EF Domain Research Articles

Reaction Time and Postural Sway Modify the Effect of Executive Function on Risk of Falls in Older People with Mild to Moderate Cognitive Impairment

To explore the relationship between cognitive performance and falls in older people with mild to moderate cognitive impairment (CI) by investigating the mediational effects of medical, medication, neuropsychological, and physiological factors. Secondary analysis, prospective cohort study. Community and low-level care. 177 older people (aged 82 ± 7 years) with mild to moderate CI (MMSE 11-23; ACE-R < 83). Global cognition and six neuropsychological domains (memory, language, visuospatial, processing speed, executive function [EF], and affect) were assessed. Participants also underwent sensorimotor and balance assessments. Falls were recorded prospectively for 12 months. The EF domain was most strongly associated with multiple falls (relative risk [RR]: 1.50, 95% CI: 1.18-1.91). Global cognition was not associated with falls (RR: 1.09, 95% CI: 0.92-1.30). Additional analyses showed that participants with poorer EF (median cutpoint) were more likely to be taking centrally acting medications and were less physically active. They also had significantly worse vision, reaction time, knee extension strength, balance (postural sway, controlled leaning balance), and higher physiological fall risk scores. Participants with poorer EF were 1.5 times (RR: 1.50, 95% CI: 1.03-2.18) more likely to have multiple falls. Mediational analyses demonstrated that reaction time and postural sway reduced the relative risk of EF on multiple falls by 31% (RR: 1.19, 95% CI: 0.81-1.74). Within this sample of older people with mild to moderate CI, poorer EF increased the risk of multiple falls. This relationship was mediated by reaction time and postural sway,suggesting cognitively impaired older people with poorer EF may benefit from fall prevention programs targeting these mediating factors.

A Comparison of Baseline Erectile Function after Ondemand 20 Mg Tadalafil vs. Daily 5 mg Tadalafil in Men with Erectile Dysfunction and Diabetes: A Prospective, Observational 2-Year Study

Objective: We studied whether long-term use of 5 mg tadalafil once daily improved baseline erectile function or prevented erectile dysfunction (ED) in men with diabetes. Design and Method: Men with ED and diabetes were assigned to 20 mg tadalafil on-demand or 5 mg tadalafil once daily. When men completed the questionnaire after 2 years of treatment, they also stopped the medication for 4 weeks to check baseline erectile function. The primary efficacy variable was the IIEF-EF score. Secondary variables included a change in the scores IIEF Q3 and Q4 from baseline, changes in all domain scores on the IIEF from baseline, SEP2 and SEP3, and GAQ. Rigiscan® measurements of nocturnal penile tumescence and rigidity (NPTR) were also carried out after the 2year treatment. Results: The study enrolled 118 men. After 2 years, daily treatment group had a greater change in IIEF-EF score from baseline (7.3 vs. 2.4, P &lt; 0.0001). The changes in IIEF from baseline on Q3 (1.4 vs. 0.4, P &lt; 0.0001) and Q4 (1.4 vs. 0.3, P &lt; 0.0001) were higher in the daily group. Differences between daily and on-demand groups were significant for SEP2 (53.8% vs. 32.3%) and SEP3 (56.6% vs. 15.4%). Normal EF domain scores at the end of study were achieved by 20.7% in daily groups. Normal NPTR at tend of study was achieved by 13.2% only in the daily group. Conclusions: Long-term use of 5 mg tadalafil once daily was more beneficial for improving baseline erectile function or preventing ED than the on-demand pattern in men with ED and diabetes.

Effect of site-directed mutagenesis at the GGEEF domain of the biofilm forming GGEEF protein from Vibrio cholerae.

Vibrio cholerae, the cause of seven noted pandemics, leads a dual lifecycle—one in the human host in its virulent form, and the other as a sessile, non-virulent bacterium in aquatic bodies in surface biofilms. Surface biofilms have been attributed to be associated with a ubiquitous protein domain present in all branches of bacteria, known as the GGD(/E)EF domain. While the diguanlyate cyclase activities of these proteins are universally established, the role of these proteins as diguanlyate-specific phosphodiesterases in conjunction with a EAL domain has also been reported. The VC0395_0300 protein from V. cholerae which shows biofilm forming abilities also acts as a phosphodiesterase. Interestingly, this GGD(/E)EF protein contains a EAL site in the reverse orientation. We attempted to mutate the GGEEF signature along the sequence by site-directed mutagenesis. The resultant mutants (Sebox5–7) did not show much difference in phosphodiesterase activity in comparison with the wild type protein (Sebox3), indicating the independence of the phosphodiesterase activity of the protein from the GGD(/E)EF domain. However, the ability of the mutants to form surface biofilm was significantly lesser in the case of mutations in the three central positions of the signature domain.

