Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation

Intensive care unit (ICU)-acquired infections as a result of multidrug-resistant Gram-negative pathogens remain a serious problem in critically ill patients. Adult ICU patients who received intravenous fosfomycin were prospectively examined to assess its safety and effectiveness as an adjunct to the antimicrobial therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae. Fosfomycin was administered intravenously in 11 patients for treatment of hospital-acquired infections caused by carbapenem-resistant K. pneumoniae. Fosfomycin (2–4 g every 6 h) was administered in combination with other antibiotics. The mean ± SD duration of treatment was 14 ± 5.6 days. All patients had good bacteriological and clinical outcome of infection. All-cause hospital mortality was two out of 11 (18.2%) patients. No patient experienced adverse events related to the administration of fosfomycin. Intravenous fosfomycin may be a beneficial and safe adjunctive treatment in the management of life-threatening ICU-acquired infections caused by carbapenem-resistant K. pneumoniae.     

Adverse effects of parenteral antimicrobial therapy for chronic bone infections

Responsible pathogens of chronic bone infections (CBI) are frequently resistant, requiring parenteral antimicrobial therapy. Therefore, adverse effects may be observed. We have determined the rate of adverse effects of antimicrobial therapy for CBI in a retrospective study of all patients receiving parenteral drugs via an implantable port. Patients from one medical ward (n = 89) and from one surgical ward (n = 40) between January 1995 and December 2005 were included in this study. The CBI included were 85 osteomyelitis (66%) and 44 prosthetic joint infections (34%). The main group of pathogens was Gram positive cocci (n = 144; 65%). The total duration of antibiotic treatment was 205 ± 200 days, including 133 ± 100 days for parenteral therapy. Thirty-three catheter-related complications were observed in 27 patients (21%). All complications led to hospitalization but none led to death. Twenty-one antibiotic-related complications occurred in 18 patients (16%), and one allergic reaction led to death. The mean duration of follow-up was 290 days. Remission was observed in 84 patients (65%). In multivariate analysis, adverse effects were mostly observed in the medical department. Adverse effects affect at least one third of the patients treated for CBI with parenteral antimicrobial therapy and are related to both the implantable port and the antibiotic compounds.     

Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study

Ventilator-associated pneumonia (VAP) as a result of multidrug-resistant Gram-negative bacteria has contributed to the revival of the use of intravenous (i.v.) colistin. However, the additional administration of inhaled colistin for VAP is controversial. We performed a retrospective cohort study of patients with microbiologically documented VAP who received i.v. colistin with or without inhaled colistin. Seventy-eight patients with VAP received i.v. plus inhaled colistin, whereas 43 patients received i.v. colistin alone. The mean ± SD daily dosage of i.v. colistin was 7.0 ± 2.4 and 6.4 ± 2.3 million international units (IU), respectively (p 0.13); the average daily dosage of inhaled colistin was 2.1 ± 0.9 million IU. The outcome of infection was cure for 62/78 (79.5%) patients who received i.v. plus inhaled colistin vs. 26/43 (60.5%) patients who received i.v. colistin alone (p 0.025); all-cause in-hospital mortality was 31/78 (39.7%) vs. 19/43 (44.2%), respectively (p 0.63); all-cause intensive care unit (ICU) mortality was 28/78 (35.9%) vs. 17/43 (39.5%), respectively (p 0.92). The use of inhaled colistin was independently associated with the cure of VAP in a multivariable analysis (OR 2.53, 95% CI 1.11–5.76). Independent predictors of mortality were a higher APACHE II score (OR 1.12, 95% CI 1.04–1.20), presence of malignancy (OR 4.11, 95% CI 1.18–14.23) and lower daily dosage of i.v. colistin (OR 0.81, 95% CI 0.68–0.96). The outcome of VAP was better in patients who received inhaled colistin with i.v. colistin than those who received i.v. colistin alone. There was no difference in all-cause in-hospital and ICU mortality between the two groups. Randomized controlled trials are needed to evaluate further the role of inhaled colistin in VAP.     

