirugía de derivación en pacientes sigue siendo discutible, ya que la falta de respuesta a la aspiración y a la instilación de agonistas alfa-adrenérgicos indica que es probable que ya hayan ocurrido cambios irreversibles en el músculo liso cavernoso. La implantación inmediata de la prótesis peneana en pacientes con PI refractario soluciona el episodio fálico, mantiene la rigidez a largo plazo necesaria para participar en relaciones sexuales penetrativas y previene el acortamiento peneano inevitable de otra manera. Aunque las tasas de complicaciones después de la implantación de la prótesis peneana en el priapismo agudo son mayores que en los casos virginales, son aún más bajas que después de la implantación en pacientes con fibrosis corporal grave debida al priapismo crónico. Independientemente de las tasas de complicaciones, la implantación de prótesis peneana en PI refractario debe ser preferida, ya que permite la preservación de la longitud del pene, que es uno de los principales factores que influyen en la satisfacción del paciente postoperatorio después de la cirugía

Objective: To review the current literature on early penile prosthesis implantation in patients with refractory ischemic priapism (IP). Acquisition of evidence: A systematic search for the terms "penile prosthesis", "priapism", "impotence", "fibrosis", "downsized prosthesis cylinders", and "patient satisfaction" has been carried out in PubMed, EMBASE, Cochrane, SCOPUS and Science Citation Index databases. Synthesis of evidence: Cavernosal tissue damage in IP is time related. Conservative measures and aspiration with or without intracorporeal instillation of alfa-adrenergic agonists are usually successful in the early stages. Shunt surgery in patients remains debatable, as the lack of response to aspiration and instillation of alfa-adrenergic agonists indicates that irreversible changes in the cavernosal smooth muscle are likely to have already occurred. Immediate penile prosthesis implantation in patients with refractory IP settles the priapic episode, maintains the long term rigidity necessary to engage in penetrative sexual intercourse and prevents the otherwise inevitable penile shortening. Although complication rates after penile prosthesis implantation in acute priapism are higher than in virgin cases, they are still lower than after implantation in patients with severe corporal fibrosis due to chronic priapism. Regardless of the complication rates, penile prosthesis implantation in refractory IP should be preferred as it allows the preservation of penile length, which is one of the main factors influencing postoperative patient's satisfaction following surgery

The management of the acute ischemic priapism: A state of the art review. / El manejo del priapismo isquémico agudo: una revisión actualizada.

OBJECTIVE: To review the current literature on early penile prosthesis implantation in patients with refractory ischemic priapism (IP). ACQUISITION OF EVIDENCE: A systematic search for the terms "penile prosthesis", "priapism", "impotence", "fibrosis", "downsized prosthesis cylinders", and "patient satisfaction" has been carried out in PubMed, EMBASE, Cochrane, SCOPUS and Science Citation Index databases. SYNTHESIS OF EVIDENCE: Cavernosal tissue damage in IP is time related. Conservative measures and aspiration with or without intracorporeal instillation of α-adrenergic agonists are usually successful in the early stages. Shunt surgery in patients remains debatable, as the lack of response to aspiration and instillation of α-adrenergic agonists indicates that irreversible changes in the cavernosal smooth muscle are likely to have already occurred. Immediate penile prosthesis implantation in patients with refractory IP settles the priapic episode, maintains the long term rigidity necessary to engage in penetrative sexual intercourse and prevents the otherwise inevitable penile shortening. Although complication rates after penile prosthesis implantation in acute priapism are higher than in virgin cases, they are still lower than after implantation in patients with severe corporal fibrosis due to chronic priapism. Regardless of the complication rates, penile prosthesis implantation in refractory IP should be preferred as it allows the preservation of penile length, which is one of the main factors influencing postoperative patient's satisfaction following surgery.

Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction.

UNLABELLED: The primary goal in the management strategy of a patient with ED would be to determine its etiology and cure it when possible, and not just to treat the symptoms alone. One of the new therapeutic strategies is the use of low intensity extracorporeal shockwave (LISW) therapy. The mechanism of shockwave therapy is not completely clear. It is suggested that LISW induces neovascularization and improvement of cavernosal arterial flow which can lead to an improvement of erectile function by releasing NO, VEGF and PCNA. MATERIALS AND METHODS: 31 patients between February and June 2013 with mild to severe ED and non-Phosphodiesterase 5 inhibitors responders were enrolled. Patients underwent four weekly treatment sessions. During each session 3600 shocks at 0.09mJ/ mm2 were given, 900 shocks at each anatomical area (right and left corpus cavernosum, right and left crus). Improvement of the erectile function was evaluated using the International Index of Erectile Function (IIEF-EF), the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3) and Global Assessment Questions (GAQ-Q1 and GAQ-Q2). RESULTS: At 3-month follow-up IIEF-EF scores improved from 16.54±6.35 at baseline to 21.03±6.38. Patients answering 'yes' to the SEP-Q2 elevated from 61% to 89% and from 32% to 62% in the SEP-Q3. A statistically significant improvement was reported to the Global Assessment Questions (GAQ-Q1 and GAQ-Q2). CONCLUSION: In conclusion, we can affirm that LISW is a confirmed therapeutic approach to erectile dysfunction that definitely needs more long-term trials to be clarified and further verified.

Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction

ABSTRACT The primary goal in the management strategy of a patient with ED would be to determine its etiology and cure it when possible, and not just to treat the symptoms alone. One of the new therapeutic strategies is the use of low intensity extracorporeal shockwave (LISW) therapy. The mechanism of shockwave therapy is not completely clear. It is suggested that LISW induces neovascularization and improvement of cavernosal arterial flow which can lead to an improvement of erectile function by releasing NO, VEGF and PCNA. Materials and Methods: 31 patients between February and June 2013 with mild to severe ED and non-Phosphodiesterase 5 inhibitors responders were enrolled. Patients underwent four weekly treatment sessions. During each session 3600 shocks at 0.09mJ/ mm2 were given, 900 shocks at each anatomical area (right and left corpus cavernosum, right and left crus). Improvement of the erectile function was evaluated using the International Index of Erectile Function (IIEF-EF), the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3) and Global Assessment Questions (GAQ-Q1 and GAQ-Q2). Results: At 3-month follow-up IIEF-EF scores improved from 16.54±6.35 at baseline to 21.03±6.38. Patients answering ‘yes’ to the SEP-Q2 elevated from 61% to 89% and from 32% to 62% in the SEP-Q3. A statistically significant improvement was reported to the Global Assessment Questions (GAQ-Q1 and GAQ-Q2). Conclusion: In conclusion, we can affirm that LISW is a confirmed therapeutic approach to erectile dysfunction that definitely needs more long-term trials to be clarified and further verified.

The P2X7 receptor is a key modulator of the PI3K/GSK3ß/VEGF signaling network: evidence in experimental neuroblastoma.

Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for neuroblastoma, we studied the role of P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3ß/MYCN and the HIF1α/VEGF pathways. In ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3ß activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3ß, leading to a decrease in cellular glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1α levels and vascular endothelial growth factor (VEGF) secretion. Systemic administration of two different P2X7 antagonists (AZ10606120 or A740003) in nude/nude mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in AlbinoJ mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB: MYCN. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment.

Intracoronary shunt prevents left ventricular function impairment during beating heart coronary revascularization.

OBJECTIVE: Beating heart coronary revascularization is becoming increasingly popular world-wide. Temporary occlusion of the coronary artery is often required in order to perform the anastomosis. An alternative method to maintain perfusion is to use an intracoronary shunt. In this study, we monitored global left ventricular function and regional wall motion in the presence or absence of a shunt using transesophageal echocardiography (TEE). METHOD: Left ventricular wall motion score index (WMSI), wall motion score (WMS) in the left anterior descending (LAD) coronary artery territory, and ejection fraction (EF%) were measured by multiplane TEE during construction of the left internal mammary artery (LIMA)-LAD coronary artery anastomosis in 40 patients undergoing revascularization with or without the use of a shunt. WMSI was assessed preoperatively, 1, 3 and 6 min during the construction of the anastomosis and after 5 min of reperfusion. WMS was assessed at 6 min during anastomosis and after 5 min of reperfusion. EF% was calculated preoperatively, 5 min into the construction of the anastomosis, and 5 min after reperfusion. RESULTS: During construction of the anastomosis, when the shunt was used, there were no changes in WMSI, WMS in the LAD territory or EF%. A significant decline in these parameters was seen in the group in which the shunt was not used, although on reperfusion all the values returned to baseline control. CONCLUSION: (i) occlusion of the LAD to perform the anastomosis results in temporary impairment in left ventricular function with complete recovery on reperfusion; (ii) the use of an intracoronary shunt presumably by maintaining myocardial perfusion prevents deterioration in ventricular function; (iii) from this data it seems therefore advisable to use an intracoronary shunt in patients with unstable angina, poor left ventricular function, or in cases in which a longer time to perform the anastomosis is anticipated.

Opioids activate G proteins in REM sleep-related brain stem nuclei of rat.

Mu opioid receptors within the pontine reticular formation contribute to opioid-induced rapid eye movement (REM) sleep inhibition. Mu receptors are coupled to guanine nucleotide binding (G) proteins and this study tested the hypothesis that the micro opioid agonist [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) would activate G proteins in rat brain stem nuclei known to regulate REM sleep. In vitro autoradiography of DAMGO-stimulated [35S]GTPgammaS binding showed that, compared with basal [35S]GTPgammaS binding, DAMGO significantly increased G protein activation in the nucleus pontis oralis (56.2%), nucleus pontis caudalis (57.3%), laterodorsal tegmental nucleus (75.8%), pedunculopontine tegmental nucleus (72.4%), nucleus locus coeruleus (77.2%) and dorsal raphe nucleus (73.4%). DAMGO stimulation of [35S]GTPgammaS binding in nuclei regulating REM sleep suggests that opioid-induced REM sleep inhibition involves activation of G proteins.

