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Aims: To compare and verify the agreement of the arm stroke efficiency (ȠF) results obtained by simplified (ȠFS) and three-dimensional (ȠF 3D) methods. Background: Arm stroke efficiency (ȠF) estimates how much of the force applied by the swimmers’ upper limbs contribute to their propulsion. To estimate ȠF, in front crawl stroke, three-dimensional (ȠF3D) and simplified (ȠFS) methods are highlighted. Objective: To verify if different methods estimate similar arm stroke efficiency values. Methods: Ten male swimmers (age: 21.5 ± 2.6 years; height: 1.78 ± 0.05 m; competitive swimming experience: 12.2 ± 5.0 years) were tested in three 25 m front crawl stroke bouts at low, moderate, and high intensities. The ȠF data were obtained after collecting swimming images with six synchronized cameras and later analyzed in motion reconstruction software. Results: The mean results of ȠF, respectively for ȠF3D and ȠFS, were: 34.7±2.1% and 47.4±6.4% at a low; 34.8±2.7% and 42.3±3.3% in moderate; and 33.1±2.6% and 32.4±2.9% at high intensity. Along the intensities, ȠF remained similar with ȠF3D and reduced with ȠFS. ȠF was lower with ȠF3D than with ȠFS at low and moderate intensities (p < 0.05) and similar at maximum intensity (p > 0.05). Conclusion: At maximum intensity, the ȠF values agree between the methods. The results obtained by both methods were not fully similar. ȠF3D and ȠFS results agree just at high intensity. The differences between the methods may be due to the different variables used to measure ȠF, stroke rate in the ȠFS and three-dimensional hand velocity in the ȠF3D.

OBJECTIVE: To assist urologists in the management of andrological and sexual medicine pathologies during the COVID-19 crisis. MATERIAL AND METHOD: Use of the formalized consensus method. RESULTS: The medical and surgical management of patients in andrology and sexual medicine must be adapted. Consultations should, as far as possible, be carried out by tele-consultation. For operative procedures, the delay between the operative decision and the date of (re)scheduling of the procedure will depend on: (1) the level of criticality of the clinical situation; (2) the type of intervention; (3) the functional and psychological repercussions, including quality of life while waiting for the procedure; (4) the notion of losing the chance of having an optimal outcome; (5) the risk of potential complications from delaying a procedure for too long; and (6) taking into account the patient's risk factors for severe forms of COVID-19. The protection of urologists from COVID-19 should be considered. Each urologist must make the best decision for the patient, taking into account the acceptable time frame and quality of life impact before surgical management, the COVID risk parameters, the technical and anesthetic feasibility and the structural possibility of the health care institution to ensure a specific dedicated pathway during the COVID-19 health crisis. CONCLUSION: The management of andrological and sexual medicine pathologies must be adapted to the COVID-19 crisis context. Some patients may require surgery, including in emergency. These recommendations are transitional and will end with the COVID-19 crisis.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

BACKGROUND Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and cafe-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Resume La pathologie congenitale de l'avant pied recouvre deux grandes entites de traitement et pronostic differents : les malformations survenant lors de la periode embryonnaire et a l'origine de defauts anatomiques ; et les deformations survenant pendant la periode fœtale sur un pied normalement constitue. Ces deformations sont d'autant plus facilement curables que leur survenue est tardive pendant la periode fœtale. Lorsque l'anomalie est bilaterale, une origine genetique doit etre evoquee. Sous le terme de deformations, on regroupe essentiellement deux entites : le metatarsus adductus et le pied en Z. Les malformations regroupent les brachydactylies (anomalies transversales), les anomalies longitudinales, les syndactylies, les polydactylies, les clinodactylies et les macrodacylies. Enfin, parmi les autres anomalies de l'avant-pied, on doit noter l'hallux valgus, dont la forme congenitale est rare, et pour lequel le traitement orthopedique est parfois suffisant. On retient aussi les sequelles de maladie des brides amniotiques, les anomalies de l'avant-pied consecutives au traitement des pathologies congenitales (pied bot varus equin et pied convexe congenital), et les pathologies de l'ongle (ongle incarne et malposition ungueale).

Most modern standards for wireless communications support physical layer adaptations, in terms of dynamic selection of channel central frequency, transmission power, modulation format, etc., in order to increase link robustness under time-varying propagation and interference conditions. In this demo, we demonstrate that another powerful solution for extending physical layer flexibility in OFDM-based technologies is the dynamic adaptation of the channel width. Although some standards already define the possibility of utilizing multiple channel widths (e.g. 20MHz, 10MHz, 5MHz forIEEE 802.11a standards), such an utilization is limited to a static configuration of a value defined during the network set-up. Conversely, we demonstrate that channel width adaptations can be performed in real-time during network operation, even on a per-packet basis.To this purpose, we propose an innovative and efficient receiver design, which allows the transmitter to take decisions about the channel width without explicitly informing the receiver.

Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity, implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving the possibilities of offering optimal care to patients. We present the results of a two-year period of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss. Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional approaches including Copy Number Variations, in silico analyses, minigene studies coupled when appropriate with complete gene sequencing, and a specific assay for STRC. This comprehensive screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the other genes (24%). Pathogenic genotypes were identified in 19 different genes, with a high prevalence of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported in 16% of the genotyped cohort. Four de novo variants were identified. This study highlights the need to develop several molecular approaches for efficient molecular diagnosis of hearing loss, as this is crucial for genetic counselling, audiological rehabilitation and the detection of syndromic forms.