A Novel Alpha Specrtin Mutation Causing Severe Innefective Erythropoiesis

A 3 months old (corrected age 1 month) ex–premature girl, born at 32/40 weeks by elective caesarean section was referred for investigation of anemia and liver failure, diagnosed antenatally. Her parents were first cousins. Their first daughter died within 24 hours from birth with anemia. Their second daughter was healthy.At birth, blood analysis showed Hb 4g/dl, hepatitis with conjugated hyperbilirunemia (ALT 138, AST 1603, ALP 690 and bilirubin 324). Blood film (BF) confirmed a low reticulocyte count (RETC) and nucleated red blood cells (NRBC). There was no fragmentation and the Coomb’s test was negative. An ultrasound scan showed smooth hepatomegaly. Upon transfer to us, she continued to have conjugated hyperbilirubinemia and low RETC. [Display omitted] There were some immature lymphoid and monocytoid cells but peripheral immunophenotyping (IP) was normal. Parvovirus PCR was negative and there was no haematinic deficiency (Vitamin B12, folate, methylmalonic acid, homocysteine, transcobalamin). Sequencing of the G6PD and pyruvate kinase deficiency genes was normal. EMA dye binding, hemoglobin electrophoresis and genotyping were normal. Causes of failure to thrive and conjugated hyperbilirunaemia (screen for inborn errors of metabolism, α-1 Antitrypsin deficiency, TORCH infection, cystic fibrosis) were excluded.Liver biopsy showed inflammation and extramedullary haemopoiesis. [Display omitted] IP excluded a clonal lymphocytic population and excess of blasts. Electron microscopy did not suggest congenital dyserythropoietic anemia (CDAs). Next generation sequencing showed no causative mutations for Diamond Blackfan anemia, Sideroblastic anemia, Dyskeratosis congenita, CDAs, Shwachman-Diamond and Pearson syndromes.She was started on regular blood transfusions to keep her Hb>10g/dl and did not respond to high-dose B12 and folinic acid replacement. The LFTS normalized within 2 months. She was discharged home after 6 months in hospital. She still has splenomegaly, low RETC, is transfusion dependent, with developmental delay and growing at <0.4 centimeWhole exome sequencing (WES) was performed on the girl and her parents, and showed that she was homozygous for a severe, novel mutation in the SPTA-1 gene, coding for alpha spectrin, with no other candidate mutations found.DiscussionAssuming autosomal recessive inheritance, WES identified 54 novel candidate mutations which predicted to be severe in the homozygous state. Of them, only one was expressed in red cells and likely to explain the phenotype. This mutation on the SPTA1 gene, not previously described in humans (exon 5, aa 2378), introduces a premature stop codon in the sequence encoding for the carboxy (C) terminal of the EF domain of á spectrin. This results in the loss of 41 amino acids from the C terminal.The known mutations on the SPTA1 gene can cause hereditary elliptocytosis (HE), hereditary spherocytosis (HS) and also hereditary pyropoikilocytosis (HPP). Most of these are missense mutations in exon 2 of the SPTA gene, and impair the formation of the spectrin á2â2 heterotetramers. In HPP an additional mutation is thought to be necessary, resulting in partial spectrin deficiency (Swierczek et al 2013). Mutations have not previously been described in the EF-domain of alpha spectrin in humans.However, Korsgren et al 2010, demonstrated that the sphIJ/sphIJ mouse with severe HS makes a mutant spectrin that lacks the last 13 amino acids of the EF domain. According to their proposed protein model, based on α-ankyrin, the EF domain amplifies the function of the α-spectrin actin binding domain in forming the spectrin-actin-4.1R complex. The loss of the 13 EF domain amino acids does not affect heterodimer assembly, but reduces F-actin binding. The mutation we identified causes deletion of the last 45 EF domain amino acids, resulting in the very severe phenotype in this family. We suggest that the red cells are too fragile to be released from the marrow, resulting in the phenotype of ineffective erythropoiesis (low reticulocytes) rather than haemolytic anemia typically associated with alpha spectrin mutations. We are currently undertaking proteomic studies to look for the presence of the truncated alpha spectrin protein in red cell membranes. DisclosuresNo relevant conflicts of interest to declare.

Testosterone Replacement Therapy with Long‒Acting Testosterone Undecanoate Improves Sexual Function and Quality‒of‒Life Parameters vs. Placebo in a Population of Men with Type 2 Diabetes

IntroductionSexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. AimThis study aimed to determine the effect of testosterone replacement with long‒acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open‒label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. MethodsThe male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double‒blind placebo‒controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52‒week open‒label follow on. Main Outcome MeasuresThe primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self‒reported quality of life. ResultsTestosterone replacement therapy with long‒acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double‒blind phase but a nine‒point improvement in EF domain during 52‒week open‒label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open‒label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. ConclusionTU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52‒week open‒label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3–6 months suggested in current guidelines.