Carbachol stimulates [35S]guanylyl 5'-(gamma-thio)-triphosphate binding in rapid eye movement sleep-related brainstem nuclei of rat.

Carbachol enhances rapid eye movement (REM) sleep when microinjected into the pontine reticular formation of the cat and rat. Carbachol elicits this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors (mAChRs). The present study used in vitro autoradiography of carbachol-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding to test the hypothesis that carbachol activates mAChRs to induce stimulation of G-proteins in brainstem nuclei contributing to REM sleep generation. The results demonstrate a heterogeneous increase in carbachol-stimulated G-protein activation across rat brainstem. Binding of [35S]GTPgammaS in the presence of carbachol, compared with basal binding, was significantly increased in the laterodorsal tegmental nucleus (75.7%), caudal pontine reticular nucleus (68.9%), oral pontine reticular nucleus (64.5%), pedunculopontine tegmental nucleus (55.7%), and dorsal raphe nucleus (54.0%) but not in the nucleus locus coeruleus. The activation of G-proteins by carbachol was concentration-dependent and antagonized by atropine, demonstrating that G-proteins were activated via mAChR stimulation. The results provide the first direct measures of mAChR-activated G-proteins in brainstem nuclei known to contribute to REM sleep generation.

cAMP and protein kinase A modulate cholinergic rapid eye movement sleep generation.

Cholinergic neurotransmission in the medial pontine reticular formation (mPRF) modulates rapid eye movement (REM) sleep generation. Microinjection of cholinergic agonists and acetylcholinesterase inhibitors into the mPRF induces a REM sleep-like state, and microdialysis data reveal increased mPRF levels of acetylcholine during REM sleep. Muscarinic cholinergic receptors (mAChRs) participate in REM sleep generation, and data suggest that mAChRs of a non-M1 subtype modulate REM sleep generation. The signal transduction pathway activated by m2 and m4 mAChRs involves a pertussis toxin-sensitive G protein, adenylate cyclase (AC), adenosine 3',5'-cyclic monophosphate (cAMP), and protein kinase A (PKA). Therefore, the present study tested the hypothesis that cAMP and PKA within the mPRF modulate the carbachol-induced REM sleep-like state. To test this hypothesis, the mPRF was microinjected with compounds known to facilitate the effects of cAMP (dibutyryl cAMP and 8-bromo-cAMP), stimulate PKA (Sp-cAMP[S]), and inhibit PKA (Rp-cAMP[S]). The results showed that compounds that fostered the intracellular effects of cAMP significantly decreased cholinergic REM sleep, while having no effect on spontaneously occurring REM sleep. These data are consistent with the recent finding that within the mPRF, AC and a pertussis toxin-sensitive G protein modulate cholinergic REM sleep generation. These new data suggest a modulatory role for pontine cAMP and PKA in cholinergic REM sleep regulation.

Vesicular acetylcholine transport inhibitor suppresses REM sleep.

The vesamicol-like compound (+/-)-4-aminobenzovesamicol (ABV) non-competitively inhibits vesicular packaging of acetylcholine (ACh) in presynaptic terminals. This study tested the hypothesis that microinjection of ABV into the medial pontine reticular formation (mPRF) of intact, unanesthetized cats would inhibit rapid eye movement (REM) sleep. Microinjection of ABV alone or before administration of the acetylcholinesterase inhibitor neostigmine was used to evaluate the effects of ABV on natural REM sleep and on the neostigmine-induced REM sleep-like state. ABV decreased (24.8%) REM sleep and significantly reduced (33.6%) the neostigmine-induced REM sleep-like state. The results show for the first time that REM sleep generation can be disrupted by blocking a synaptic vesicle protein that modulates ACh transport in localized regions of the mPRF.

Pertussis toxin-sensitive G proteins mediate carbachol-induced REM sleep and respiratory depression.

Microinjecting cholinomimetics into the medial pontine reticular formation (mPRF) of conscious cats causes a rapid eye movement (REM) sleep-like state and state-dependent respiratory depression. Muscarinic receptors within the mPRF have been shown to mediate this state-dependent respiratory depression, but the specific signal transduction mechanisms remain poorly understood. This study tested the hypothesis that the cholinergically induced REM sleep-like state and state-dependent respiratory depression are mediated by guanine nucleotide binding proteins (G proteins). Cholera toxin, pertussis toxin, 5'-guanylylimidodiphosphate, and forskolin were microinjected alone and in combination with carbachol into the mPRF of intact unanesthetized cats. All of the G protein-altering compounds significantly reduced the ability of carbachol to produce the REM sleep-like state. Pertussis toxin caused the greatest decrease in the percent of time spent in the carbachol-evoked REM sleep-like state, showing for the first time mediation by a pertussis toxin-sensitive (Gi- or G(o)-like) G protein. Cholera toxin blocked the carbachol-induced respiratory depression, indicating mediation by a Gs-like G protein. Forskolin significantly decreased carbachol-evoked REM sleep. These data provide the first demonstration that adenylyl cyclase within the mPRF contributes to the carbachol induction of REM sleep and respiratory depression.