Carcinoid tumors belong to the families of neuroendocrine tumors. The major sites are the gastrointestinal tract 65% and lungs 25%. The small intestine, specifically the ileum, is the most common. These tumors although rare, are more common in tumors of neuroendocrine origin gastro-entero-pancreatic. In both cases we observe the different clinical presentations that may have carcinoid tumor; in case 1 ulceration of the tumor mass causing the elimination of melena, and severe diarrhea caused by neuroendocrine secretion. Case 2 typical course, totally asymptomatic incidental finding.

Los tumores carcinoides pertenecen a las familias de tumores neuroendocrinos. Las localizaciones principales son el tracto gastrointestinal 65% y en los pulmones 25%. Los del intestino delgado, y más concretamente los de íleon, son los más frecuentes. Estos tumores, aunque raros, son los más comunes entre las neoplasias gastroentero-pancreáticas de origen neuroendocrino. Se presentan dos casos de tumor carcinoide. En estos dos casos observamos las distintas formas de presentación clínica que puede tener el tumor carcinoide; en el caso 1 ulceración de la masa tumoral provocando melena, y diarrea aguda causada por la secreción neuroendocrina. El caso 2 curso típico, totalmente asintomático y hallazgo casual Carcinoid tumors belong to the families of neuroendocrine tumors. The major sites are the gastrointestinal tract 65% and lungs 25%. The small intestine, specifically the ileum, is the most common. These tumors although rare, are more common in tumors of neuroendocrine origin gastro-entero-pancreatic. In both cases we observe the different clinical presentations that may have carcinoid tumor; in case 1 ulceration of the tumor mass causing the elimination of melena, and severe diarrhea caused by neuroendocrine secretion. Case 2 typical course, totally asymptomatic incidental finding

International audience; Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Resume La galactosemie congenitale et le syndrome de Rogers ou anemie megaloblastique thiamine-dependante sont 2 maladies metaboliques hereditaires rares. L’association de ces 2 affections n’a jamais ete rapportee dans la litterature. Nous decrivons le cas d’une fillette suivie pour galactosemie congenitale depuis l’âge de 8 j, presentant une anemie megaloblastique thiamine-dependante diagnostiquee a l’âge de 10 mois. La galactosemie congenitale s’exprime dans les 2 premieres semaines de vie avec un tableau d’insuffisance hepatique severe. Une eviction totale du galactose permet la regression complete et la prevention des symptomes precoces mais n’evite pas la survenue des complications tardives. Le syndrome de Rogers associe une anemie megaloblastique, une surdite et un diabete qui debutent dans l’enfance. Une supplementation par thiamine permet la regression de l’anemie et previent la survenue du diabete au moins jusqu’a l’adolescence.

Aims: To evaluate auxological parameters in children and adults with a 22q11.2 microdeletion syndrome (22q11.2 DS) and to compare prevalence of obesity to that in the French general population. Methods: 102 patients with 22q11.2 DS (49 males, 53 females) were recruited from birth to adulthood through a reference center in southern France. Results: Mean BMI Z score and mean height were normal (0.07 ± 1.49 SD, –0.87 ± 1.36 SDS, respectively). 16.1% of patients were overweight (including obese), 57% out of them being born small for gestational age for length versus 25% of non-overweight patients. During infancy, BMI increased in girls (+0.89 SD Z score). Childhood: 14.7% were overweight, prevalence similar to that of the in French children population. Adulthood: 19.2% were overweight. BMI Z scores were inversely correlated with neonatal length (p = 0.026) and female sex (p = 0.032) but positively associated with neonatal weight (p = 0.036). From analysis of neonatal data, 22q11.2 DS newborns were significantly shorter with regard to their weight (p < 0.01), even though mean neonatal measures were above –2 SDS. Conclusions: Our study did not find a higher prevalence of overweight in 22q11.2 DS to that in the French population. The BMI Z score was inversely correlated with neonatal length and female gender but positively associated with neonatal weight.

