154. Zur Behandlung arterieller GefäBverletzungen im iliaco-femoralen Abschnitt

ZusammenfaBung 81 frische arterielle GefäBverletzungen im iliacofemoralen Abschnitt wurden von 1966-1976 in unserer Klinik behandelt. 24mal war die Verletzung unfallbedingt, hier wurden meist Umleitungs- oder Interpositionsverfahren angewandt. Bei den 57 iatrogenen Verletzungen konnte überwiegend durch direkte Naht rekonstruiert werden. Alle Rekonstruktionen innerhalb der 12 h-Grenze waren erfolgreich, spätere Rekonstruktionsversuche schlugen fehl. Posttraumatische Extremitätenischämien müBen daher innerhalb 4 h angiographisch oder durch Probefreilegung abgeklärt werden. Prognostisch unterscheiden sich beide Verletzungsarten nicht.     

A double-blind,randomized, placebo-controlled clinical trial evaluating the safety and efficacy of autologous muscle derived cells in female subjects with stress urinary incontinence

Purpose

The purpose of the study was to assess safety and efficacy of autologous muscle derived cells for urinary sphincter repair (AMDC-USR) in female subjects with predominant stress urinary incontinence.

Methods

A randomized, double-blind, multicenter trial examined intra-sphincteric injection of 150?×?10⁶ AMDC-USR versus placebo in female subjects with stress or stress predominant, mixed urinary incontinence. AMDC-USR products were generated from vastus lateralis needle biopsies. Subjects were randomized 2:1 to receive AMDC-USR or placebo and 1:1 to receive 1 or 2 treatments (6 months after the first). Primary outcome was composite of ≥?50% reduction in stress incontinence episode frequency (IEF), 24-h or in-office pad weight tests at 12 months. Other outcome data included validated subject-recorded questionnaires. Subjects randomized to placebo could elect to receive open-label AMDC-USR treatment after 12 months. Subject follow-up was up to 2 years.

Results

AMDC-USR was safe and well-tolerated with no product-related serious adverse events or discontinuations due to adverse events. Interim analysis revealed an unexpectedly high placebo response rate (90%) using the composite primary outcome which prevented assessment of treatment effect as designed and thus enrollment was halted at 61% of planned subjects. Post hoc analyses suggested that more stringent endpoints lowered placebo response rates and revealed a possible treatment effect.

Conclusions

Although the primary efficacy finding was inconclusive, these results inform future trial design of AMDC-USR to identify clinically meaningful efficacy endpoints based on IEF reduction, understanding of placebo response rate, and refinement of subject selection criteria to more appropriately align with AMDC-USR’s proposed mechanism of action.

     

Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized,placebo-controlled,double-blind phase III studies

Objectives

Nocturia is prevalent and bothersome in men with lower urinary tract symptoms suggestive of BPH (LUTS/BPH). α-Adrenoceptor antagonists without subtype selectivity have inconsistently shown significant effects on nocturia in these patients. We explored the effects of the α_1A-adrenoceptor subtype-selective antagonist silodosin on nocturia by analyzing three placebo-controlled registration studies.

Methods

Responses to question 7 of the IPSS questionnaire were analyzed for the entire study population and patients with ≥2 voids/night at baseline. Improvement/worsening rates for nocturia were calculated for once-daily silodosin 8 mg and placebo. Silodosin effects on the mean number of nocturnal voids were compared with placebo, and the number of patients in whom nocturia was reduced to <2 times was calculated.

Results

In total, 1,479 men were treated with silodosin or placebo; 1,266 men (85 %) had ≥2 voids/night at baseline. Compared to placebo, more men treated with silodosin reported about nocturia improvement (53.4 vs. 42.8 %, p < 0.0001) and fewer patients about worsening (9.0 vs. 14.3 %, p < 0.0001). Silodosin significantly reduced nocturia within each study and pooled cohort compared to placebo (p < 0.001). In men with ≥2 nocturnal voids at baseline, 61 and 49 % of patients with silodosin and placebo had reductions of ≥1 voids/night, respectively (p = 0.0003), and significantly more patients with silodosin had <2 nocturia episodes at study end compared to placebo (29.3 vs. 19.0 %; p = 0.0002).