Validation of the functional and social performance – DSF-84 checklist: preliminary study

Purpose: To develop, implement and validate an instrument for assessing the functional and social performance of young male adults with lower limb amputees based on the international classification of functionality, incapacity, and health. Methods: Developed the instrument, the items were grouped into domains (organic aspects – OA, daily activities – DA, performance components – PC, social participation – SP and environmental factors – EF) for statistical analysis. The implementation of the instrument was filmed for validation. Four assessors watched the films on two occasions and gave scores. Intra-class correlation was used to evaluate intra- and inter-rater reproducibility and to the internal consistency was calculated by Cronbach’s alpha and the criterion validity was assessed by Student’s t-test and the Mann–Whitney U-test. Results: The results showed good reliability in the scores for OA, DA, PC and SP domains and a reasonable reliability for the EF domain. The differences between assessors performed by the analysis of variance were not significant. The reliability intra-rater, performed through the test–retest method, showed in all domains high levels of intra-rater correspondence. Conclusions: The results show the validity and reliability of DSF-84 to young male adults with amputation of the lower limb, being useful for this population.Implications for RehabilitationIn this study have been developed, implemented, and validated an instrument (DSF-84) for assessing the functional and social performance of young male adults with lower limb amputees based on the ICF.The results show the validity and reliability of DSF-84 to young male adults with amputation of the lower limb, being useful for this population.

Crystal structure of a catalytically active GG(D/E)EF diguanylate cyclase domain from Marinobacter aquaeolei with bound c-di-GMP product

Recent studies of signal transduction in bacteria have revealed a unique second messenger, bis-(3'-5')-cyclic dimeric GMP (c-di-GMP), which regulates transitions between motile states and sessile states, such as biofilms. C-di-GMP is synthesized from two GTP molecules by diguanylate cyclases (DGC). The catalytic activity of DGCs depends on a conserved GG(D/E)EF domain, usually part of a larger multi-domain protein organization. The domains other than the GG(D/E)EF domain often control DGC activation. This paper presents the 1.83 Å crystal structure of an isolated catalytically competent GG(D/E)EF domain from the A1U3W3_MARAV protein from Marinobacter aquaeolei. Co-crystallization with GTP resulted in enzymatic synthesis of c-di-GMP. Comparison with previously solved DGC structures shows a similar orientation of c-di-GMP bound to an allosteric regulatory site mediating feedback inhibition of the enzyme. Biosynthesis of c-di-GMP in the crystallization reaction establishes that the enzymatic activity of this DGC domain does not require interaction with regulatory domains.

1481 A RANDOMIZED, PLACEBO CONTROLLED, DOUBLE BLIND, MULTICENTER THERAPEUTIC EXPLORATORY CLINICAL STUDY FOR THE EVALUATION OF THE EFFICACY AND SAFETY OF AVANAFIL IN THE PATIENTS WITH ERECTILE DYSFUNCTION

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Medical and Non-Surgical Therapy1 Apr 20121481 A RANDOMIZED, PLACEBO CONTROLLED, DOUBLE BLIND, MULTICENTER THERAPEUTIC EXPLORATORY CLINICAL STUDY FOR THE EVALUATION OF THE EFFICACY AND SAFETY OF AVANAFIL IN THE PATIENTS WITH ERECTILE DYSFUNCTION Hyun Jun Park, Nam Cheol Park, Se Woong Kim, Je Jong Kim, Sung Won Lee, Jae Weung Paick, Tae Young Ahn, Kwangsung Park, and Jong Kwan Park Hyun Jun ParkHyun Jun Park Busan, Korea, Republic of More articles by this author , Nam Cheol ParkNam Cheol Park Busan, Korea, Republic of More articles by this author , Se Woong KimSe Woong Kim Seoul, Korea, Republic of More articles by this author , Je Jong KimJe Jong Kim Seoul, Korea, Republic of More articles by this author , Sung Won LeeSung Won Lee Seoul, Korea, Republic of More articles by this author , Jae Weung PaickJae Weung Paick Seoul, Korea, Republic of More articles by this author , Tae Young AhnTae Young Ahn Seoul, Korea, Republic of More articles by this author , Kwangsung ParkKwangsung Park Gwangju, Korea, Republic of More articles by this author , and Jong Kwan ParkJong Kwan Park Jeonju, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2003AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Avanafil is a newly developed selective PDE5 inhibitor for the treatment of ED. The aim of this exploratory clinical study is to evaluate the efficacy and safety of avanafil in the treatment of ED in Korean men. METHODS 158 patients with ED were participated in a placebo controlled, double blind, multicenter trial and randomized to receive placebo, 50mg, 100mg or 200mg of avanafil for 8 weeks. The primary efficacy variable was the change of IIEF-EF domain score. The secondary efficacy measures included the response to SEP Q2-3, the change of score in IIEF Q3-4, GEAQ and normal erectile function rate (IIEF EF domain score¡Ã26). RESULTS The change in EF domain scores of each dosage was statistically significant. In multiple comparisons, all dosage groups except for avanafil 50mg showed significant difference compared to placebo. In SEP Q2 and Q3, the change in success rate of each dosage group was statistically significant. However, avanafil 50mg did not show a significant difference compared to placebo. The change in score of IIEF Q3and Q4 of each dosage group was statistically significant. In multiple comparisons, all dosage groups of avanafil showed significant difference compared to placebo in IIEF Q3. However, only avanafil 200mg showed significant difference compared to placebo in IIEF Q4. All dosage groups except for avanafil 50mg showed significant difference compared to placebo in GEAQ. Ratio of normal erectile function of each dosage was significant, and avanafil 200mg showed significant difference compared to placebo. Most treatment-emergent adverse event was of mild intensity, recovering spontaneously. CONCLUSIONS Avanafil at 100mg and 200mg was an effective and well tolerated in the treatment for the ED in Korea men. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e600 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hyun Jun Park Busan, Korea, Republic of More articles by this author Nam Cheol Park Busan, Korea, Republic of More articles by this author Se Woong Kim Seoul, Korea, Republic of More articles by this author Je Jong Kim Seoul, Korea, Republic of More articles by this author Sung Won Lee Seoul, Korea, Republic of More articles by this author Jae Weung Paick Seoul, Korea, Republic of More articles by this author Tae Young Ahn Seoul, Korea, Republic of More articles by this author Kwangsung Park Gwangju, Korea, Republic of More articles by this author Jong Kwan Park Jeonju, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Erectile Dysfunction after Plaque Incision and Grafting: Short‐term Assessment of Incidence and Predictors

