Prostatic Arterial Supply: Anatomic and Imaging Findings Relevant for Selective Arterial Embolization

PurposeTo describe the anatomy and imaging findings of the prostatic arteries (PAs) on multirow-detector pelvic computed tomographic (CT) angiography and digital subtraction angiography (DSA) before embolization for symptomatic benign prostatic hyperplasia (BPH).Materials and MethodsIn a retrospective study from May 2010 to June 2011, 75 men (150 pelvic sides) underwent pelvic CT angiography and selective pelvic DSA before PA embolization for BPH. Each pelvic side was evaluated regarding the number of independent PAs and their origin, trajectory, termination, and anastomoses with adjacent arteries.ResultsA total of 57% of pelvic sides (n = 86) had only one PA, and 43% (n = 64) had two independent PAs identified (mean PA diameter, 1.6 mm ± 0.3). PAs originated from the internal pudendal artery in 34.1% of pelvic sides (n = 73), from a common trunk with the superior vesical artery in 20.1% (n = 43), from the anterior common gluteal–pudendal trunk in 17.8% (n = 38), from the obturator artery in 12.6% (n = 27), and from a common trunk with rectal branches in 8.4% (n = 18). In 57% of pelvic sides (n = 86), anastomoses to adjacent arteries were documented. There were 30 pelvic sides (20%) with accessory pudendal arteries in close relationship with the PAs. No correlations were found between PA diameter and patient age, prostate volume, or prostate-specific antigen values on multivariate analysis with logistic regression.ConclusionsPAs have highly variable origins between the left and right sides and between patients, and most frequently arise from the internal pudendal artery.     

Effect of low-level laser therapy on proliferation, differentiation, and adhesion of steroid-treated osteoblasts

There has recently been constant effort to evaluate therapies that may have a positive effect on bone regeneration. However, there are few studies in the literature on the effects of low-level laser therapy (LLLT) involving tissues treated with anabolic steroids. The present study evaluated the effects of LLLT (AsGaAl 780?nm, 3?J/cm(2), 10?mW, beam spot of 0.04?cm(2), total energy 0.12?J) on the proliferation, adhesion, and differentiation of osteoblasts cultured in the presence of nandrolone decanoate (ND). The MTT method was employed to evaluate cell proliferation and adhesion. Cell differentiation was evaluated by measuring alkaline phosphatase activity. There was a significant decrease in cell proliferation in the irradiated group treated with 50 μM ND when compared to the control group, after 48?h. After 72 h, cell proliferation was significantly greater in the control group than in the irradiated groups treated with the steroid at concentrations of 10, 25, and 50 μM. With regard to cell differentiation, alkaline phosphatase activity was significantly higher in the irradiated group treated with 50 μM ND than in the control group, irradiated non-treated group, and irradiated group treated with 25 μM ND. After 60 min of plating, the irradiated non-treated group and irradiated groups treated with the steroid at concentrations of 5, 10, and 25 μM exhibited a significant increase in cell adhesion compared to the control group. LLLT in combination with a high concentration of steroid inhibited cell proliferation, possibly by inducing cell differentiation, while irradiation combined with lower concentrations of the steroid induced an increase in cell adhesion.     

Femoral offset is underestimated on anteroposterior radiographs of the pelvis but accurately assessed on anteroposterior radiographs of the hip

The aim of this retrospective cohort study was to identify any difference in femoral offset as measured on pre-operative anteroposterior (AP) radiographs of the pelvis, AP radiographs of the hip and corresponding CT scans in a consecutive series of 100 patients with primary end-stage osteoarthritis of the hip (43 men and 57 women with a mean age of 61 years (45 to 74) and a mean body mass index of 28 kg/m(2) (20 to 45)). Patients were positioned according to a standardised protocol to achieve reproducible projection and all images were calibrated. Inter- and intra-observer reliability was evaluated and agreement between methods was assessed using Bland-Altman plots. In the entire cohort, the mean femoral offset was 39.0 mm (95% confidence interval (CI) 37.4 to 40.6) on radiographs of the pelvis, 44.0 mm (95% CI 42.4 to 45.6) on radiographs of the hip and 44.7 mm (95% CI 43.5 to 45.9) on CT scans. AP radiographs of the pelvis underestimated femoral offset by 13% when compared with CT (p < 0.001). No difference in mean femoral offset was seen between AP radiographs of the hip and CT (p = 0.191). Our results suggest that femoral offset is significantly underestimated on AP radiographs of the pelvis but can be reliably and accurately assessed on AP radiographs of the hip in patients with primary end-stage hip osteoarthritis. We, therefore, recommend that additional AP radiographs of the hip are obtained routinely for the pre-operative assessment of femoral offset when templating before total hip replacement.     