Conclusions

Although a weak impact on nocturia is already known from α-adrenoceptor antagonists without subtype selectivity, the individual placebo-controlled studies and the pooled data analysis showed that the α_1A-adrenoceptor subtype-selective antagonist silodosin consistently and significantly improves nocturia in men with LUTS/BPH.     

Opposing effects of monomeric and pentameric C-reactive protein on endothelial progenitor cells

C-reactive protein (CRP) has been linked to the pathogenesis of atherosclerosis. The dissociation of native, pentameric (p)CRP to monomeric (m)CRP on the cell membrane of activated platelets has recently been demonstrated. The dissociation of pCRP to mCRP may explain local pro-inflammatory reactions at the site of developing atherosclerotic plaques. As a biomarker, pCRP predicts cardiovascular adverse events and so do reduced levels and function of circulating endothelial progenitor cells (EPCs). We hypothesised that mCRP and pCRP exert a differential effect on EPC function and differentiation. EPCs were treated with mCRP or pCRP for 72?h, respectively. Phenotypical characterisation was done by flow cytometry and immunofluorescence microscopy, while the effect of mCRP and pCRP on gene expression was examined by whole-genome gene expression analysis. The functional capacity of EPCs was determined by colony forming unit (CFU) assay and endothelial tube formation assay. Double staining for acetylated LDL and ulex lectin significantly decreased in cells treated with pCRP. The length of tubuli in a matrigel assay with HUVECs decreased significantly in response to pCRP, but not to mCRP. The number of CFUs increased after pCRP treatment. RNA expression profiling demonstrated that mCRP and pCRP cause highly contradictory gene regulation. Interferon-responsive genes (IFI44L, IFI44, IFI27, IFI 6, MX1, OAS2) were among the highly up-regulated genes after mCRP, but not after pCRP treatment. In conclusion, EPC phenotype, genotype and function were differentially affected by mCRP and pCRP, strongly arguing for differential roles of these two CRP conformations. The up-regulation of interferon-inducible genes in response to mCRP may constitute a mechanism for the local regulation of EPC function.     

Amyloid Plaques Dissociate Pentameric to Monomeric C‐Reactive Protein: A Novel Pathomechanism Driving Cortical Inflammation in Alzheimer's Disease?

Beta-amyloid (Aβ) plaques and local inflammation are central to the pathogenesis of Alzheimer's disease. Although an association between circulating pentameric C-reactive protein (pCRP) and Alzheimer's disease has been reported no pathomechanistic link has been established. We hypothesized that Aβ plaques induce the dissociation of pCRP to individual monomers (mCRP), which possess strong pro-inflammatory properties not shared with pCRP and localizing inflammation to Alzheimer's plaques. pCRP was incubated with Aβ plaques generated in vitro and with non-aggregated Aβ(42) peptide. pCRP dissociation to mCRP was found only when co-incubated with Aβ plaques. Furthermore, sections of frontal cortex from brains of patients with and without Alzheimer's disease were stained with antibodies specific for mCRP and pCRP. There was significantly more mCRP in the cortex of Alzheimer's disease patients (P ≤ 0.01). In contrast, there was no significant difference in pCRP staining. These findings establish that Aβ plaques possess a previously unrecognized potential to dissociate pentameric CRP to monomeric CRP. The existence of mCRP but not pCRP in the brains of Alzheimer's disease patients strongly indicates that this newly described biological effect of Aβ plaques is relevant in Alzheimer pathobiology; potentially localizing and amplifying inflammation via the strong pro-inflammatory effects of locally generated mCRP.