Introduction La vessie neurologique complique la grande majorite des lesions medullaires. La prise en charge de la vessie neurologique associe traitement medical (anticholinergiques par voie orale ou injections intradetrusoriennes de toxine botulique) et vidanges vesicales pluriquotidiennes par sondage. La neurostimulation des racines sacrees anterieures apres rhizotomies posterieures (technique de Brindley) represente une alternative a cette prise en charge. La therapie genique ELPIS, option therapeutique non encore sur le marche, combinee a la neurostimulation permettrait de s’affranchir des sondages vesicaux et de la rhizotomie, d’eviter les effets secondaires du traitement pharmacologique, tout en ameliorant l’efficacite clinique et la qualite de vie des patients. Notre objectif etait de simuler le ratio cout–utilite (RCU) de la therapie ELPIS comparativement aux deux strategies de prise en charge actuelles. Methodes Un modele cout–utilite a ete elabore. Nous avons construit un modele de Markov sur un horizon temporel de 10 ans, avec des cycles d’un an et un taux d’actualisation de 4 % en adoptant la perspective de l’Assurance maladie francaise. Les scores d’utilite et les probabilites de transition des strategies de prise en charge actuelle ont ete valorises a partir des donnees de la litterature. Les couts ont ete estimes a partir de l’Echelle nationale de couts et des donnees de la litterature. Les probabilites de transition, les scores d’utilite et les couts associes a la therapie ELPIS ont ete etablis a partir d’avis d’experts. Le ratio d’efficience est exprime en cout par annee de vie gagnee en etat de parfait bien-etre (QALY). L’incertitude sur la valeur des parametres du modele a ete prise en compte dans une analyse probabiliste et par des analyses de scenarii. Resultats Pour une cohorte fictive de 1000 individus suivis pendant 10 ans, la therapie ELPIS presentait un gain de 2154 QALY (intervalle de confiance a 95 % [IC] : 865 ; 3468) et un differentiel de couts de −10 982 173 € (IC : −40 280 229 € ; 22 810 710 €) comparativement au traitement pharmacologique associe aux sondages soit un RCU estime a −5099 €/QALY gagne. Comparativement a la technique de Brindley, la therapie ELPIS presentait un gain de 490 QALY (IC : −1223 ; 1939) et un differentiel de couts de −18 757 674 € (IC : −37 519 477 € ; −4 480 981 €) soit un RCU simule estime a −38 318 €/QALY gagne. Dans les analyses de scenarii, avec des hypotheses conservatrices, la probabilite d’efficience minimale estimee au seuil de 30 000 € par QALY gagne de la therapie ELPIS etait de 97,8 % comparativement au traitement pharmacologique associe aux sondages et de 47 % comparativement a la technique de Brindley. Conclusion Comparee aux prises en charge actuelles, la therapie ELPIS permettrait a l’Assurance maladie de faire des economies, tout en ameliorant le bien-etre des personnes atteintes de vessie neurologique suite a une lesion medullaire. Ce travail de simulation fournit des estimations utiles a la recherche d’investissements pour le financement de la poursuite du developpement de l’innovation.

Pharmaceutical research and development in France is an important and dynamic economic sector that places France among the countries most involved in research. However, economic constraints have precipitated major changes in this industry. The costs associated with the genesis of a drug, from discovery to marketing, are increasing, forcing the industry to adapt. Here we discuss the motivations of the pharmaceutical industry in oncology so that the medico-surgical specialist of the cancers of the genito-urinary tract can best understand the situation.

Penile erection is a neurovascular process controlled by numerous tightly regulated events, and occurs in response to the activation of pro-erectile autonomic pathways. It is dependent on an adequate inflow of blood to the erectile tissue through both endothelium-dependent vasodilatation and corporal smooth muscle relaxation. Pathologic alteration in the endothelium of penile vasculature and/or erectile tissue and/or impairment of neurovascular processes can result in erectile dysfunction (ED). Both cardiovascular disease (CVD) and ED have been linked to endothelial dysfunction. Endothelial dysfunction is a vascular condition resulting in a diminished vasodilatory response to pharmacologic and physiologic stressors. Endothelial dysfunction may be a pathophysiologic mechanism underlying both ED and CVD, forming a unifying link between these two conditions. Furthermore, in the general population and in men with diabetes or obesity, ED may be a valuable early marker for serious subclinical CVD, coronary artery disease and atherosclerosis.

Resume But Etudier l’impact des differences de pharmacocinetique des IPDE5 sur l’intervalle entre prise du traitement et rapport sexuel. Materiel Etude observationnelle, prospective, realisee sur un an aupres de 916 medecins generalistes dont 462 ont recrute au moins un patient repondant aux criteres d’inclusion : patients souffrant de dysfonction erectile (DE), traites par IPDE5 depuis au moins trois mois et suivis pendant deux mois. Resultats Mille quatre cent deux patients analyses, 939 (67 %) traites par sildenafil, 116 (8,3 %) par vardenafil, 347 (24,8 %) par tadalafil, avec en moyenne, un âge de 57,9 ans, une DE depuis 1,8 ans, traites depuis 11,1 mois. La dose la plus faible, la dose initiale recommandee et la dose la plus forte ont ete respectivement 25, 50 et 100 mg pour le sildenafil, 5, 10 et 20 mg pour le vardenafil et 5, 10 et 20 mg pour le tadalafil. Le sildenafil etait pris a la dose initiale recommandee dans 77 % des cas, contre respectivement 55 et 23 % pour le vardenafil et le tadalafil qui necessitaient plus frequemment que le sildenafil des doses superieures a la dose initiale recommandee pour etre efficaces. Sur la periode d’etude, les donnees de 5842 rapports sexuels de 780 patients ont ete analysees. La mediane [IC : 95 %] de l’intervalle de temps entre prise du traitement et rapport sexuel etait notamment : 1,0 heure [1,0–1,0] pour le sildenafil, 1,0 heure [1,0–1,0] pour le vardenafil et 1,5 heures [1,3–1,5] pour le tadalafil. Les scores de qualite de vie et de satisfaction du traitement ne montraient pas de difference selon l’IPDE5. Conclusion Cette etude realisee dans un contexte de pratique medicale non specialise suggere qu’en depit de profils pharmacocinetiques differents, la planification de la prise du traitement en vue d’un rapport sexuel reste en pratique semblable avec les differents IPDE5.

