Understanding the Effects of Sildenafil Treatment on Erection Maintenance and Erection Hardness

IntroductionErectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. Although intuitively related, the link between erection hardness and erection maintenance has not been formally established and quantified.AimTo understand the components of erection maintenance through statistical modeling.MethodsData from a double-blind placebo-controlled trial of fixed-dose sildenafil (100 or 50 mg, 8 weeks) with open-label extension of flexible-dose sildenafil (100 and 50 mg, 4 weeks) were analyzed. Erection maintenance was assessed with item 4 (how often erection was maintained) or item 5 (difficulty in maintaining erection) of the International Index of Erectile Function (IIEF). Erection hardness was assessed with the Erection Hardness Score.Main Outcome MeasuresLongitudinal modeling estimated mean treatment differences averaged over the double-blind phase for sildenafil 100 mg vs. placebo and 50 mg vs. placebo. Statistical mediation analysis was applied to partition the effect of sildenafil (pooled into one treatment group) on erection maintenance directly and indirectly through erection hardness.ResultsLongitudinal mean differences for sildenafil 100 and 50 mg vs. placebo were high (P < 0.0001 for each), with large standardized effect sizes (>0.8). Mediation modeling showed that sildenafil treatment affected maintenance directly as well as indirectly via erection hardness, when measured by IIEF item 4 (direct effect, 44.6%; indirect effect, 55.4%) or IIEF item 5 (direct effect, 56.9%; indirect effect, 43.1%).ConclusionsSildenafil treatment significantly improved erection maintenance, a physiologic requirement for satisfactory sexual performance. According to our model, only approximately half of the effect of sildenafil on erection maintenance was estimated to be driven through direct effects. Rather, the effect of sildenafil on erection maintenance seems to be substantially driven by erection hardness. Therefore, achievement of optimal initial erection hardness appears to be an important treatment goal for enhancing erection maintenance and achieving successful ED treatment. Claes HIM, Goldstein I, Althof SE, Berner MM, Cappelleri JC, Bushmakin AG, Symonds T, and Schnetzler G. Understanding the effects of sildenafil treatment on erection maintenance and erection hardness.     

Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty

IntroductionThe free radial forearm (FRFA) flap is universally still considered as the gold standard technique in penile reconstruction. Typically, a considerably large flap is required, often involving almost the entire circumference of the forearm. Partial necrosis may occur at the distal-most (dorsoradial) part of the flap as a result of insufficient perfusion.AimTo describe a new technique using the posterior interosseous artery (PIOA) to supercharge FRFA phalloplasty.MethodsIn a 12-month period, all patients having FRFA flap phalloplasty were enrolled. Perioperative, after complete flap dissection, an indocyanine green perfusion scan was performed. In case of insufficient perfusion at the distalmost part of the flap, a supramicrosurgical anastomosis was performed between the FRFA pedicle and the PIOA (artery only).Main Outcome MeasuresStudied outcomes included the rate of marginal necrosis, surgical time, postoperative posterior interosseous nerve damage and urethral complications (fistula, stenosis or necrosis).ResultsA total of 27 FRFA flap phalloplasties was performed. Anastomosis of the PIOA was needed in 15 cases. No marginal necrosis was observed in these cases. There were no cases of postoperative posterior interosseous nerve damage. There were no significant differences in urethral complications (fistula, stenosis or necrosis) between the 2 groups.Clinical ImplicationsIn selected cases where insufficient perfusion of the dorsoradial part of the flap is present, patients may benefit from arterial supercharging to prevent postoperative marginal necrosis.Strength & LimitationsStrengths include a single surgeon, thus lending continuity of skill and technique, a consecutive series, and 100% short-term follow-up. Limitations include single institution series and a limited number of patients.ConclusionArterial supercharging is effective in improving perfusion of large FRFA flaps used in phalloplasty when dorsoradial hypoperfusion is detected on an indocyanine green perfusion scan. It is a technically challenging addition to the standard technique because of the small size of the vessels, the close relationship between the PIOA and the posterior interosseous nerve, and the vulnerability of the newly constructed intra-flap anastomosis.De Wolf E, Claes K, Sommeling CE, et al. Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty. J Sex Med 2019;16:1111–1117.     

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System

Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing‐based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high‐throughput diagnostic methods to detect disease‐causing variations, including single‐nucleotide variations (SNVs), insertions/deletions (Indels), and copy‐number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss. One‐hundred thirty one presumed autosomal‐recessive NSHL (arNSHL) patients of Western‐European ethnicity were analyzed for SNVs, Indels, and CNVs. In addition, we established a straightforward variant classification system to deal with the large number of variants encountered. We estimate that combining prescreening of GJB2 with our panel leads to a diagnosis in 25%–30% of patients. Our data show that after GJB2, the most commonly mutated genes in a Western‐European population are TMC1, MYO15A, and MYO7A (3.1%). CNV analysis resulted in the identification of causative variants in two patients in OTOA and STRC. One of the major challenges for diagnostic gene panels is assigning pathogenicity for variants. A collaborative database collecting all identified variants from multiple centers could be a valuable resource for hearing loss diagnostics.     

A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR‐based approach and next generation sequencing

Implementing DNA diagnostics in clinical practice for extremely heterogeneous diseases such as hearing loss is challenging, especially when attempting to reach high sensitivity and specificity in a cost‐effective fashion. Next generation sequencing has enabled the development of such a test, but the most commonly used genomic target enrichment methods such as hybridization‐based capture suffer from restrictions. In this study, we have adopted a new flexible approach using microdroplet PCR‐based technology for target enrichment, in combination with massive parallel sequencing to develop a DNA diagnostic test for autosomal recessive hereditary hearing loss. This approach enabled us to identify the genetic basis of hearing loss in 9 of 24 patients, a success rate of 37.5%. Our method also proved to have high sensitivity and specificity. Currently, routine molecular genetic diagnostic testing for deafness is in most cases only performed for the GJB2 gene and a positive result is typically only obtained in 10–20% of deaf children. Individuals with mutations in GJB2 had already been excluded in our selected set of 24 patients. Therefore, we anticipate that our deafness test may lead to a genetic diagnosis in roughly 50% of unscreened autosomal recessive deafness cases. We propose that this diagnostic testing approach represents a significant improvement in clinical practice as a standard diagnostic tool for children with hearing loss. © 2012 Wiley Periodicals, Inc.     

Mechanical Analysis of Extra-Articular Knee Ligaments. Part One: Native knee ligaments

Background

The aim of this study was to provide a characterization of the tensile properties of the medial collateral ligament (MCL), lateral collateral ligament (LCL), anterolateral ligament (ALL) and medial patellofemoral ligament (MPFL). Our hypothesis was that extra-articular knee ligaments are heterogeneous in nature and possess distinct material properties.

Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): Co-expression in metastatic serous ovarian carcinoma

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P=0.048), protein expression (P=0.046) and gelatinolytic activity (P=0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P=0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P=0.046), but enzyme activity showed inverse relationship with both p-ERK (P=0.05) and p-p38 (P=0.033) expression. EMMPRIN expression correlated with MMP-1 (P<0.001), MMP-2 (P=0.042) and MMP-9 (P=0.029) expression, as well as with ERK activity (P=0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy. This revised version was published online in July 2006 with corrections to the Cover Date.