Plaque incision and grafting (PIG) surgery for Peyronie's disease (PD) is a recognized management strategy. One of the recognized complications of PIG surgery is the development of postoperative erectile dysfunction (ED). To determine the incidence of ED after PIG surgery and attempt to define predictors of ED development. All patients underwent preoperative cavernosometry. Grafting was performed with either cadaveric pericardium (Tutoplast) or intestinal submucosa (Surgisis). Prior to 2006, the procedure used an H-type incision, whereas after this date, the Egydio approach has been used. Men undergoing PIG completed preoperative and 6-month postoperative International Index of Erectile Function (IIEF) questionnaires. 56 patients were analyzed. Mean patient and partner ages were 57 ± 22 and 54 ± 18 years, respectively. Mean duration of PD at the time of PIG was 22 ± 9 months. Seventy-five percent had curvature alone, 11% had hourglass/indentation deformity, and the remainder had combined curvature/indentation. Mean preoperative curvature was 52 ± 23°. Fifty-two had grafting with Tutoplast, while four had grafting with Surgisis. All men at baseline were capable of generating a penetration rigidity erection. Preoperatively, 50% of men had cavernosal insufficiency and 21% had venous leak (baseline and postoperative erectile function [EF] domain scores were 23 ± 4 and 17 ± 9, respectively [P < 0.01]). Forty-six percent of men experienced a ≥6-point decrease in EF domain score after PIG. The predictors of a ≥6-point reduction in IIEF-EF domain score on multivariable analysis were degree of preoperative curvature, type of plaque incision, patient age, and baseline venous leak. Conclusions. Almost one-half of men had significant reduction in their erectile rigidity after PIG. Reduction was predicted by larger baseline curvature, the Egydio plaque incision technique, older patient age, and the presence of venous leak at baseline. Based on these data, we discourage older men, those with venous leak, and those with profound curvature from considering PIG surgery.

Diabetes mellitus and erectile dysfunction in Japanese men

Background Diabetes mellitus (DM) is frequently associated with difficult-to-treat erectile dysfunction (ED). We performed two investigations about treatment for DM associated with ED in Japanese. The first investigation was to compare efficacy between Vardenafil 20 mg and 10 mg, whereas the second investigation was to observe whether Vardenafil allows successful intercourse initiated rapidly after dosing in Japanese patients with DM and ED. Methods In the first investigation, 954 patients were recruited and randomly assigned into three groups, i.e., placebo group, valdenafil 10mg group and valdenafil 20mg group. Patients were instructed to take a single dose 1 h prior to sexual intercourse and not to take more than one dose per day with at least 24 h elapsing between doses. In the second investigation, a total of 778 patients were randomized to treatment, and 778 were included in the intent-to-treat analysis of efficacy. Patients received vardenafil 10 mg, 20 mg, or placebo, and were instructed to start sexual activity an hour after dosing. Results First investigation revealed that Vardenafil 20 mg demonstrated superior efficacy to that of 10mg. The difference on efficacy between 10mg and 20mg was more evident in severe ED patients (base-line IIEF EF domain score <11). Second investigation revealed that Vardenafil allowed for successful completion of sexual activity irrespective of the time when men chose to initiate insertion after drug dosing, with treatment differences over placebo noted from as early as 15 min. Conclusions Vardenafil 20mg demonstrated superior efficacy compared to 10mg, suggesting incremental clinical benefit in using the higher dose in this difficult-to-treat population in Japanese men with DM and ED. In addition, early onset of activity with vardenafil is also achievable in Japanese ED patients with DM.