The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cerebral control of ejaculation has been investigated for years; nevertheless the function of different dopamine receptors subclasses and their exact interrelations merit additional research. One hundred nanograms of a preferential D3 agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propylaminotetralin hydrobromide) was microinjected unilaterally into the MPOA of male rats anesthetized with urethane. An ejaculation-related response (bulbospongiosus muscles rhythmic contractions and/or seminal vesicle pressure increases and/or expulsion of a semen plug) was observed in 8 of 10 rats devoid of sexual stimuli, while a similar response was observed in only one rat administered with 10 ng of 7-OH-DPAT. The effect of 7-OH-DPAT 100 ng was mostly abolished by simultaneous MPOA microinjection of 300 ng of a preferential D3 antagonist N-[(n-butyl-2-pyrrolidinyl) methyl]-1-methoxy-4-cyanonaphthalene-2-carboxamide tartrate (nafadotride). Our results support the hypothesis that supraspinal command of ejaculation is mediated by D2-like receptors, probably by D3 receptors, in the MPOA, and draw attention to the idea of these receptors serving as a promising target for pharmacological treatment of human ejaculatory disorders.

Objectives The aim of the study was to determine whether dapoxetine, a short-acting selective serotonin reuptake inhibitor, acts at the spinal or supraspinal level to inhibit the ejaculatory reflex. Methods The pudendal motoneuron reflex discharges (PMRDs) model was used as an experimental paradigm of the ejaculatory expulsion reflex in anaesthetised male rats. A spinal site of action was evaluated by testing the effect of intrathecal delivery of dapoxetine on PMRDs elicited by electric stimulation of the dorsal nerves of the penis (DNP). A supraspinal site of action was evaluated by testing the effect of intravenous administration of dapoxetine on DNP-induced PMRDs in rats with chemical bilateral lesion of the lateral paragigantocellular nucleus (LPGi). Results Compared with control (NaCl 0.9%, intrathecally), intrathecal injection of dapoxetine (1 and 80μg) significantly increased amplitude of DNP-elicited PMRDs in a similar fashion than serotonin (5-HT; 10 and 100μg, intrathecally). In rats having received bilaterally NaCl 0.9% into LPGi, intravenous treatment with dapoxetine (3mg/kg) induced significant delay in PMRD latency and decrease in PMRD amplitude compared with pretreatment values. These effects were abolished in rats having received bilaterally kainic acid into LPGi 1 d before testing. Conclusions The present study showed that dapoxetine inhibits ejaculatory expulsion reflex by acting at a supraspinal level with LPGi as a necessary brain structure for this effect.

Resume Ici sont rapportees les principales informations extraites de l'etude Repair concernant la prise en charge de la dysfonction erectile apres prostatectomie totale. Vingt pour cent des urologues n'evaluent pas la fonction erectile preoperatoire de leurs patients. Tous prennent en charge la dysfonction erectile de leurs patients mais seuls 38 % realisent une prise en charge systematique, les autres proposant une prise en charge a la demande. La prise en charge, lorsqu'elle est proposee, est initiee 8 fois sur 10 dans les trois mois suivant l'intervention. L'attitude de prise en charge est standardisee puisque 88 % des urologues ont toujours recours a un meme protocole. Dans 76 % des cas, ces protocoles reposent sur la prescription d'injections intracaverneuses. La reeducation pharmacologique est frequemment proposee. Enfin, les patients acceptent d'autant mieux un traitement qu'il est prescrit systematiquement et precocement.

In addition to serotonin, dopamine within the CNS is known to play a primary role in the control of ejaculation. However, whether D(2) and/or D(3) dopamine receptor subtypes mediate this effect is still unclear. In order to clarify this issue, a pharmacological competitive study using the preferential D(3) agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT) alone or in combination with competitive nonpreferential or preferential D(2) and D(3) antagonists delivered intracerebroventricularly (i.c.v.) was undertaken in anesthetized rats. Urethane-anesthetized male rats were implanted into the cerebral ventricle with a cannula for i.c.v. injections, and recording electrodes were placed within the bulbospongiosus (BS) muscle to monitor BS muscle contractions, which were used as a marker for the expulsion phase of ejaculation. Following i.c.v. injection, 7-OH-DPAT induced ejaculation and rhythmic BS muscle contractions. Co-injected i.c.v. with 7-OH-DPAT, the nonselective D(2)/D(3) antagonist (raclopride), and the preferential D(3) antagonist (S(-)-N[n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyanonaphtalene-2-carboxamide; nafadotride) but not the preferential D(2) antagonist ((+/-)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole; L 741,626) inhibited the occurrence of ejaculation and BS muscle contractions. These results suggest that i.c.v. delivery of 7-OH-DPAT does represent a pertinent model to investigate the physio-pharmacology of ejaculation. It is inferred that targeting brain D(3) receptors may provide a therapeutic approach for treating ejaculatory disorders in humans.

