Sexual function after sacrospinous fixation for vaginal vault prolapse: bad or mad?

BACKGROUND: The main indication for sacrospinous ligament suspension is to correct either total procidentia, a posthysterectomy vaginal vault prolapse with an associated weak cardinal uterosacral ligament complex, or a posthysterectomy enterocele. This study aimed to evaluate sexual function and anatomic outcome for patients after sacrospinous ligament suspension. METHODS: For this study, 52 patients who had undergone sacrospinous ligament fixation during the preceding 5 years were asked to complete the Female Sexual Function Index (FSFI) questionnaire. The patients were vaginally examined using the ICS POP score, and the results were compared with their preoperative status. For statistical analysis, GraphPad for Windows, version 4.0, was used. RESULTS: The 52 patients were examined during a follow-up period of 38 months. No major intraoperative complications were noted. Recurrence of symptomatic apical descent was noted in 6% of the patients and de novo prolapse in 13.5%. Only one patient was symptomatic. Three patients experienced de novo dyspareunia, which resolved in two cases after stitch removal. Sexual function was good, rating higher than three points for each of the domains including satisfaction, lubrication, desire, orgasm, and pain. CONCLUSION: Sacrospinous ligament fixation still is a valuable option for the treatment of vaginal vault prolapse. Sexual function is satisfactory, with few cases of de novo dyspareunia.

The complement inhibitor low molecular weight dextran sulfate prevents TLR4-induced phenotypic and functional maturation of human dendritic cells

Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1beta, IL-6, IL-12p70, and TNF-alpha. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of IkappaB-alpha and activation of NF-kappaB. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.

Secondary intraocular lenses in eyes with aphakia or dislocated IOL: impact of suture fixation on early and late complications

BACKGROUND: Secondary intraocular lens (IOL) implantation is exposed to an increased risk of complications, including endophthalmitis and retinal detachment. The present analysis compares the outcomes and complications experienced in our own series of patients. PATIENTS AND METHODS: We retrospectively reviewed a consecutive series of secondary posterior chamber IOL implantations performed in a single centre, two surgeon setting over a period of 8 years and with a follow up-time of at least 4 months. RESULTS: Between 1997 and 2005, 75 patients received a sulcus-supported secondary IOL without suture fixation, whereas suture fixation was required in 137 instances. Visual acuity improved in both groups (group 1: from 0.36 +/- 0.39 (0.01-1.2) to 0.73 +/- 0.33 (0.02-1.0; p = 0.18); group 2: from 0.33 +/- 0.34 (0.02-1.0) to 0.46 +/- 0.33 (0.01-1.0; p = 0.006), but more pronounced in eyes not requiring suture fixation (p = 0.012). IOL placement was more likely to be combined with endophacoemulsification in the not suture-fixed IOLs (12.7 vs. 5.3 %). In contrast, retinal tears (10.6 vs. 8.6 %, respectively) and retinal detachment (5.3 vs. 2.2 %, respectively) were equally distributed. In the early postoperative phase, IOP was lower in suture-fixed eyes, which showed a higher incidence of minor intraocular haemorrhages and cystoid macular edema (5.3 vs. 8.0 %); late complications up to 5 years postoperatively were equally distributed. CONCLUSION: A preoperatively less complicated anterior segment situation and a lower incidence of postoperative macular edema may account for a better visual outcome after placement of a sulcus supported IOLs without suturing. If required, suture fixation may be performed without exposing the eye to an increased risk of late postoperative complications.

Minimally invasive strabismus surgery for rectus muscle posterior fixation

AIMS: To present a novel, minimally invasive strabismus surgery (MISS) technique for rectus muscle posterior fixation. METHODS: This study reports the results of 32 consecutive MISS rectus muscle posterior fixation surgeries performed on 19 patients by applying only two small L-shaped openings where the two retroequatorial scleromuscular sutures were placed. RESULTS: On the first postoperative day, in primary position, redness was hardly visible in 16 eyes (50%) and only moderate redness was visible in 6 eyes (19%). No serious complication occurred. Preoperative visual acuity and refraction remained unchanged at 6 months (p > 0.1). The preoperative convergence excess (n = 13) decreased from 10.3 +/- 4.1 to 5.2 +/- 4.0 degrees at 6 months (p < 0.005). In all patients operated on for gaze incomitance (n = 6) improvement was achieved at 6 months. CONCLUSIONS: This study shows that keyhole minimal-dissection rectus muscle posterior fixation surgery is feasible and effective to improve ocular alignment. The MISS technique seems to be superior in the direct postoperative period since only minimal conjunctival swelling and no corneal complications were observed.