Caudal bupivacaine supplemented with morphine or clonidine,or supplemented with morphine plus clonidine in children undergoing infra-umbilical urological and genital procedures: a prospective,randomized and double-blind study

Purpose  

We aimed to evaluate postoperative analgesia of morphine, or clonidine, or morphine plus clonidine, added to caudal bupivacaine in children undergoing infra-umbilical urological and genital procedures.     

CNS myelin induces regulatory functions of DC-SIGN–expressing,antigen-presenting cells via cognate interaction with MOG

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN–dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th₁₇-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG–DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.Professional APCs are equipped with receptors that recognize, capture, and internalize antigens to facilitate their processing and presentation to T cells. Among APCs, DCs are unique in their capacity to stimulate naive T cells; however, their function is not restricted to the initiation of strong immune responses against pathogens, but also to regulate T cell homeostasis and prevent autoimmunity. Indeed, DCs efficiently support the in vitro generation and expansion of iT reg cells, regulate T reg cell homeostasis in vivo (Fehérvári and Sakaguchi, 2004; Cong et al., 2005), and even induce T cell anergy (Hawiger et al., 2001). Targeting of antigen to resting DCs via DEC-205 resulted in an unsustained expansion of antigen-specific CD4⁺ T cells that did not differentiate into effector cells (Hawiger et al., 2001). Similar functional unresponsiveness was observed in naive antigen-specific CD8⁺ T cells when splenic lymphoid DCs were exposed to dying cells loaded with cognate antigen (Liu et al., 2002). Unfortunately, reports on DC-lacking mice are controversial (Birnberg et al., 2008; Ohnmacht et al., 2009) and the precise role of DCs in the maintenance of peripheral tolerance in humans remains to be determined.C-type lectin receptors (CLRs), such as DEC-205 and DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN), have been proposed to play an important role in homeostatic control. DC-SIGN is a type II transmembrane receptor equipped with a Ca²⁺-dependent mannose-binding carbohydrate recognition domain with specificity for antigens decorated with high-mannose or Lewis-type structures (Appelmelk et al., 2003). Signaling crosstalk with TLRs has been demonstrated for DC-SIGN and some other CLRs on DCs (Geijtenbeek and Gringhuis, 2009). Although eight mouse genetic homologues are known (Park et al., 2001; Powlesland et al., 2006), none has the same glycan specificity, expression profile, or signaling properties as human DC-SIGN (García-Vallejo and van Kooyk, 2013). Hence, knowledge on the physiological functions of DC-SIGN is based on human in vitro data. Contrary to other antigen-uptake receptors, pathogen recognition by DC-SIGN often results in immune escape (van Kooyk and Geijtenbeek, 2003; Rappocciolo et al., 2008; Wang et al., 2008) and the carbohydrate ligands of DC-SIGN are also found on host glycoproteins, suggesting that DC-SIGN participates in the control of immune homeostasis (García-Vallejo and van Kooyk, 2009). Interaction of DC-SIGN with its ligands on immune cells mediates adhesion and favors communication during (cognate) interactions. DC-SIGN ligands on nonimmunological tissues, such as the tumor-associated epithelial proteins CEA and CEACAM1 (van Gisbergen et al., 2005) can enhance the cytokine response of DCs to the TLR4 ligand LPS in a similar way, as previously reported for the M. tuberculosis DC-SIGN ligand ManLAM, by synergistically increasing the LPS-mediated secretion of IL-10 (Geijtenbeek et al., 2003). Additionally, supernatants from CEA and CEACAM1-producing cell lines inhibited DC maturation and attenuated Th₁ skewing (Nonaka et al., 2008). Apparently, both tumor and pathogens have ways to escape immune activation by targeting a receptor that is able to transform proinflammatory into tolerogenic signals. DC-SIGN has therefore been proposed to be a homeostatic receptor that can be subverted by pathogens and tumors through changes in their glycan phenotype. However, DC-SIGN has not yet been found to recognize any autoantigen, or to support any role in the maintenance of peripheral tolerance in humans.The central nervous system (CNS) has evolved as an immune-privileged site to protect its vital functions from detrimental insults, by immune-mediated inflammation. Microglia are CNS-based APCs that continuously evaluate local changes in the CNS to activate the immune system during injury (Olson and Miller, 2004) or to maintain homeostasis in the steady state (Lambert et al., 2008). Accumulating evidence suggests that glycosylation plays a role in the control of peripheral tolerance to brain autoantigens. Induction of experimental autoimmune encephalomyelitis, the animal model of MS, is much more efficient when recombinant unglycosylated myelin oligodendrocyte glycoprotein (MOG) is used, in contrast to native MOG (Smith et al., 2005). Also, alterations in glycosyltransferases (Husain et al., 2008; Brynedal et al., 2010) or glycan-binding proteins (Hoppenbrouwers et al., 2009) have been linked to a higher incidence of MS. Yet, the molecular mechanisms behind this association remain unclear.Here, we show for the first time that a major autoantigen in MS, MOG, is recognized by DC-SIGN on APCs within the human brain, including microglia. The interaction results in the transmission of a tolerogenic signal characterized by increased IL-10 secretion and decreased T cell proliferation. Conversely, myelin particles lacking DC-SIGN ligands induce immunogenic signals characterized by inflammasome activation and enhanced T cell proliferation. Our results help to explain how an immunosuppressive milieu in the healthy human CNS is maintained through the glycosylation status of MOG/myelin that engages DC-SIGN, keeping local APCs in an immature nonpathogenic state.     