Melanocortins have been reported to play a role in the control of both male and female sexual behavior. The present study examined the effects of melanotan-II (MT-II), a cyclic peptide analogue of alpha-melanocyte stimulating hormone on appetitive and consummatory aspects of female sexual behavior, including aspects of sexual proceptivity (solicitations, hops and darts, ear wiggling, pacing) and receptivity (lordosis). One group of ovariectomized Long-Evans rats (n=7) was primed subcutaneously with estradiol benzoate (EB) and progesterone (P) (10 microg and 500 microg respectively) and another group (n=7) with EB (10 microg) and oil (EB alone). Paced mating tests were performed with sexually experienced males in unilevel chambers, which were bisected by a Plexiglas divider containing three holes, through which only the female could pass. MT-II (1 and 3 mg/kg) or saline was injected intravenously 10 min before each 30-min paced mating test. Each female received the 3 treatments. In females primed with EB+P both doses of MT-II increased the number of hops and darts and ear wiggling significantly, but did not alter pacing or lordosis. With EB alone, no effect of MT-II was observed on any of the parameters measured. These results suggest that P can interact with MT-II to increase proceptive behaviors. Because hops and darts are essentially solicitations, made in close proximity to the male, that indicate a desire on the part of females to receive mounts and intromissions, these data suggest that activation of melanocortin receptors may represent a promising mode of action for the treatment of women with hypoactive sexual desire.

Objectives Increased urinary bladder detrusor smooth muscle phasic contractility has been suggested to be associated with idiopathic bladder overactivity (OAB). We examined the role of voltage-dependent l -type calcium channels, adenosine triphosphate-sensitive potassium (K ATP ) channels, and calcium-activated potassium (BK Ca and SK Ca ) channels in the regulation of human detrusor phasic contractile activity. Methods Isolated human bladder strip phasic contractions were measured and quantified as the mean area under the force-time curve, amplitude, and frequency of phasic contractions in 22 bladder samples. Results Human detrusor strips displayed myogenic phasic contractions in the presence of atropine (10 −6 M), phentolamine (10 −6 M), propranolol (10 −6 M), suramin (10 −5 M), and tetrodotoxin (10 −6 M). The l -type calcium channel inhibitor nifedipine (300 nM) abolished the contractile activity. Blockade of K ATP channels by glibenclamide (1 and 10 μM) did not alter myogenic contractions. In contrast, the K ATP channel opener pinacidil (10 μM) markedly inhibited phasic contractility. Iberiotoxin (100 nM) and apamin (100 nM), potent and selective inhibitors of BK Ca and SK Ca channels, respectively, significantly increased the area under the force-time curve and the amplitude of contractions. Conclusions Phasic contractions of human detrusor are dependent on calcium entry through l -type calcium channels. BK Ca and SK Ca channels play a key role in the modulation of human detrusor smooth muscle phasic contractility. Furthermore, these observations support the concept that increasing conductance through K ATP , BK Ca , and SK Ca channels may represent attractive pharmacologic targets for decreasing phasic contractions of detrusor smooth muscle in OAB.

Introduction Female rats display a repertoire of behaviors during a sexual encounter with a male, including sexually receptive (the lordosis response) and proceptive (darts and hops, and ear wigglings) behaviors. Aim We investigated the effects of subcutaneous injection of the 5‐HT 2A/2C receptor agonist (2,5‐dimethoxy‐4‐idophenyl)‐2‐aminopropane hydrochloride (DOI) on sexual behaviors of ovariectomized female rat hormonally supplemented with estradiol benzoate (10 µg) and progesterone (250 µg). Methods Both female and male sexual behaviors were observed for 10 minutes (pretest). Then females were injected with the treatment and after a 10‐minute delay replaced with the same male for a 30‐minute mating test (posttreatment period). Results DOI (0.5 and 1 mg/kg) significantly increased the number of darts and hops/mounts. In contrast, no significant differences in ear wigglings/mounts were observed. In addition, DOI failed to modify sexual receptivity. Conclusion These data suggest that 5‐HT 2A/2C receptors are important in the regulation of female proceptivity. Rossler A‐S, Bernabe J, Denys P, Alexandre L, and Giuliano F. Effect of the 5‐HT 2A/2C receptor agonist DOI on female rat sexual behavior.J Sex Med 2006;3:432–441.

The occurrence of ejaculation, which consists of 2 distinct phases (emission and expulsion), requires a tight coordination of peripheral autonomic and somatic nerves. However, some aspects of the mechanism of ejaculation are not clearly defined. To clarify this issue, we used the p-chloroamphetamine (PCA)-induced ejaculation model in anesthetized rats and investigated the effects of selective peripheral nerves lesions on seminal vesicle and bulbospongiosus (BS) muscle activities as representing physiological markers of emission and expulsion phases, respectively. In intact rats, ejaculation induced with PCA (intraperitoneal 5 mg/kg) correlated with coordinated increases in seminal vesicle pressure (SVP) and BS electromyographic activity. PCA-induced ejaculation was still observed in rats with bilateral lesion of hypogastric nerves (HNx), lumbar paravertebral sympathetic chain (LSCx), or dorsal nerves of the penis (DNPx). Conversely, bilateral section of pelvic nerves (PNx) or L6-S1 dorsal roots (DRx) abolished PCA-induced ejaculation. The amplitude of SVP increases induced by PCA was reduced in PNx, HNx, and LSCx rats, whereas it was unchanged in DRx and DNPx rats. The time interval between SVP increases and BS muscle contractions induced by PCA was comparable in the different neural lesion groups. In conclusion, PCA initiates both emission and expulsion independently from each other. In this model, afferents conveyed by the pelvic nerves appear to be unnecessary for occurrence of BS muscle contractions but are essential for a complete ejaculatory response.