Low molecular weight dextran sulfate as complement inhibitor and cytoprotectant in solid organ and islet transplantation

Complement is an essential part of the innate immune system and plays a crucial role in organ and islet transplantation. Its activation, triggered for example by ischemia/reperfusion (I/R), significantly influences graft survival, and blocking of complement by inhibitors has been shown to attenuate I/R injury. Another player of innate immunity are the dendritic cells (DC), which form an important link between innate and adaptive immunity. DC are relevant in the induction of an immune response as well as in the maintenance of tolerance. Modulation or inhibition of both components, complement and DC, may be crucial to improve the clinical outcome of solid organ as well as islet transplantation. Low molecular weight dextran sulfate (DXS), a well-known complement inhibitor, has been shown to prevent complement-mediated damage of the donor graft endothelium and is thus acting as an endothelial protectant. In this review we will discuss the evidence for this cytoprotective effect of DXS and also highlight recent data which show that DXS inhibits the maturation of human DC. Taken together the available data suggest that DXS may be a useful reagent to prevent the activation of innate immunity, both in solid organ and islet transplantation.

Stability after bilateral sagittal split osteotomy advancement surgery with rigid internal fixation: a systematic review

PURPOSE: The purpose of this systematic review was to evaluate horizontal relapse and its causes in bilateral sagittal split advancement osteotomy (BSSO) with rigid internal fixation of different types. MATERIALS AND METHODS: A search of the literature was performed in the databases PubMed, Ovid, Cochrane Library, and Google Scholar Beta. From 488 articles identified, 24 articles were finally included. Six studies were prospective, and 18 were retrospective. The range of postoperative study records was 6 months to 12.7 years. RESULTS: The short-term relapse for bicortical screws was between 1.5% and 32.7%, for miniplates between 1.5% and 18.0%, and for bioresorbable bicortical screws between 10.4% and 17.4%, at point B. The long-term relapse for bicortical screws was between 2.0% and 50.3%, and for miniplates between 1.5% and 8.9%, at point B. CONCLUSIONS: BSSO for mandibular advancement is a good treatment option for skeletal Class II, but seems less stable than BSSO setback in the short and long terms. Bicortical screws of titanium, stainless steel, or bioresorbable material show little difference regarding skeletal stability compared with miniplates in the short term. A greater number of studies with larger skeletal long-term relapse rates were evident in patients treated with bicortical screws instead of miniplates. The etiology of relapse is multifactorial, involving the proper seating of the condyles, the amount of advancement, the soft tissue and muscles, the mandibular plane angle, the remaining growth and remodeling, the skill of the surgeon, and preoperative age. Patients with a low mandibular plane angle have increased vertical relapse, whereas patients with a high mandibular plane angle have more horizontal relapse. Advancements in the range of 6 to 7 mm or more predispose to horizontal relapse. To obtain reliable scientific evidence, further short-term and long-term research into BSSO advancement with rigid internal fixation should exclude additional surgery, ie, genioplasty or maxillary surgery, and include a prospective study or randomized clinical trial design with correlation statistics.

Endothelial cell protection and complement inhibition in xenotransplantation: a novel in vitro model using whole blood

BACKGROUND: Studying the interactions between xenoreactive antibodies, complement and coagulation factors with the endothelium in hyperacute and acute vascular rejection usually necessitates the use of in vivo models. Conventional in vitro or ex vivo systems require either serum, plasma or anti-coagulated whole blood, making analysis of coagulation-mediated effects difficult. Here a novel in vitro microcarrier-based system for the study of endothelial cell (EC) activation and damage, using non-anticoagulated whole blood is described. Once established, the model was used to study the effect of the characterized complement- and coagulation inhibitor dextran sulfate (DXS, MW 5000) for its EC protective properties in a xenotransplantation setting. METHODS: Porcine aortic endothelial cells (PAEC), grown to confluence on microcarrier beads, were incubated with non-anticoagulated whole human blood until coagulation occurred or for a maximum of 90 min. PAEC-beads were either pre- or co-incubated with DXS. Phosphate buffered saline (PBS) experiments served as controls. Fluid phase and surface activation markers for complement and coagulation were analyzed as well as binding of DXS to PAEC-beads. RESULTS: Co- as well as pre-incubation of DXS, followed by washing of the beads, significantly prolonged time to coagulation from 39 +/- 12 min (PBS control) to 74 +/- 23 and 77 +/- 20 min, respectively (P < 0.005 vs. PBS). DXS treatment attenuated surface deposition of C1q, C4b/c, C3b/c and C5b-9 without affecting IgG or IgM deposition. Endothelial integrity, expressed by positivity for von Willebrand Factor, was maintained longer with DXS treatment. Compared with PBS controls, both pre- and co-incubation with DXS significantly prolonged activated partial thromboplastin time (>300 s, P < 0.05) and reduced production of thrombin-antithrombin complexes and fibrinopeptide A. Whilst DXS co-incubation completely blocked classical pathway complement activity (CH50 test) DXS pre-incubation or PBS control experiments showed no inhibition. DXS bound to PAEC-beads as visualized using fluorescein-labeled DXS. CONCLUSIONS: This novel in vitro microcarrier model can be used to study EC damage and the complex interactions with whole blood as well as screen ''endothelial protective'' substances in a xenotransplantation setting. DXS provides EC protection in this in vitro setting, attenuating damage of ECs as seen in hyperacute xenograft rejection.