Idursulfase treatment of Hunter syndrome in children younger than 6 years: Results from the Hunter Outcome Survey

PurposeTo use the Hunter Outcome Survey, an international database, to assess the safety and effectiveness of enzyme replacement therapy with idursulfase in patients with Hunter syndrome who started treatment before 6 years of age.MethodsThe study population included all patients enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) before 6 years of age and who had at least one follow-up examination recorded.ResultsThe study population included 124 patients, younger than 6 years, who had a mean age at start of idursulfase of 3.6 ± 1.6 years (mean ± SD). The mean duration of treatment was 22.9 ± 14.6 months. A total of 69 infusion-related reactions occurred in 33 (26.6%) patients, including three serious infusion-related reactions occurring in a single patient. After at least 6 months of idursulfase, urine glycosaminoglycan levels decreased from 592 ± 188 to 218 ± 115 μg/mg creatinine (P < 0.0001, n = 34). Liver size, estimated by palpation, was also significantly decreased (P = 0.005, n = 23). Similar safety and effectiveness results were seen in patients who were aged 6 years or older when initiating idursulfase.Conclusion: No new safety concerns were identified in patients younger than 6 years, and clinical benefit was suggested by the reduction in liver size. Genet Med 2011:13(2):102–109.     

The pharmacokinetic profile of raltegravir-containing antiretroviral therapy in HIV-infected individuals over 60 years of age

Background:

Antiretroviral safety and efficacy and may differ in older versus younger HIV-infected patients. The objective of this study was to assess the pharmacokinetic (PK) profile in older HIV-infected subjects (>60?years) switching combination antiretroviral therapy (cART) to a raltegravir (RAL) containing regimen.

Methods:

Nineteen HIV-infected patients over 60?years of age on effective cART (HIV-RNA Results:

In HIV-infected subjects over the age of 60 (mean?±?SD age: 66?±?3.4?years, n?=?19) switching to a RAL containing regimen, we observed no safety concerns, no plasma virological rebounds, and no differences in RAL apparent oral clearance when compared to younger HIV-infected populations (mean?±?SD age: 41?±?9.2?years, n?=?38) based on population pharmacokinetic analysis. After 24?weeks of study therapy a decline in cognitive function was observed [change in (SD) global score of (0.91 (1.3), P?=?0.018].

Conclusions:

No significant changes in RAL exposure associated with age were observed.     

Pituitary-adrenal effects on sexual behavior in isolated and group-housed mice.

The duration and intensity of some components of the male copulatory pattern was studied in ten male (seven experienced, three inexperienced) and two female New Zealand white rabbits by using high speed cinematography, accelerometry and by recording the pressure of the seminal vesicles. Duration of mounts varied greatly within and among subjects. Effective mounts, i.e., those terminating in ejaculation, lasted less (2.61±1.50 sec, mean ± SD; n, 59) than ineffective mounts (3.08 ± 2.16 sec, mean ± SD; n, 199). Frequency of pelvic thrusting was significantly higher in effective (13.54 ± 1.11 sec, mean ± SD; n, 59) than in ineffective mounts (12.08 ± 0.98 sec, mean ± SD; n, 176). No pelvic thrusting occurred during intromission which usually lasted less than one second (722 ± 266 msec SD; n, 43). Shortly after intromission (230 ± 107 msec, mean ± SD; n, 32) the pressure of the seminal vesicles raised. This rise in pressure outlasted copulation (1040 ± 369 msec, mean ± SD; n, 32). The mounting pattern of inexperienced rabbits was similar to that of experienced rabbits. The mounting pattern of females differed from that of males both in rate of pelvic thrusting and duration of pelvic thrusts.     

Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia

Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p?=?0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p?<?0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.     

Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis

Immune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA‐B molecules associated with uveitis, such as HLA‐B27 and 51, which shares amino acid homologies with a retinal‐S antigen (S‐Ag)‐derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behçet’s disease and posterior uveitis (BD‐posterior uveitis; n = 33) in comparison with non‐Behçet anterior uveitis (AU, n = 14), Behçet’s patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6‐day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2·8 ± 1·3) than those with AU (SI 1·5 ± 0·4), BD without uveitis (SI 1·1 ± 0·4) and HC (SI 1·1 ± 0·6) for B27PD (P < 0·0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3·3 ± 1·6) than AU (SI 1·5 ± 0·4), BD without uveitis (SI 1·2 ± 0·3) and HC (SI 1·1 ± 0·6) (P < 0·0001). A significant correlation between the responses to PDSAg and B27PD (r = 0·56, P < 0·001) was observed. Elevated levels of IL‐2 and tumour necrosis factor‐alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross‐reactive HLA‐B and S‐Ag‐derived peptides might play a role in the pathogenesis of posterior uveitis in BD.     

Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset

In a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two weeks of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n=14), polysomnography (n=22), actigraphy (n=13), sleep log (n=22), and subjective sleep quality (n=25). Mean dim light melatonin onset (DLMO) (±SD), before treatment, occurred at 23.17 hours (±138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.     