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT(4) receptor antagonist, at inhibiting the 5-HT(4)-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM-100 microM) were constructed in the absence or presence of 1 or 100 nM of piboserod. The experiments were performed in the presence of methysergide (1 microM) and ondansetron (3 microM) to block 5HT(1)/5HT(2) and 5-HT(3) receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0+/-19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0+/-7.9 and 38.7+/-8.7%, respectively. A mean apparent antagonist dissociation constant value (K(B)) of 0.56+/-0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT(4) receptor might represent an attractive pharmacological target for the treatment of overactive bladder.

The outer interface of a tear film was studied with the aid of a model system able to investigate the interfacial phenomena derived from the spreading of an insoluble lipid multilayer onto a tear-like aqueous fluid. The interactions of such a layer with proteins dissolved in the aqueous phase beneath were also investigated. Emphasis was given to evaporation phenomena because the increased rate of tear evaporation in humans is often related to a number of ocular dysfunctions. The model tear was studied as a pendant drop that permitted a functional evaluation of the effect of lipids and proteins upon the evaporation of water from the tear film.

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Widely distributed throughout the body, cyclic nucleotide phosphodiesterases (PDEs) are functionally heterogeneous enzymes with potential roles in a number of physiological actions. Among these enzymes, PDE type 5 has received particular attention because of the widespread use of the PDE5 inhibitor sildenafil citrate as an oral therapy for erectile dysfunction. Within the corpus cavernosum of the penis, PDE5 catalyzes the enzymatic degradation (inactivation) of cyclic 3 ∀ ,5∀ -guanosine monophosphate, which is a second messenger and key mediator of vascular and trabecular erectile tissue smooth muscle relaxation. By amplifying the nitric oxide‐cyclic nucleotide signalling pathway, PDE5 inhibitors serve as ‘contingent agonists’ of the physiological response to sexual arousal. In experimental models, tadalafil increased the sensitivity of penile resistance arteries and erectile tissues to three stimuli of smooth muscle relaxation, namely electrical field stimulation, sodium nitroprusside, and acetylcholine. In randomized, double-blind, placebo-controlled trials, sildenafil and the investigational agents tadalafil and vardenafil significantly enhanced erectile function in the majority of patients and were well tolerated. (Eur Heart J Supplements 2002; 4 (Suppl H): H7‐H12)

Tadalafil, a potent, selective and reversible inhibitor of phosphodiesterase type 5 that is under review as an oral therapy for erectile dysfunction, has a time to maximum concentration of 2h and a half-life of 17·5 h. Systemic tadalafil exposure was not clinically significantly altered by age or diabetes. Food did not alter the rate and extent of absorption of tadalafil, and no restrictions regarding food or alcohol intake were imposed on patients in tadalafil clinical trials. Furthermore, the time of dosing had no significant effect on the systemic distribution of tadalafil. Integrated analyses of data from five phase III trials demonstrated that tadalafil at doses from 5m g to 20 mg significantly improved erectile function (vs placebo) by all efficacy measures. Tadalafil was safe and well tolerated in the phase III studies, with headache and dyspepsia being the most frequent adverse events. Additionally, in a separate study of patients with erectile dysfunction and diabetes, tadalafil 10 mg and 20 mg significantly improved all efficacy measures as compared with placebo. (Eur Heart J Supplements 2002; 4 (Suppl H): H24‐H31)

In the male rat, serotoninergic neurons of the ventrolateral medulla send direct projections onto spinal preganglionic neurons that innervate the penis. The role of the paraventricular nucleus of the hypothalamus in the control of penile erection is well recognized. Our aim was to demonstrate anatomical relation between paraventricular neurons and medullary serotoninergic neurons innervating the penis. In adult male rats, stereotaxic iontophoretic injections of Phaseolus vulgaris leuco-agglutinin were performed in the paraventricular nucleus. Neurons in the ventrolateral medulla were retrogradely labelled using transneuronal retrograde transport of pseudorabies virus injected in the corpus cavernosum. Sections of the ventro-lateral medulla were processed for double immunofluorescence to reveal both Phaseolus vulgaris leuco-agglutinin and pseudorabies virus using specific antibodies. Sections were also processed for the simultaneous detection of pseudorabies virus and serotonin. Pseudorabies virus-infected neurons in the ventrolateral medulla were present in the nucleus paragigantocellularis, reticular formation of the medulla, raphe pallidus and raphe magnus. In the nucleus paragigantocellularis, all pseudorabies virus-infected-neurons were immunoreactive for serotonin. Some of them received Phaseolus vulgaris leuco-agglutinin-labelled varicose fibres that ran along the soma of pseudorabies virus-infected neurons. Confocal microscopy suggested the presence of several close appositions between them, which were demonstrated using three-dimensional reconstruction of serial optical sections. Our results show that paraventricular neurons send direct projections in the nucleus paragigantocellularis onto neurons that innervate the penis. They suggest a possible role of the paraventricular nucleus in penile erection through the control of descending serotoninergic raphe-spinal neurons. The neurotransmitter used in this pathway remains to be determined.