Multimeric tyrosine sulfate acts as an endothelial cell protectant and prevents complement activation in xenotransplantation models

BACKGROUND: Activation of endothelial cells (EC) in xenotransplantation is mostly induced through binding of antibodies (Ab) and activation of the complement system. Activated EC lose their heparan sulfate proteoglycan (HSPG) layer and exhibit a procoagulant and pro-inflammatory cell surface. We have recently shown that the semi-synthetic proteoglycan analog dextran sulfate (DXS, MW 5000) blocks activation of the complement cascade and acts as an EC-protectant both in vitro and in vivo. However, DXS is a strong anticoagulant and systemic use of this substance in a clinical setting might therefore be compromised. It was the aim of this study to investigate a novel, fully synthetic EC-protectant with reduced inhibition of the coagulation system. METHOD: By screening with standard complement (CH50) and coagulation assays (activated partial thromboplastin time, aPTT), a conjugate of tyrosine sulfate to a polymer-backbone (sTyr-PAA) was identified as a candidate EC-protectant. The pathway-specificity of complement inhibition by sTyr-PAA was tested in hemolytic assays. To further characterize the substance, the effects of sTyr-PAA and DXS on complement deposition on pig cells were compared by flow cytometry and cytotoxicity assays. Using fluorescein-labeled sTyr-PAA (sTyr-PAA-Fluo), the binding of sTyr-PAA to cell surfaces was also investigated. RESULTS: Of all tested compounds, sTyr-PAA was the most effective substance in inhibiting all three pathways of complement activation. Its capacity to inhibit the coagulation cascade was significantly reduced as compared with DXS. sTyr-PAA also dose-dependently inhibited deposition of human complement on pig cells and this inhibition correlated with the binding of sTyr-PAA to the cells. Moreover, we were able to demonstrate that sTyr-PAA binds preferentially and dose-dependently to damaged EC. CONCLUSIONS: We could show that sTyr-PAA acts as an EC-protectant by binding to the cells and protecting them from complement-mediated damage. It has less effect on the coagulation system than DXS and may therefore have potential for in vivo application.

Xenograft rejection: IgG1, complement and NK cells team up to activate and destroy the endothelium

Acute vascular rejection represents a formidable barrier to clinical xenotransplantation and it is known that this type of rejection can also be initiated by xenoreactive antibodies that have limited complement-activating ability. Using a sophisticated mouse model, a recent study has provided in vivo evidence for the existence of an IgG(1)-mediated vascular rejection, which uniquely depends on both the activation of complement and interactions with FcgammaRIII on natural killer (NK) cells.

Lack of galactose-alpha-1,3-galactose expression on porcine endothelial cells prevents complement-induced lysis but not direct xenogeneic NK cytotoxicity