Mutant prevention concentration of colistin alone and in combination with rifampicin for multidrug-resistant <Emphasis Type="Italic">Acinetobacter baumannii</Emphasis>

Colistin-susceptible isolates of Acinetobacter baumannii often contain subpopulations that are resistant to colistin. Monotherapy with colistin can lead to selective growth of these subpopulations and emergence of colistin-resistant strains. Our objectives were to explore the susceptibility pattern of colistin-resistant subpopulations and investigate if combining colistin with a second antibiotic could prevent their selective growth. Four colistin-susceptible clinical isolates of A. baumannii and one reference isolate were used. The mutant prevention concentration (MPC) of colistin, i.e. the concentration required to block growth of all single-step-mutant subpopulations, was determined by plating an inoculum of 10⁹ CFU on Mueller Hinton agar (MHA)-plates containing 2-fold dilutions of colistin (0.125–128 mg/L). Susceptibility testing of colistin-resistant subpopulations, obtained in the MPC assay, was performed with Etest. The MPC of colistin, in combination with rifampicin, was determined by plating an inoculum of 10⁹ CFU on MHA-plates containing colistin (0.125–128 mg/L) and fixed concentrations of rifampicin (1.1 mg/L or 4.4 mg/L). The colistin-resistant subpopulations demonstrated increased susceptibility to a number of agents compared to their main populations. These subpopulations were even susceptible to agents that normally are inactive against gram-negative bacteria and all had rifampicin MICs of?<?0.002 mg/L. The combination of colistin and rifampicin completely inhibited the growth of all colistin-resistant subpopulations and significantly lowered the MPC of colistin for A. baumannii. Combining colistin with rifampicin could be a way to prevent selective growth of colistin-resistant subpopulations of A. baumannii and possibly the emergence of colistin-resistant strains.     

Evaluation of colistin susceptibility in multidrug-resistant clinical isolates from cystic fibrosis, France

The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125–0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75–3.0 mg/L), whereas three isolates had high MICs (32–256 mg/L). The diameters of zone inhibition with a 50-μg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤12 mm for a 50-μg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.     

Cerebrospinal Fluid Penetration and Pharmacokinetic/Pharmacodynamic Parameters of Intravenously Administered Colistin in a Case of Multidrug-Resistant <Emphasis Type="Italic">Acinetobacter baumannii</Emphasis> Meningitis

Described here is a case of meningitis caused by multidrug-resistant Acinetobacter baumannii susceptible only to colistin, which was treated successfully with intravenous colistin sulfomethate sodium (5 mg/kg/day). The levels of colistin in serum and cerebrospinal fluid and the pharmacokinetic/pharmacodynamic parameters of colistin were determined. In this case, intravenously administered colistin penetrated cerebrospinal fluid (25% of serum levels) at levels sustaining bactericidal concentrations. Electronic Publication     

Prednisolone disposition in steroid-dependent asthmatic children

The pharmacokinetics of a 40-mg intravenous dose of prednisolone were determined in 10 steroid-dependent asthmatic children with highly variable prednisone requirements (5 mg every other day to 40 mg a day). Concentrations of prednisolone and cortisol in plasma over a 24-hr test period were measured by high-performance liquid chromatography. Eosinophil concentrations and the concentration-dependent protein binding of prednisolone were also determined. The mean (±SD) apparent half-life of prednisolone in these children was 2.5 ± 0.5 hr. The mean total volume of distribution was 52.8 ± 14.5 L/1.73 m² and mean plasma clearance was 246 ± 62 ml/min/1.73 m². These pharmacokinetic parameters, as well as the protein binding and eosinopenic response, were similar to values from healthy and steroid-dependent asthmatic adults. The data were also similar in both responsive and relatively resistant patients. The pharmacokinetics and protein binding of prednisolone are not responsible for the highly variable prednisone requirement and clinical response of these children to prednisone therapy.     

Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex

The insular cortex is injured in obstructive sleep apnea (OSA) and responds inappropriately to autonomic challenges, suggesting neural reorganization. The objective of this study was to assess whether the neural changes might result from γ‐aminobutyric acid (GABA) and glutamate alterations. We studied 14 OSA patients [mean age ± standard deviation (SD): 47.5 ± 10.5 years; nine male; apnea–hypopnea index (AHI): 29.5 ± 15.6 events h^?1] and 22 healthy participants (47.5 ± 10.1 years; 11 male), using magnetic resonance spectroscopy to detect GABA and glutamate levels in insular cortices. We localized the cortices with anatomical scans, and measured neurochemical levels from anterior to mid‐regions. Left and right anterior insular cortices showed lower GABA and higher glutamate in OSA versus healthy subjects [GABA left: OSA n = 6: 0.36 ± 0.10 (mean ± SD), healthy n = 5: 0.62 ± 0.18; P < 0.05), right: OSA n = 11: 0.27 ± 0.09, healthy n = 14: 0.45 ± 0.16; P < 0.05; glutamate left: OSA n = 6: 1.61 ± 0.32, healthy n = 8: 0.94 ± 0.34; P < 0.05, right: OSA n = 14: 1.26 ± 0.28, healthy n = 19: 1.02 ± 0.28; P < 0.05]. GABA and glutamate levels were correlated only within the healthy group in the left insula (r: ?0.9, P < 0.05). The altered anterior insular levels of GABA and glutamate may modify integration and projections to autonomic areas, contributing to the impaired cardiovascular regulation in OSA.     

Metabolic rates of minke whales (Balaenoptera acutorostrata) in cold water

Body temperature, blubber thickness and lung capacity (V_e) were recorded in newly killed minke whales, while respiratory frequency (f) was determined in free-swimming animals. Mean deep (thoracic) body temperature was 34.7±0.8 (SD) °C (n= 14). Weighted mean core/blubber interface temperature in animals caught in 2.5-5.5 °C water was 28.8±1.7 °C (n= 8). The minimum average rate of sensible heat loss (HL_s) was 3.81±0.53 (SD) W kg_w^-0.75 (n= 8) in animals with body masses (w) in the range of 1840 to 5740 kg, HL_s being inversely proportional to ω (HL_S= - 2.98 10^-4 w + 4.89 W kgω^{-0 75} (n= 8, r^-2= 0.73, P < 0.01)). The average rate of respiratory heat loss (HL_r) was 0.26±0.04 (SD) W kg_w^-0.75, regardless of w, in the same 8 animals. Total rates of heat loss (HL=HL_r+HL_s) in 2.5-5.5 °C water ranged between 3.40 and 4.87 W kg_w^-0.75, with an average of 4.06±0.52 (SD) W kg_w^-0.75 (n= 8). Estimates of oxygen consumption based on records of f and V_c and data on oxygen extraction from other cetaceans, yielded a range of metabolic rates which compared nicely with the calculated HL values.     

Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement

Experience with debridement and prosthesis retention in early prosthetic joint infections (PJI) due to Staphylococcus aureus is scarce. The present study aimed to evaluate the outcome and predictors of failure. Patients prospectively registered with an early PJI due to S. aureus and 2 years of follow-up were reviewed. Demographics, co-morbidity, type of implant, clinical manifestations, surgical treatment, antimicrobial therapy and outcome were recorded. Remission was defined when the patient had no symptoms of infection, the prosthesis was retained and C-reactive protein (CRP) was ≤1 mg/dL. Univariate and multivariate analysis were performed. Fifty-three patients with a mean ± SD age of 70 ± 10.8 years were reviewed. Thirty-five infections were on knee prosthesis and 18 were on hip prosthesis. The mean ± SD duration of intravenous and oral antibiotics was 10.6 ± 6.7 and 88 ± 45.9 days, respectively. After 2 years of follow-up, 40 (75.5%) patients were in remission. Variables independently associated with failure were the need for a second debridement (OR 20.4, 95% CI 2.3–166.6, p 0.006) and a CRP > 22 mg/dL (OR 9.8, 95% CI 1.5–62.5, p 0.01). The onset of the infection within the 25 days after joint arthroplasty was at the limit of significance (OR 8.3, 95% CI 0.8–85.6, p 0.07). Debridement followed by a short period of antibiotics is a reasonable treatment option in early PJI due to S. aureus. Predictors of failure were the need for a second debridement to control the infection a CRP > 22 mg/dL and the infection onset within the first 25 days after joint arthroplasty.     

Ceftazidime- and Imipenem-Induced Endotoxin Release During Treatment of Gram-Negative Infections

To determine whether ceftazidime and imipenem, which target two different penicillin-binding proteins, result in different amounts of endotoxin and cytokine release in patients with gram-negative infection, plasma endotoxin, interleukin-6, and tumor necrosis factor alpha were measured during the first 24 h of antibiotic therapy in 27 patients with gram-negative infection who had been randomized to receive either ceftazidime 2 g t.i.d. (n=12) or imipenem/cilastatin 1 g t.i.d. (n=15). The source of infection was the digestive tract (n=13), the urinary tract (n=5), the respiratory tract (n=2), soft tissue (n=2), i.v. line (n=2), or other (n=3). After the first antibiotic injection, a significant increase in the median concentration of plasma interleukin-6 and plasma tumor necrosis factor alpha was noted, without significant differences related to the antibiotic administered. Antibiotic-induced endotoxemia was detectable in nine patients (including 7 with bacteremia). In conclusion, ceftazidime and imipenem had similar effects on endotoxin and cytokine release during the treatment of gram-negative infections. Electronic Publication     

Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment, but resistance always ensues. In previous years, efforts have focused on new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, for example the “metronomic” approaches. In metronomic scheduling studies, cyclophosphamide (CPA) in GL261 GBM growing subcutaneously in C57BL/6 mice was shown not only to activate antitumor CD8⁺ T‐cell response, but also to induce long‐term specific T‐cell tumor memory. Accordingly, we have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/kg) or TMZ (range 140–240 mg/kg) metronomic administration (every 6 days) were performed in tumor‐bearing mice. Tumor evolution was monitored at 7 T with MRI (T₂‐weighted, diffusion‐weighted imaging) and MRSI‐based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6 ± 21.0 days, n = 30) compared with control (19.4 ± 2.4 days, n = 18). Best results were obtained with 140 mg/kg TMZ (treated, 44.9 ± 29.0 days, n = 12, versus control, 19.3 ± 2.3 days, n = 12), achieving a longer survival rate than previous group work using three cycles of TMZ therapy at 60 mg/kg (33.9 ± 11.7 days, n = 38). Additional interesting findings were, first, clear edema appearance during chemotherapeutic treatment, second, the ability to apply the semi‐supervised source analysis previously developed in our group for non‐invasive TMZ therapy response monitoring to detect CPA‐induced response, and third, the necropsy findings in mice cured from GBM after high TMZ cumulative dosage (980–1400 mg/kg), which demonstrated lymphoma incidence. In summary, every 6 day administration schedule of TMZ or CPA improves survival in orthotopic GL261 GBM with respect to controls or non‐metronomic therapy, in partial agreement with previous work on subcutaneous GL261.     

Doubly selective multiple quantum chemical shift imaging and T1 relaxation time measurement of glutathione (GSH) in the human brain in vivo

Mapping of a major antioxidant, glutathione (GSH), was achieved in the human brain in vivo using a doubly‐selective multiple quantum filtering based chemical shift imaging (CSI) of GSH at 3 T. Both in vivo and phantom tests in CSI and single voxel measurements were consistent with excellent suppression of overlapping signals from creatine, γ‐Amino butyric acid (GABA) and macromolecules. GSH concentration in the fronto‐parietal region was 1.20 ± 0.16 µmol/g (mean ± SD, n = 7). The longitudinal relaxation time (T₁) of GSH in the human brain was 397 ± 44 ms (mean ± SD, n = 5), which was substantially shorter than that of other metabolites. This GSH‐CSI method permits us to address regional differences of GSH in the human brain under conditions where oxidative stress has been implicated, including multiple sclerosis, aging and neurodegenerative diseases. Copyright © 2012 John Wiley & Sons, Ltd.     

Nasal nitric oxide is increased in allergic rhinitis

Background Nitric oxide (NO) plays a major role in the regulation of vascular tone and in non-specific host defence. The epithelium in the paranasal sinuses was recently identified as the major site of NO production in the upper airways. Objective To investigate NO status in allergic rhinitis, we compared the NO concentration in the nasal cavities of control subjects (n= 19) and in patients with allergic rhinitis (n= 36) with symptoms (WS, n= 17) or without symptoms (WOS, n= 19) on the day of the test. Methods NO concentration was measured using a chemiluminescent analyser aspiring from each nasal cavity at a sampling flow rate of 0.7L/min, before and 10min after administration of a nasal vasoconstrictor. Results The mean NO concentration (± se) in the control was 235 ± 11 ppb and 225 ± 9 ppb in the right and left nostrils respectively, and was decreased by 14% and 12% by the nasal vasoconstrictor (P < 0.001). The NO concentration in patients with allergic rhinitis was significantly higher in the right and left nostrils (382 × 20 ppb and 396 ± 28 respectively, P < 0.0001 versus control). All WOS patients demonstrated normal or increased NO concentrations in both nostrils, whereas two WS patients showed decreased NO concentrations in the left nostril. Inhalation of a nasal vasoconstrictor increased NO concentration by 6% and 27% in the right and left nostrils respectively in WS patients. Conclusion Nasal NO concentration is increased in patients with allergic rhinitis. Interestingly, patients without symptoms on the day of the test also showed a clear-cut increase in nasal NO production, which could reflect a permanent inflammation of the sinus mucosa.