Introduction Les lipomes sont des tumeurs adipocytaires frequentes en pediatrie. Generalement isoles et benins, ils peuvent par contre etre revelateurs de genodermatoses en cas de formes multiples (lipomatoses) et precoces. Nous rapportons 2 cas originaux de syndromes de Cowden (SC)/Bannayan-Riley-Ruvalcaba (SBRB) dont le diagnostic fut pose precocement devant une lipomatose. Observations Deux enfants âges de 3,5 ans consultaient pour des lipomes cutanes multiples du tronc d’apparition progressive. A l’examen, les 2 enfants avaient une macrocephalie significative a +2DS (deviation standard) sans autre signe associe en dehors d’un angiome plan du tronc chez un d’entre eux. La croissance staturoponderale et le developpement etaient normaux. Dans les antecedent, on notait pour le premier enfant une polydactylie bilaterale des mains operee et un torticolis congenital ; un frein prepucial court multi-opere et des otites seromuqueuses repetees a l’origine d’une diminution de l’acuite auditive chez le second. Les analyses genetiques ont mis en evidence chez les 2 enfants une mutation germinale et pathogene du gene PTEN, permettant de poser le diagnostic de SC/SBRB. Discussion Les lipomatoses sont des conditions rares chez le petit enfant et imposent la plus grande prudence. En effet, les lipomatoses familiales benignes surviennent generalement a l’âge adulte. Ainsi, en cas de lipomatose congenitale, il faut savoir evoquer une lipomatose encephalo-crânio-cutanee qui associe des lipomes du cuir chevelu, une alopecie et des manifestations oculaires et neurologiques ; en cas de lipomatose acquise de l’enfant, une genodermatose sous-jacente telle que le syndrome de Protee, le syndrome de Gardner ou les SC/SBRB. Le diagnostic est generalement oriente selon les antecedents familiaux et les signes cliniques dermatologiques ou extra-dermatologiques associes. Le SC et le SBRB, recemment unifies sous la meme terminologie de syndrome PTEN MATCHS, sont lies a des mutations du gene suppresseur de tumeur PTEN a l’origine d’un sur-risque de certains cancers solides. Ils sont caracterises par de nombreuses manifestations cutanees telles que trichilemmomes, papillomatose orale, keratose palmoplantaire ou lentiginose prepuciale. Dans nos observations, il n’y avait aucun signe cutane associe a la lipomatose au moment du diagnostic. C’est la co-existence de la macrocephalie qui nous a amene a rechercher une mutation germinale de PTEN. A notre connaissance, il s’agit des premiers cas rapportes de diagnostic de SC/SBRB etabli de maniere precoce en l’absence d’autres signes cutanes caracteristiques ( Fig. 1 ). Conclusion Devant un enfant avec une lipomatose, mesurer le perimetre crânien car l’association lipomatose–macrocephalie justifie la recherche de mutation du gene PTEN. De cette maniere, il est possible de diagnostiquer tres precocement des SC/SBRB et de mettre en place un suivi personnalise.

An exclusive central site of action for the proerectile effect of apomorphine, including not only the brain but also the spinal cord, is supported by extensive experimental data. Assuming that the mechanisms of action of apomorphine are similar in humans and animal models, its use for the treatment of erectile dysfunction (ED) validates the emerging idea that erectile response could be enhanced by acting directly within the central nervous system (CNS). It also emphasized the key role of the dopaminergic system in the control of erection. As exemplified with the clinical development of apomorphine, targeting the CNS does not rule out the occurrence of undesirable side effects. Because the rare event of syncope induced by apomorphine is not well understood, further research should be conducted to explore its possible mechanisms. In clinical practice, however, approved doses of apomorphine SL are well tolerated. It is noteworthy that no modification of sexual desire was observed with apomorphine. Indeed, drugs acting within the CNS may more likely interact with sexual desire than peripherally acting drugs, and care should be taken to assess this point in the future. Although our knowledge of the control of penile erection by the CNS is restricted, there are many potential sites for CNS-acting ED drugs. New centrally acting therapy for ED should concentrate on receptor targets more specific to erectile command. Clinical efficacy of new centrally-acting compounds will assess the well-founded purpose of this rationalization.

The aim of this review is to discuss the negative effects on sexual function of medications for lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS-BPH).An international non-systematic literature review was performed. It included randomized trials of seven drugs of interest and the summaries of the characteristics of these products. This work did not aim comparison between the drugs.Only maximal reported frequencies are presented in this abstract. With prolonged-release alfuzosin, they were 2.8% vs. 1.3% for erectile dysfunction, compared to placebo and 1% vs. 0% for ejaculatory dysfunction. With doxazosin, the incidence was 5.8% vs. 3.3% for erectile dysfunction, 3.6% vs. 1.9% for reduced libido and 0.4% vs. 1.4% for ejaculatory disorders. The incidence of ejaculatory disorders with tamsulosin, was 11% vs.1% with the placebo and with silodosin, it was 28.1% vs. 1.1%. With finasteride, at 12 months, the highest frequency was 9% vs. 5% for erectile dysfunction, 4.4% vs. 1.5% for ejaculatory disorders and 6.4% vs. 3.4% for reduced libido. At 24 months, for dutatsteride, frequencies were 7.3% vs. 4.0% for erectile dysfunction, 2.2% vs. 0.8% for ejaculatory disorders and 4.2% vs. 2.1% for reduced libido. For tadalafil, a phosphodiesterase-5 inhibitor, and tolerodine, an anticholinergic drug, no negative effect on ejaculation or libido has been reported. For plant extracts, no sexual adverse effects (AEs) were reported among the most common AEs.The medications for LUTS-BPH may alter erection, ejaculation or libido. A greater knowledge of the adverse effects of each of these drugs could guide physicians in the clinical management of men with BPH-LUTS.