Direct Activation of Human Phospholipase C by Its Well Known Inhibitor U73122

Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCβ3 (hPLCβ3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCβ3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6±5 μm. Activation of hPLCβ3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 μm) also activated hPLCγ1 (>10-fold) and hPLCβ2 (∼2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes.

1637 SEMINAL VESICLE PRESERVATION DOES NOT IMPROVE FUNCTIONAL OUTCOME OF PATIENTS TREATED WITH BILATERAL NERVE SPARING RADICAL RETROPUBIC PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 20111637 SEMINAL VESICLE PRESERVATION DOES NOT IMPROVE FUNCTIONAL OUTCOME OF PATIENTS TREATED WITH BILATERAL NERVE SPARING RADICAL RETROPUBIC PROSTATECTOMY Andrea Gallina, Alberto Briganti, Nazareno Suardi, Umberto capitanio, Di Trapani Dario, Rayan Matloob, Marco Bianchi, Manuela Tutolo, Valerio Di Girolamo, Luigi Barbieri, Patrizio Rigatti, and Francesco Montorsi Andrea GallinaAndrea Gallina Milan, Italy More articles by this author , Alberto BrigantiAlberto Briganti Milan, Italy More articles by this author , Nazareno SuardiNazareno Suardi Milan, Italy More articles by this author , Umberto capitanioUmberto capitanio Milan, Italy More articles by this author , Di Trapani DarioDi Trapani Dario Milan, Italy More articles by this author , Rayan MatloobRayan Matloob Milan, Italy More articles by this author , Marco BianchiMarco Bianchi Milan, Italy More articles by this author , Manuela TutoloManuela Tutolo Milan, Italy More articles by this author , Valerio Di GirolamoValerio Di Girolamo Milan, Italy More articles by this author , Luigi BarbieriLuigi Barbieri Milan, Italy More articles by this author , Patrizio RigattiPatrizio Rigatti Milan, Italy More articles by this author , and Francesco MontorsiFrancesco Montorsi Milan, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1746AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Controversy exists on the role of seminal vesicle (SV) preservation on functional outcomes of patients treated with nerve sparing radical prostatectomy (NSRP). We tested the association of SV preservation on functional outcomes in a large series of patients treated by a single high volume surgeon at a tertiary referral center. METHODS The study included 348 patients treated by a single high volume surgeon with retropubic bilateral NSRP (BNSRP) between 2002 and 2009 at a tertiary referral center. Patients were divided into two groups according to the type of surgical approach: preservation (Group 1; n=247) vs no preservation of the tip of SV (Group 2 ; n=101) during BNSRP. All patients were assessed post-operatively every 3 months and were asked to complete the International Index of Erectile Function (IIEF) during each visit. Post-operative EF recovery was defined as an EF domain score of the IIEF (IIEF-EF) ≥22, while UC recovery was defined as the absence of any protection device (no pads). Kaplan-Meier curves assessed the time to EF and UC recovery in the overall patient population as well as in each group. The association between SV preservation and functional outcomes was also assessed in univariable and multivariable Cox regression models after adjusting for age and PSA at surgery, biopsy Gleason score, clinical stage and pre-operative EF. RESULTS Mean age at surgery was 63.2 yrs (median 63.1; range 42–72 yrs). Pre-operative IIEF-EF domain score assessment showed severe, moderate, mild to moderate, mild and no ED in 21.6, 5.6,5.6,19.5 and 46.7% of patients, respectively. Overall, 177/348 (50.9%) reached a IIEF-EF domain score ≥22 while 305/348 (87.6%) recovered complete UC after a mean follow-up of 21 months (median 19; range: 2–61). At Kaplan-Meier analyses, no difference in terms of EF as well as UC recovery between the two groups of patients was found (1 and 2-year EF recovery rates in group 1 vs group 2: 42 and 54 vs 33 and 54%, respectively; p=0.5; 1 and 2-year UC recovery rates in group 1 vs group 2: 78 and 85 vs 72 and 88%, respectively; p=0.6). These results were confirmed at multivariable analysis where the preservation of the tip of the SV did not achieve an independent predictor status for either EF or UC recovery after adjusting for all the mentioned predictors (all p≥0.4). CONCLUSIONS We demonstrated that SV preservation is not associated with better functional outcomes of selected patients treated by a single high volume surgeon with BNSRP. These retrospective results need to be confirmed in larger prospective, randomized trials. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e657 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Gallina Milan, Italy More articles by this author Alberto Briganti Milan, Italy More articles by this author Nazareno Suardi Milan, Italy More articles by this author Umberto capitanio Milan, Italy More articles by this author Di Trapani Dario Milan, Italy More articles by this author Rayan Matloob Milan, Italy More articles by this author Marco Bianchi Milan, Italy More articles by this author Manuela Tutolo Milan, Italy More articles by this author Valerio Di Girolamo Milan, Italy More articles by this author Luigi Barbieri Milan, Italy More articles by this author Patrizio Rigatti Milan, Italy More articles by this author Francesco Montorsi Milan, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The carboxyterminal EF domain of erythroid α-spectrin is necessary for optimal spectrin-actin binding

