Adjuvant glycerol is not beneficial in experimental pneumococcal meningitis

Bacterial meningitis in children causes high rates of mortality and morbidity. In a recent clinical trial, oral glycerol significantly reduced severe neurological sequelae in paediatric meningitis caused by Haemophilus influenzae type b, and a tendency towards a benefit of adjunctive glycerol was seen in pneumococcal meningitis.

Steam pops during irrigated radiofrequency ablation: feasibility of impedance monitoring for prevention

BACKGROUND: Steam pops are a risk of irrigated radiofrequency catheter ablation (RFA) and may cause cardiac perforation. Data to guide radiofrequency (RF) energy titration to avoid steam pops are limited. OBJECTIVE: This study sought to assess the frequency and consequence of audible pops and to determine the feasibility of using the magnitude of impedance change to predict pops. METHODS: We reviewed consecutive endocardial open-irrigated RFA for ventricular tachycardia (VT) with continuously recorded ablation data in 142 patients with structural heart disease. Steam pops were defined as an audible pop associated with a sudden spike in impedance. Ablation lesions before or after pops served as controls. RESULTS: From a total of 4,107 ablation lesions, 62 (1.5%) steam pops occurred in 42 procedures in 38 patients. Perforation with tamponade occurred with 1 of 62 (2%) pops. Applications with pops had a greater impedance decrease (22 +/- 7 Omega vs. 18 +/- 8 Omega, P = .001) and a higher maximum power (45 +/- 5 W vs. 43 +/- 6 W, P = .011), but did not differ in maximum catheter tip temperature (40 degrees C +/- 4 degrees C vs. 40 degrees C +/- 4 degrees C, P = .180) from applications without pops. Eighty percent of pops occurred after impedance decreased by at least 18 Omega. CONCLUSION: During VT ablation with open irrigation, audible pops are infrequent and do not usually cause perforation. Limiting RF power to achieve an impedance decrease of <18 Omega is a feasible method of reducing the likelihood of a pop when perforation risk is of concern.

Association between elevated brain tissue glycerol levels and poor outcome following severe traumatic brain injury

OBJECT: Glycerol is considered to be a marker of cell membrane degradation and thus cellular lysis. Recently, it has become feasible to measure via microdialysis cerebral extracellular fluid (ECF) glycerol concentrations at the patient's bedside. Therefore the aim of this study was to investigate the ECF concentration and time course of glycerol after severe traumatic brain injury (TBI) and its relationship to patient outcome and other monitoring parameters. METHODS: As soon as possible after injury for up to 4 days, 76 severely head-injured patients were monitored using a microdialysis probe (cerebral glycerol) and a Neurotrend sensor (brain tissue PO2) in uninjured brain tissue confirmed by computerized tomography scanning. The mean brain tissue glycerol concentration in all monitored patients decreased significantly from 206 +/- 31 micromol/L on Day 1 to 9 +/- 3 micromol/L on Day 4 after injury (p < 0.0001). Note, however, that there was no significant difference in the time course between patients with a favorable outcome (Glasgow Outcome Scale [GOS] Scores 4 and 5) and those with an unfavorable outcome (GOS Scores 1-3). Significantly increased glycerol concentrations were observed when brain tissue PO2 was less than 10 mm Hg or when cerebral perfusion pressure was less than 70 mm Hg. CONCLUSIONS: Based on results in the present study one can infer that microdialysate glycerol is a marker of severe tissue damage, as seen immediately after brain injury or during profound tissue hypoxia. Given that brain tissue glycerol levels do not yet add new clinically significant information, however, routine monitoring of this parameter following traumatic brain injury needs further validation.

Glycerol metabolism is important for cytotoxicity of Mycoplasma pneumoniae

Glycerol is one of the few carbon sources that can be utilized by Mycoplasma pneumoniae. Glycerol metabolism involves uptake by facilitated diffusion, phosphorylation, and the oxidation of glycerol 3-phosphate to dihydroxyacetone phosphate, a glycolytic intermediate. We have analyzed the expression of the genes involved in glycerol metabolism and observed constitutive expression irrespective of the presence of glycerol or preferred carbon sources. Similarly, the enzymatic activity of glycerol kinase is not modulated by HPr-dependent phosphorylation. This lack of regulation is unique among the bacteria for which glycerol metabolism has been studied so far. Two types of enzymes catalyze the oxidation of glycerol 3-phosphate: oxidases and dehydrogenases. Here, we demonstrate that the enzyme encoded by the M. pneumoniae glpD gene is a glycerol 3-phosphate oxidase that forms hydrogen peroxide rather than NADH(2). The formation of hydrogen peroxide by GlpD is crucial for cytotoxic effects of M. pneumoniae. A glpD mutant exhibited a significantly reduced formation of hydrogen peroxide and a severely reduced cytotoxicity. Attempts to isolate mutants affected in the genes of glycerol metabolism revealed that only the glpD gene, encoding the glycerol 3-phosphate oxidase, is dispensable. In contrast, the glpF and glpK genes, encoding the glycerol facilitator and the glycerol kinase, respectively, are essential in M. pneumoniae. Thus, the enzymes of glycerol metabolism are crucial for the pathogenicity of M. pneumoniae but also for other essential, yet-to-be-identified functions in the M. pneumoniae cell.