A spinal generator for ejaculation (SGE) has been identified in the rat that orchestrates peripheral events leading to ejaculation. Despite physiological evidence of cerebral influences exerted on the SGE, brain-descending pathways to the SGE have not been fully delineated. A tracing study combining retrograde and anterograde approaches was undertaken in adult male rats in order to identify brain sites containing neurons that directly project onto SGE neurons. Fluorogold (FG) was microinjected as a retrograde tracer into the SGE area in the central medial gray of the third lumbar (L3) spinal segment. FG-positive neurons were found in various structures in medulla oblongata, pons, and forebrain. Among the brain structures already known as participating in the brain control of ejaculation and harboring retrogradelly-labeled neurons, the ventrolateral part of the gigantocellular nucleus and the raphe pallidus/magnus in medulla oblongata as well as the lateral hypothalamus were targeted with the anterograde tracer dextran amine (DA). Galanin and substance P receptor (NK1) were used as markers of SGE neurons. DA-positive fibers and varicosities originating in the targeted brain sites were found to make close appositions with neurons expressing galanin or NK1 receptors in central medial gray of L3-L4 spinal segments. This study provides new insights regarding the anatomical support for the brain control of ejaculation via direct influences onto the SGE.

We evaluated the relationship between NE expression and well-known prognostic factors and assessed whether tumor relapse after radical surgery correlates with the extent of NE differentiation. Radical prostatectomy specimens from 110 patients with clinically localized prostate cancer were assessed. Patients were followed up every three months for the first two years after surgery and six monthly for 5 additional years until failure, or for a mean of 48 months from the time of surgery for those who did not experience failure. The percentage of cells showing CgA immunoreactivity was evaluated using a visual quantitative method. Tumor staining was categorized as positive if greater than 10 percent and negative if less than 10 percent of tumor cells were stained, to ensure that only cases with significant positivity were included in the positive group. The median follow-up was 5.4 years (range 1.8 to 7.2). The median time to clinical recurrence was 7.5 years and the median time to biochemical recurrence was 2.8 years. Of 31 patients (28 percent) who experienced a PSA recurrence, 15 developed a clinical recurrence. The mean preoperative PSA level was 9 ng/ml (range 2.7 to 25). Most cases were well differentiated (Gleason score less than 7), intraprostatic (less than pT2) tumors. Immunoreactivity in >or= 10 percent of the cells was seen in 17.2 percent (n=19) of the tumor specimens. The preoperative PSA level, Gleason score, use of neoadjuvant or adjuvant therapy, lymphnode positivity were not statistically associated with NE expression. Only the primary pathologic stage appeared to be associated with CgA staining in the primary tumor (p=0.001). On the univariate analysis NE expression did not predict biochemical recurrence free survival, whereas it was associated with clinical recurrence. NE differentiation in clinically localized prostate cancer can be associated with failure after definitive surgical treatment, even if no conclusions can be drawn regarding its value as an independent prognostic factor.

Les mecanismes locaux de l’ejaculation comprenant l’emission et l’expulsion du sperme sont commandes non seulement par la composante sympathique de l’innervation autonome mais egalement par l’innervation parasympathique auxquelles s’associe l’innervation somatique de la musculature striee perineale empruntant le nerf pudendal. Les 2 phases de l’ejaculation sont mediees par des reflexes organises aux etages spinaux thoraco-lombaires et sacres dont l’organisation et la coordination demeurent mal connues. De nombreux neuromediateurs peripheriques participent a la survenue de l’ejaculation: les neuromediateurs classiques: noradrenaline et acetylcholine mais egalement des neuromediateurs non adrenergiques non cholinergiques c’est a dire peptidergiques, purinergiques et le monoxyde d’azote. Le role des afferences de l’ensemble tractus seminal dans le declenchement de l’ejaculation n’a pas ete explore a l’exception de l’innervation de la verge representee par le nerf dorsal de la verge. La participation de plusieurs centres supraspinaux a la modulation de l’activite des centres spinaux qui commandent l’ejaculation a ete mise en evidence: des noyaux hypothalamiques, l’amygdale, et le noyau paragigantocellulaire. Sur la base de ces donnees anatomiques et neurophysiologiques, la physiopathologie des perturbations de l’ejaculation est ensuite discutee. L’ejaculation prematuree pourrait etre liee a l’existence d’une hypersensibilite a la stimulation a la fois peripherique et centrale. Les autres troubles de l’ejaculation resultent d’alterations des mecanismes de commande centraux et/ou peripheriques.