AbstractSpectrin and protein 4.1R crosslink F-actin, forming the membrane skeleton. Actin and 4.1R bind to one end of β-spectrin. The adjacent end of α-spectrin, called the EF domain, is calmodulin-like, with calcium-dependent and calcium-independent EF hands. The severely anemic sph1J/sph1J mouse has very fragile red cells and lacks the last 13 amino acids in the EF domain, implying that the domain is critical for skeletal integrity. To test this, we constructed a minispectrin heterodimer from the actin-binding domain, the EF domain, and 4 adjacent spectrin repeats in each chain. The minispectrin bound to F-actin in the presence of native human protein 4.1R. Formation of the spectrin-actin-4.1R complex was markedly attenuated when the minispectrin contained the shortened sph1J α-spectrin. The α-spectrin deletion did not interfere with spectrin heterodimer assembly or 4.1R binding but abolished the binary interaction between spectrin and F-actin. The data show that the α-spectrin EF domain greatly amplifies the function of the β-spectrin actin-binding domain (ABD) in forming the spectrin-actin-4.1R complex. A model, based on the structure of α-actinin, suggests that the EF domain modulates the function of the ABD and that the C-terminal EF hands (EF34) may bind to the linker that connects the ABD to the first spectrin repeat.

Durability of Response Following Cessation of Tadalafil Taken Once Daily as Treatment for Erectile Dysfunction

Research has focused on improvement of erectile function during treatment with phosphodiesterase type 5 (PDE5) inhibitors, but less is known about what occurs after treatment cessation. The aim of this retrospective analysis was to examine durability of response, defined as sustainability of erectogenic benefits following treatment cessation, in men with erectile dysfunction (ED) following long-term treatment with daily tadalafil. The subjects (N=160) had participated in a 12-week double-blind trial followed by a one-year, open-label extension of tadalafil 5mg once daily. The extension was followed by a 4-week, treatment-free follow-up period. A total of 158 subjects completed International Index of Erectile Function-Erectile Function (IIEF-EF) domain score and were included in this analysis. The primary measures for this analysis were changes in ED severity category as captured by the IIEF-EF domain score. At the end of the 1-year open-label treatment period, a majority (86.1%, n=136) of subjects had either improved by at least one ED severity category (e.g., Severe to Moderate) (n=128), or maintained Normal erectile function (EF domain score ≥26) (n=8), compared to baseline. Following the 4-week, treatment-free period, 63 of those subjects (46.3% of the 136 subjects) had continued improvement of at least one ED severity category (n=61) or maintained scores in the Normal category (n=2) compared with baseline. Subjects who showed a sustained benefit of treatment were considered to have demonstrated a "durable response." Seventy-three subjects (53.7%) did not have a durable response following treatment cessation. A few patient characteristics were associated with durability of response. Of those men who demonstrated improved erectile function while taking tadalafil 5mg once daily for 1 year, 46.3% continued to show improvement compared with baseline following a 4-week treatment free period. Durability of response should be a focus of future research.

Correlation between Lower Urinary Tract Symptoms (LUTS) and Sexual Function in Benign Prostatic Hyperplasia: Impact of Treatment of LUTS on Sexual Function

Although many reports have shown a relationship between lower urinary tract symptoms (LUTS) and sexual function (SF), it is not known which symptom(s) among LUTS should be treated to improve SF. Thus, the aim of this study was to investigate correlations between LUTS and SF and to determine which symptom(s) should be improved to increase SF. The correlation between the severity of LUTS and erectile dysfunction (ED) was investigated, and changes in LUTS were compared and analyzed to determine which symptom(s) should be eliminated to improve SF. The correlation between LUTS and SF was investigated in 365 men (62.04 +/- 8.26) with benign prostatic hyperplasia. To measure the severity of the LUTS and ED, the International Prostate Symptom Score (IPSS), frequency of nocturia, uroflowmetry, residual urine, transrectal ultrasonography, and the International Index of Erectile Function (IIEF)-5 were performed at the first visit. After 3 months of treatment with alpha-blockers (n = 304), they were assessed again to evaluate the effectiveness of the treatment. All parameters of LUTS (IPSS, age, residual urine, uroflow rate, and nocturia) except prostate volume correlated significantly with the total and each domain of IIEF-5 (P < 0.01). After 3 months, the changed scores in the IPSS-VD domain and IPSS-quality of life (QoL) correlated significantly with the improvement in total IIEF-5 and the domains of IIEF-5 (P < 0.05). The changed rates of the mean uroflow correlated significantly with the improvement in total IIEF-5 and the EF domain (P < 0.05). Among the LUTS parameters, improvement in the IPSS-VD domain, IPSS-QoL, and mean uroflow significantly correlated with an increased score in the IIEF-5 EF domain. Thus, it is expected that the improvement of voiding symptoms and uroflow will be associated with the improvement in erectile function.