The galactose-alpha-1,3-galactose (alphaGal) carbohydrate epitope is expressed on porcine, but not human cells, and therefore represents a major target for preformed human anti-pig natural Abs (NAb). Based on results from pig-to-primate animal models, NAb binding to porcine endothelial cells will likely induce complement activation, lysis, and hyperacute rejection in pig-to-human xenotransplantation. Human NK cells may also contribute to innate immune responses against xenografts, either by direct recognition of activating molecules on target cells or by FcgammaRIII-mediated xenogeneic Ab-dependent cellular cytotoxicity (ADCC). The present study addressed the question as to whether the lack of alphaGal protects porcine endothelial cells from NAb/complement-induced lysis, direct xenogeneic NK lysis, NAb-dependent ADCC, and adhesion of human NK cells under shear stress. Homologous recombination, panning, and limiting dilution cloning were used to generate an alphaGal-negative porcine endothelial cell line, PED2*3.51. NAb/complement-induced xenogeneic lysis of PED2*3.51 was reduced by an average of 86% compared with the alphaGal-positive phenotype. PED2*3.51 resisted NK cell-mediated ADCC with a reduction of lysis ranging from 30 to 70%. However, direct xenogeneic lysis of PED2*3.51, mediated either by freshly isolated or IL-2-activated human NK cells or the NK cell line NK92, was not reduced. Furthermore, adhesion of IL-2-activated human NK cells did not rely on alphaGal expression. In conclusion, removal of alphaGal leads to a clear reduction in complement-induced lysis and ADCC, but does not resolve adhesion of NK cells and direct anti-porcine NK cytotoxicity, indicating that alphaGal is not a dominant target for direct human NK cytotoxicity against porcine cells.

Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum

Acute or even hyperacute humoral graft rejection, mediated by classical pathway complement activation, occurs in allo- and xenotransplantation due to preformed anti-graft antibodies. Intravenous immunoglobulin (IVIg) preparations can prevent complement-mediated tissue injury and delay hyperacute xenograft rejection. It is known that IgM-enriched IVIg (IVIgM) has a higher capacity to block complement than IVIgG. Different IVIgs were therefore tested for specificity of complement inhibition and effect on anti-bacterial activity of human serum. IVIgM-I (Pentaglobin), 12% IgM), IVIgM-II (IgM-fraction of IVIgM-I, 60% IgM), and three different IVIgG (all >95% IgG) were used. The known complement inhibitor dextran sulfate was used as control. Hemolytic assays were performed to analyze pathway-specificity of complement inhibition. Effects of IVIg on complement deposition on pig cells and Escherichia coli were assessed by flow cytometry and cytotoxicity as well as bactericidal assays. Complement inhibition by IVIgM was specific for the classical pathway, with IC50 values of 0.8 mg/ml for IVIgM-II and 1.7 mg/ml for IVIgM-I in the CH50 assay. Only minimal inhibition of the lectin pathway was seen with IVIgM-II (IC50 15.5 mg/ml); no alternative pathway inhibition was observed. IVIgG did not inhibit complement in any hemolytic assay. Classical pathway complement inhibition by IVIgM was confirmed in an in vitro xenotransplantation model with PK15 cells. In contrast, IVIgM did not inhibit (mainly alternative pathway mediated) killing of E. coli by human serum. In conclusion, IgM-enriched IVIg is a specific inhibitor of the classical complement pathway, leaving the alternative pathway intact, which is an important natural anti-bacterial defense, especially for immunosuppressed patients.

In vitro comparison of the complement-scavenging capacity of different intravenous immunoglobulin preparations

BACKGROUND AND OBJECTIVES: Complement inhibition is considered important in the mechanism of action of intravenous immunoglobulin (IVIG) in a number of inflammatory and autoimmune disorders. The capacity of different IVIG preparations to 'scavenge' activated C3 and thereby inhibit complement activation was assessed by a new in vitro assay. MATERIALS AND METHODS: Diluted human serum as a complement source, with or without addition of different concentrations of IVIG, was incubated in microtitre plates coated with heat-aggregated human IgG. Complement scavenging was measured by detecting reduced C3 binding and determining fluid phase C3b-IgG complex formation. Complement activation induced by the IVIG preparations was measured as C5a formation. RESULTS: All IVIG preparations exhibited a dose-dependent inhibition of C3b deposition, correlating strongly with binding of C3b to fluid-phase IgG, but the extent of complement scavenging varied considerably between different IVIG preparations. At an IVIG concentration of 0.9 mg/ml, the inhibition of C3b deposition ranged from 72 +/- 16% to 22 +/- 4.1%. The reduction of C3b deposition on the complement-activating surface was not due to IVIG-induced complement activation in the fluid phase, as shown by the low C5a formation in the presence of serum. CONCLUSION: In vitro analysis allows comparison of the complement-inhibitory properties of IVIG preparations. The extent of complement scavenging varies between the products.

Complement Factor P in choroidal neovascular membranes of patients with age-related macular degeneration

To evaluate whether complement Factor P (properdin) was present in surgically removed choroidal neovascular membranes of patients with age-related macular degeneration (AMD) and to investigate whether associated pre- and postoperative clinical characteristics can be correlated.