In Vitro Activity of Solithromycin against Erythromycin-Resistant Streptococcus agalactiae

The in vitro antibacterial activity of solithromycin (CEM-101) against macrolide-resistant isolates (n = 62) of Streptococcus agalactiae (group B streptococcus [GBS]) was determined. Phenotypic characterization of macrolide-resistant strains was performed by double-disc diffusion testing. A multiplex PCR was used to identify the erm(B), erm(TR), and mef(A/E) genes, capsular genotypes, and alpha-like (Alp) protein genes from the GBS strains. Determination of MIC was carried out using the microdilution broth method. The Etest method was used for penicillin, azithromycin, clarithromycin, and erythromycin. Solithromycin had a MIC₅₀ of ≤0.008 μg/ml and a MIC₉₀ of 0.015 μg/ml against macrolide-susceptible S. agalactiae. These MICs were lower than those displayed by penicillin (MIC₅₀ of 0.032 μg/ml and MIC₉₀ of 0.047 μg/ml), the antibiotic agent of choice for prophylaxis and treatment of GBS infections. Against macrolide-resistant S. agalactiae, solithromycin had a MIC₅₀ of 0.03 μg/ml and a MIC₉₀ of 0.125 μg/ml. Against erm(B) strains, solithromycin had a MIC₅₀ of 0.03 μg/ml and a MIC₉₀ of 0.06 μg/ml, while against mef(A) strains, it had a MIC₅₀ of 0.03 μg/ml and a MIC₉₀ of 0.125 μg/ml. Most erythromycin-resistant GBS strains were of serotype V (64.5%) and associated significantly with alp2-3. Moreover, a statistically significant association was observed between the constitutive macrolide-lincosamide-streptogramin B resistance (cMLS_B) phenotype and the erm(B) gene-carrying strains, the alp2-3 gene and the M phenotype, and the mef(A/E) gene and epsilon. Overall, our results show that solithromycin had lower or similar MICs than penicillin and potent activity against macrolide-resistant strains independent of their genotype or phenotype, representing a valid therapeutic alternative where β-lactams cannot be used.     

In Vitro Activity of the New Fluoroketolide Solithromycin (CEM-101) against Macrolide-Resistant and -Susceptible Mycoplasma genitalium Strains

Mycoplasma genitalium has become well established as an etiological agent of sexually transmitted infections, but due to its fastidious growth requirements, only a few M. genitalium strains are available to determine the MICs of currently used and new antimicrobial agents. Recent clinical trials have suggested that treatment with azithromycin has decreasing efficacy due to an increasing prevalence of macrolide resistance, and alternative treatment with moxifloxacin is similarly under pressure from emerging resistance. Thus, there is an urgent need for new antimicrobials. The in vitro activity of the newly developed fluoroketolide solithromycin (CEM-101) was evaluated against a collection of 40 M. genitalium strains, including 15 with high-level macrolide resistance and 5 multidrug-resistant strains with resistance to both macrolides and quinolones. Furthermore, the MIC of solithromycin was correlated with mutations in the 23S rRNA gene and in the genes encoding ribosomal proteins L4 and L22. The in vitro results showed that solithromycin has activity against M. genitalium superior to that of other macrolides, doxycycline, and fluoroquinolones. Accordingly, this new fluoroketolide might be an effective option for treatment of M. genitalium infections. However, the efficacy of solithromycin in clinical trials with follow-up for test of cure and detection of genotypic and phenotypic resistance needs to be evaluated prior to widespread use. In a phase 2 clinical trial, solithromycin was highly effective as a single oral dose against C. trachomatis and Neisseria gonorrhoeae, suggesting that solithromycin could be a treatment option for several sexually transmitted infections, including in syndromic treatment of urethral and vaginal discharge.