Do N-arachidonyl-glycine (NA-glycine) and 2-arachidonoyl glycerol (2-AG) share mode of action and the binding site on the β 2 subunit of GABA A receptors?

NA-glycine is an endogenous lipid molecule with analgesic properties, which is structurally similar to the endocannabinoids 2-AG and anandamide but does not interact with cannabinoid receptors. NA-glycine has been suggested to act at the G-protein coupled receptors GPR18 and GPR92. Recently, we have described that NA-glycine can also modulate recombinant α1β2γ2 GABAA receptors. Here we characterize in more detail this modulation and investigate the relationship of its binding site with that of the endocannabinoid 2-AG.

Lessons from the Multilateral Trading System for Reforming the Architecture of the International Environmental Regime

Recent studies on environmental regimes suggest that important lessons and policy recommendations may be drawn from the functioning of the multilateral trading regime. This brief compares the needs and goals of the trade and environment regimes, and discusses how insights from over sixty years of experience of the multilateral trading system might provide ideas for redesigning the architecture of the international environmental regime. It further calls for a better dialogue and improved complementarities between the two fields in order to enhance coherence within international law.

Cattle immunized against the pathogenic L-α-glycerol-3-phosphate oxidase of Mycoplasma mycoides subs. mycoides fail to generate neutralizing antibodies and succumb to disease on challenge

The membrane-associated enzyme L-α-glycerol-3-phosphate oxidase (GlpO) of Mycoplasma mycoides subs. mycoides (Mmm), the causal agent of contagious bovine pleuropneumonia (CBPP) has been identified as a virulence factor responsible for the release of toxic by-products such as H2O2 that mediate host cell injury. Since CBPP pathogenesis is based on host inflammatory reactions, we have determined the capacity of recombinant GlpO to generate in vivo protective responses against challenge in immunized cattle. We also investigated whether sera raised against recombinant GlpO in cattle and mice inhibit production of H2O2 by Mmm. Immunization of cattle with recombinant GlpO did not protect against challenge with a virulent strain of Mmm. Further, although both murine and bovine antisera raised against recombinant GlpO detected recombinant and native forms of GlpO in immunoblot assays with similar titres, only murine antibodies could neutralize GlpO enzymatic function. The data raise the possibility that Mmm has adapted to evade potential detrimental antibody responses in its definitive host.

4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation

BACKGROUND AND PURPOSE 4'-O-methylhonokiol (MH) is a natural product showing anti-inflammatory, anti-osteoclastogenic, and neuroprotective effects. MH was reported to modulate cannabinoid CB2 receptors as an inverse agonist for cAMP production and an agonist for intracellular [Ca2+]. It was recently shown that MH inhibits cAMP formation via CB2 receptors. In this study, the exact modulation of MH on CB2 receptor activity was elucidated and its endocannabinoid substrate-specific inhibition (SSI) of cyclooxygenase-2 (COX-2) and CNS bioavailability are described for the first time. METHODS CB2 receptor modulation ([35S]GTPγS, cAMP, and β-arrestin) by MH was measured in hCB2-transfected CHO-K1 cells and native conditions (HL60 cells and mouse spleen). The COX-2 SSI was investigated in RAW264.7 cells and in Swiss albino mice by targeted metabolomics using LC-MS/MS. RESULTS MH is a CB2 receptor agonist and a potent COX-2 SSI. It induced partial agonism in both the [35S]GTPγS binding and β-arrestin recruitment assays while being a full agonist in the cAMP pathway. MH selectively inhibited PGE2 glycerol ester formation (over PGE2) in RAW264.7 cells and significantly increased the levels of 2-AG in mouse brain in a dose-dependent manner (3 to 20 mg kg(-1)) without affecting other metabolites. After 7 h from intraperitoneal (i.p.) injection, MH was quantified in significant amounts in the brain (corresponding to 200 to 300 nM). CONCLUSIONS LC-MS/MS quantification shows that MH is bioavailable to the brain and under condition of inflammation exerts significant indirect effects on 2-AG levels. The biphenyl scaffold might serve as valuable source of dual CB2 receptor modulators and COX-2 SSIs as demonstrated by additional MH analogs that show similar effects. The combination of CB2 agonism and COX-2 SSI offers a yet unexplored polypharmacology with expected synergistic effects in neuroinflammatory diseases, thus providing a rationale for the diverse neuroprotective effects reported for MH in animal models.