Safety and efficacy of sildenafil citrate in treating erectile dysfunction in patients with combat‐related post‐traumatic stress disorder: a double‐blind, randomized and placebo‐controlled study

To evaluate the safety and efficacy of sildenafil citrate for treating erectile dysfunction (ED) in patients with combat-related post-traumatic stress disorder (PTSD). In all, 266 combat-exposed war veterans with ED (aged 37-59 years) were recruited. They met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for PTSD according to the Structured Clinical Interview for Patients, Investigator Version. The patients were also evaluated with the Clinician-Administered PTSD Scale, both to establish the diagnosis of PTSD and to measure symptom severity. Only patients with psychogenic ED were included in the study. Patients with comorbid conditions (diabetes mellitus, hypercholesterolaemia, hypertension, Peyronie's disease) and smokers of more than five cigarettes daily were excluded. The patients were randomly divided into a group of 133 who received 100 mg of on-demand sildenafil 0.75-2 h before sexual stimulation, and 133 who received placebo. Patients were asked to use > or =16 doses or attempts at home. The efficacy of the treatments was assessed every four attempts during treatment, and at the end of the study, using responses to the 15-question International Index of Erectile Function (IIEF), Sexual Encounter Profile diary questions 2 and 3, Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, patients' event logs of sexual activity, and a Global Assessment Question about erections. Sildenafil did not produce significantly and substantially greater improvement than placebo in each of the primary and secondary outcome measures (P = 0.08). A normal EF domain score (> or =26) at endpoint was reported by 13 (9.8%), and 11 (8.3%) of patients on the sildenafil and placebo regimens, respectively (P = 0.09). Patients treated with sildenafil had no statistically significantly greater improvement in the five sexual function domains of the IIEF questionnaire than those treated with placebo (P = 0.08). The incidences of treatment-emergent adverse events were significantly greater in the sildenafil arm than in the placebo group (P = 0.01). Sildenafil is no better than placebo in treating PTSD-emergent ED. Further randomized clinical trials are warranted in combat veterans and other populations with PTSD to better elucidate the role of phosphodiesterase type 5 inhibitors in treating PTSD-emergent ED.

Vasculogenic Erectile Dysfunction Is a Predictor of Abnormal Stress Echocardiography

Erectile dysfunction (ED) and atherosclerotic vascular disease have the same risk factors; furthermore, endothelial dysfunction has been shown to be a common link between these conditions. A high prevalence of silent coronary artery disease (CAD) in patients with ED has been observed. The aims of this article were to define the prevalence and identify predictors of occult obstructive CAD in patients with documented vasculogenic ED. Duplex Doppler penile ultrasonography (DUS); exercise stress echocardiography; IIEF; CAD risk factors. Methods. Patients presenting with ED who had penile vascular insufficiency documented by DUS and who had no history of diabetes or symptoms of CAD were prospectively enrolled for noninvasive cardiac stress testing using exercise stress echocardiography. Forty-nine men (mean age 517 years) with an average duration of ED of 2.52 years were evaluated. Penile arterial insufficiency was present in 94%, and venous leak in 20% of patients. Comorbidities included hypertension (51%), hyperlipidemia (41%), and smoking (35%). All patients had at least one vascular risk factor, with 40% having two, 15% three, and 15% four risk factors. Ten patients (20%) had abnormal cardiac stress test. On univariate analysis, age, IIEF-EF domain score, cavernosal artery insufficiency, presence of venous leak, and history of a first-degree relative with CAD were significant predictors. On multivariate analysis, cavernosal artery insufficiency, venous leak, and family history of CAD continued to be predictors of an abnormal stress test. A significant proportion of men with vasculogenic ED have abnormal cardiac stress test. The greatest chance for abnormal cardiac stress test was observed in those with corporo-venocclusive dysfunction or family history of CAD. In some men presenting with ED, even without a CAD history, performing penile DUS or cardiology referral for stress testing should be considered.

