Synergistic Effects of BAY 60‐4552 and Vardenafil on Relaxation of Corpus Cavernosum Tissue of Patients with Erectile Dysfunction and Clinical Phosphodiesterase Type 5 Inhibitor Failure

IntroductionOverall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5‐i) for erectile dysfunction (ED) are 60–70%. PDE5‐i treatment failures currently have to resort to invasive treatment options for restoration of erectile function.AimsTo assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5‐i nonresponders compared with healthy controls. To evaluate the effects of BAY 60‐4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5‐i nonresponders.Main Outcome MeasuresmRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t‐test or Mann–Whitney test based upon number of groups and normality of data.MethodsHCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α‐smooth muscle actin (aSMA) and β‐actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60‐4552, or both simultaneously.ResultsThe main targets in the NO/cGMP/sGC pathway were downregulated in PDE5‐i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60‐4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5‐i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples.ConclusionDespite downregulation of the NO/cGMP/PKG pathway, combining BAY 60‐4552 with vardenafil significantly enhanced relaxation HCC strips of PDE5‐i nonresponders.     

No effect of additional screw fixation of a cementless,all-polyethylene press-fit socket on migration,wear, and clinical outcome

Background and purpose — Additional screw fixation of the all-polyethylene press-fit RM cup (Mathys) has no additional value for migration, in the first 2 years after surgery. However, the medium-term and long-term effects of screw fixation remain unclear. We therefore evaluated the influence of screw fixation on migration, wear, and clinical outcome at 6.5 years using radiostereometric analysis (RSA).

Patients and methods — This study involved prolonged follow-up from a previous randomized controlled trial (RCT). We analyzed RSA radiographs taken at baseline and at 1-, 2-, and 6.5-year follow-up. Cup migration and wear were assessed using model-based RSA software. Wear was calculated as translation of the femoral head model in relation to the cup model. Total translation, rotation, and wear were calculated mathematically from results of the orthogonal components.

Results — 27 patients (15 with screw fixation and 12 without) were available for follow-up at 6.5 (5.6–7.2) years. Total translation (0.50?mm vs. 0.56?mm) and rotation (1.01 degrees vs. 1.33 degrees) of the cup was low, and was not significantly different between the 2 groups. Wear increased over time, and was similar between the 2 groups (0.58?mm vs. 0.53?mm). Wear rate (0.08?mm/year vs. 0.09?mm/year) and clinical outcomes were also similar.

Interpretation — Our results indicate that additional screw fixation of all-polyethylene press-fit RM cups has no additional value regarding medium-term migration and clinical outcome. The wear rate was low in both groups.     

Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti‐thrombotic drugs

Background and Aim: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti‐thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. Methods: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti‐thrombotic therapy. VCE studies were re‐evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti‐thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti‐thrombotic therapy was resumed before the VCE study. Results: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty‐two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti‐thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20–60.42, P = 0.032). Conclusions: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti‐thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.     

Serum triiodothyronine levels and inflammatory cytokine production capacity

Increasing evidence suggests that pro-inflammatory cytokines are at play in lowering peripheral thyroid hormone levels during critical illness. Conversely, thyroid hormones have been suggested to enhance production of inflammatory cytokines. In view of these considerations, we hypothesized a mutual association between triiodothyronine and pro-inflammatory cytokines. Therefore we evaluated the relation between both circulating and induced inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study. We found that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, higher serum free triiodothyronine levels were related to higher production capacity of pro-inflammatory cytokines after stimulation with lipopolysaccharide. By combining in vivo and ex vivo data, we were able to demonstrate for the first time the existence of a potential feedback mechanism between thyroid function and immune production capacity. We conclude that maintenance of normal thyroid function might be important for a preserved immune response in elderly human populations.     

Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.