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.     

Perceived pain during rapid maxillary expansion in children with different expanders:: A prospective study

ObjectivesTo evaluate and compare the intensity of pain caused by rapid maxillary expansion (RME) with two expanders: Hyrax and Haas type, in growing patients.Materials and MethodsThirty-nine patients (23 girls and 16 boys) with an average age of 9.3 years (SD = 1.39 years) were randomized into two groups and treated with Hyrax- and Haas-type expanders. In both groups, initial activation of the expander screw was one full turn on the first day followed by 2/4 of a turn two times a day (morning and night) for 7 days. Inclusion criteria were patients presenting with a posterior crossbite or maxillary atresia between 7 and 12 years old. To evaluate the intensity of pain during the active phase of the treatment, a combination of the Numerical Rating Scale and Wong-Baker Faces Pain Scale was used. Mann-Whitney test was used to compare the two treatment groups.ResultsThere was significant inverse correlation between days following insertion and pain. During the expansion period, 100% of the children reported some pain. Hyrax expander subjects reported greater pain than those treated with the Haas-type expander only on the first day. The level of pain remained greater in girls throughout treatment.ConclusionsPain was reported regardless of the type of expander and was higher in the Hyrax group only on the first day of activation.     

Distribution of serotypes and evaluation of antimicrobial susceptibility among human and bovine Streptococcus agalactiae strains isolated in Brazil between 1980 and 2006

Streptococcus agalactiae is a common agent of clinical and subclinical bovine mastitis and an important cause of human infections, mainly among pregnant women, neonates and nonpregnant adults with underlying diseases. The present study describes the genetic and phenotypic diversity among 392 S. agalactiae human and bovine strains isolated between 1980 and 2006 in Brazil. The most prevalent serotypes were Ia, II, III and V and all the strains were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampicin and tetracycline was observed. Among the erythromycin resistant strains, mefA/E, ermA and, mainly, ermB gene were detected, and a shift of prevalence from the macrolide resistance phenotype to the macrolide-lincosamide-streptogramin B resistance phenotype over the years was observed. The 23 macrolide-resistant strains showed 19 different pulsed-field gel electrophoresis profiles. Regarding macrolide resistance, a major concern in S. agalactiae epidemiology, the present study describes an increase in erythromycin resistance from the 80s to the 90s followed by a decrease in the 2000–2006 period. Also, the genetic heterogeneity described points out that erythromycin resistance in Brazil is rather due to horizontal gene transmission than to spreading of specific macrolide-resistant clones.     

Congenital lobar emphysema: 30-year case series in two university hospitals

OBJECTIVE:

To review the cases of patients with congenital lobar emphysema (CLE) submitted to surgical treatment at two university hospitals over a 30-year period.

METHODS:

We reviewed the medical records of children with CLE undergoing surgical treatment between 1979 and 2009 at the Botucatu School of Medicine Hospital das Clínicas or the Mogi das Cruzes University Hospital. We analyzed data regarding symptoms, physical examination, radiographic findings, diagnosis, surgical treatment, and postoperative follow-up.

RESULTS:

During the period studied, 20 children with CLE underwent surgery. The mean age at the time of surgery was 6.9 months (range, 9 days to 4 years). All of the cases presented with symptoms at birth or during the first months of life. In all cases, chest X-rays were useful in defining the diagnosis. In cases of moderate respiratory distress, chest CT facilitated the diagnosis. One patient with severe respiratory distress was misdiagnosed with hypertensive pneumothorax and underwent chest tube drainage. Only patients with moderate respiratory distress were submitted to bronchoscopy, which revealed no tracheobronchial abnormalities. The surgical approach was lateral muscle-sparing thoracotomy. The left upper and middle lobes were the most often affected, followed by the right upper lobe. Lobectomy was performed in 18 cases, whereas bilobectomy was performed in 2 (together with bronchogenic cyst resection in 1 of those). No postoperative complications were observed. Postoperative follow-up time was at least 24 months (mean, 60 months), and no late complications were observed.

CONCLUSIONS:

Although CLE is an uncommon, still neglected disease of uncertain etiology, the radiological diagnosis is easily made and surgical treatment is effective.     

Pneumomediastinum,subcutaneous emphysema,and pneumothorax after a pulmonary function testing in a patient with bleomycin-induced interstitial pneumonitis

Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which includes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The pathophysiological mechanism involved is the emergence of a pressure gradient between the alveoli and surrounding structures, causing alveolar rupture with subsequent dissection of the peribronchovascular sheath and infiltration of the mediastinum and subcutaneous tissue with air. Known triggers include acute exacerbations of asthma and situations that require the Valsalva maneuver. We described and documented with HRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced interstitial lung disease underwent pulmonary function testing. Although uncommon, the association between pulmonary function testing and air leak syndromes has been increasingly reported in the literature, and lung diseases, such as interstitial lung diseases, include structural changes that facilitate the occurrence of this complication.