ORIGINAL RESEARCH—SURGERY: Anatomical Radical Retropubic Prostatectomy in Patients with a Preexisting Three-Piece Inflatable Prosthesis: A Series of Case Reports

Only few reports addressed the outcome of patients submitted to anatomical radical retropubic prostatectomy (RRP) with an indwelling inflatable penile prosthesis (IPP). To assess the feasibility and safety of RRP in patients with clinically localized prostate cancer and a previously implanted with an IPP. We evaluated the surgical parameters and the follow-up functional results in this particular patient population. Four patients previously submitted to IPP implant for severe erectile dysfunction underwent RRP for organ-confined prostate cancer. Patients' charts were carefully reviewed to investigate pre- and perioperative details. Patients were evaluated by the International Index of Erectile Function (IIEF) preoperatively and at 6 months postoperatively. Patients were then contacted to assess long-term functional and oncological outcome. The outcome of the procedures was comparable to a normal population in terms of operating time, estimated blood loss, hospitalization time, and pathological outcome. No injury to the preexisting penile implant was reported. Continence was obtained in 3 (75%) patients at catheter removal, and in 1 (25%) patient at the 1-month follow-up. No major intra- and postoperative complications were reported. All patients were able to use their prosthesis after RRP. No statistical difference in pre- and post-RRP EF domain scores was found. The presence of an IPP in patients with prostate cancer is not a contraindication to perform an anatomical RRP. Surgery can be performed safely without injuring the implant and the clinical outcome in these patients is satisfactory. Postoperative implant use is not affected by RRP.

Efficacy, tolerability and satisfaction with sildenafil citrate 100‐mg titration compared with continued 50‐mg dose treatment in men with erectile dysfunction

To evaluate the efficacy, tolerability, and treatment satisfaction after initiating treatment with sildenafil 50 mg and later titrating to 100 mg, compared with continuing treatment with sildenafil 50 mg, in men with erectile dysfunction (ED). A multicentre, parallel-group trial was conducted in two 4-week periods. In period 1, patients received 50-mg doses of sildenafil single-blinded for 4 weeks. In period 2, patients were randomized to double-blind, placebo-controlled treatment with sildenafil 50 mg or sildenafil 100 mg for 4 weeks. All patients were aged >or=18 years with a documented clinical diagnosis of ED (score of <or=25 on the International Index of Erectile Function, IIEF, Erectile Function, EF, domain), and met the prescribing criteria for sildenafil 50 mg and 100 mg. Of 492 enrolled patients (mean age 53 years, SD 11), 476 (97%) completed period 1 and 473 (96%) completed period 2. Patients receiving sildenafil 50 mg in period 1 had an increase in the mean (SD) baseline EF domain score from 12.8 (5.2) to 22.5 (6.6) (P < 0.001), and improved scores on the Quality of Erection Questionnaire (QEQ) and Sexual Experience Questionnaire (SEX-Q). The IIEF EF domain scores were similar in the two groups at baseline and randomization. Patients titrated to the 100-mg dose (237 men) showed a significantly greater improvement than those who continued on the 50-mg dose (240; P < 0.001). There was a significant increase in QEQ and SEX-Q scores in patients titrated to sildenafil 100 mg compared with patients continuing at sildenafil 50 mg. At either sildenafil dose, headache, flushing and hot flushes were the most common adverse events. Neither the frequency nor the severity of adverse events increased with titration to sildenafil 100 mg. After initial treatment with sildenafil 50 mg, patients titrated to 100 mg showed further increases in efficacy and satisfaction with no increase in the number or severity of adverse events than in those remaining on the starting dose.

Can the International Index of Erectile Function distinguish between organic and psychogenic erectile function?

To define the ability of the International Index of Erectile Function (IIEF) to differentiate between organic and psychogenic erectile dysfunction (ED). Patients presenting for the evaluation and treatment of ED who had penile duplex Doppler ultrasonography (DUS) completed the IIEF questionnaire. Accepted ranges of the IIEF EF domain were used to grade baseline severity (severe, moderate and mild < or =11, 11-17, 18-25, respectively). Accepted criteria were used to define normality on DUS (peak systolic velocity >30 cm/s and end-diastolic velocity <5 cm/s). Patients with documented Peyronie's disease, hypogonadism and a history of radical prostatectomy were excluded. In all, 112 patients were enrolled, with a mean (sd) age and duration of ED of 56 (16) and 2 (0.6) years, respectively. The vascular risk-factor profile included diabetes in 15%, hypertension in 26% and hyperlipidaemia in 20%. The baseline severity of ED was mild, moderate and severe in 28%, 41% and 32% men, respectively. All patients had normal testosterone levels. Patients also with a normal DUS were diagnosed with psychogenic ED, in 50%, 13% and 17% of men with mild, moderate and severe ED by the IIEF, respectively. No patient with venous leak had mild ED, and 62% of men with venous leak had severe ED. These results indicate that the IIEF is not completely accurate in differentiating between organic and psychogenic ED, and that almost a fifth of men in this study population with severe ED by the IIEF had normal erectile haemodynamics. These data have potential ramifications for evaluating the baseline severity of ED in trials of erectogenic agents.