Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life

Daycare attendance and siblings are associated with viral-induced wheezing in children. Preexisting immunologic factors may influence the expression of viral infections in infancy, and in turn, recurrent infections may influence the development of immune responses. A total of 285 children were enrolled in the Childhood Origins of Asthma Project at birth and followed for at least 1 year. Cord blood and 1-year mononuclear cells were stimulated with phytohemagglutinin, and cytokine-response profiles were measured by enzyme-linked immunosorbent assay. Nasal lavage was performed for moderate to severe respiratory illnesses. Daycare attendance and/or siblings significantly increased the likelihood of contracting respiratory syncytial virus (1.5-1.6-fold increase) and rhinovirus (1.8-2.1-fold increase), and increased the risk of rhinovirus-induced wheezing (14-18% vs. 2%, p = 0.011). Cord blood IFN-gamma responses were inversely related to the frequency of viral respiratory infections (r(s) = -0.11, p = 0.05), and more significant for subjects with high exposure to other children (r(s) = -0.27, p = 0.028). The interval change in infantile IFN-gamma responses correlated positively with the frequency of viral infections in infancy (r(s) = 0.12, p = 0.047). These data suggest that neonatal IFN-gamma responses may influence antiviral activity, or may represent a marker of antiviral immunity maturation. Conversely, the frequency of viral infections in infancy can influence IFN-gamma responses.     

Effect on vigilance of a single administration of clobazam

Two groups of 30 outpatients, each with various types of anxiety and sleep-disturbance, were treated with 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (Clobazam, Frisium 20) for 28 days. The double-blind, randomized study was designed to find out whether there is a significant difference between the application of the drug in the morning (group A) or at night (group B). The results of 22 patients of group A and 24 of group B could be evaluated. The following tests had been made at the beginning, after 1,2 and 4 weeks of treatment, respectively: 1. Clinical global impression (CGI) of therapeutic effect and side-effects. 2. Symptoms of psychic and somatic anxiety (HAM-A). 3. Sleep (documented by self-rating and investigator). 4. Daytime-drowsiness/dizziness (self-rating scale). 5. Choice reaction time (CRT) tested between 8 and 9 a.m. on the same day once a week. 6. Critical flicker fusion (CFF) tested between 8 and 9 a.m. on the same day once a week. Sleep and daytime-drowsiness/dizziness have been tested daily within the first week. Significant therapeutic improvement could be stated after 4-week treatment by the CGI-test. The CFF-frequency as indicator for vigilance rose to a significantly higher level while the reaction time in the CRT-test was simultaneously reduced. This result was in accordance with earlier studies. Both groups compared with each other, however, did not differ significantly in any of the parameters used. Symptoms of psychic and somatic anxiety have been reduced significantly in both groups after the first, second and fourth week. There was however one remarkable difference between both groups: this refers to the psychic anxiety factor (HAM-A) only. Here the patients of group B (clobazam in the morning) showed better results than the others. This phenomenon may be due to elevated serum levels during daytime. Therefore we recommend in case of predominant psychic anxiety clobazam to be taken in the morning or in divided doses in the morning and in the evening.     

Continuous arteriovenous haemofiltration in children

Continuous arteriovenous haemofiltration (CAVH) was used in 7 critically ill children: a premature neonate with hypervolaemia secondary to hydrops foetalis and six children aged 9 days to 7 years with acute oliguric renal failure. Biospal 0.5 m², Renaflo 0.25 m², Gambro 0.15 m² and Amicon 0.015 m² filters were used according to the weights and ages of the patients.Adequate removal of water and solutes was obtained in 6 patients. One of the patients with the smallest filter needed a change to a filter with a larger surface area to improve water and solute removal. Haemofiltration was maintained for between 17 hours and 31 days and was well tolerated. CAVH was discontinued because of recovery of renal function in three patients, improvement of the hypervolaemic state in one, death in three, and transfer to continuous ambulatory peritoneal dialysis because of chronic renal failure in one patient. CAVH is a useful technique for the treatment of acute renal failure and hypervolaemia in critically ill children.     

Plasma and gastric juice levels of prostaglandins in critically ill children.

The levels of prostaglandin (PG) E2 and 6-keto-PGF1 alpha (stable metabolite of prostacyclin) in plasma and gastric juice were determined in 113 critically ill children and adolescent, and compared to those registered in a plasma control group of 24 children and a gastric juice control group of 15. The gastric juice concentration of PGE2 is our patients [9.2 +/- 3.1 (SEM) pg/ml] was significantly lower (p = 0.001) than in the control group [81.1 +/- 18.1 (SEM) pg/ml]. There were no differences in plasma levels of PGE2 and plasma gastric juice levels of 6-keto-PGF1 alpha between the patients and the control groups. Children who died had lower plasma levels of PGE2 [6.2 +/- 2.2 (SEM) pg/ml] and gastric juice levels of PGE2 [2.3 +/- 0.8 (SEM) pg/ml] than the survivors (p less than 0.05). The gastric juice concentration of PGE2 was also lower in children who suffered important upper gastrointestinal bleeding, although the difference did not reach statistical significance.     

Comparison of capillary zone electrophoresis and isotachophoresis determination of dimethindene enantiomers in pharmaceuticals using charged carboxyethyl-beta-cyclodextrin as a chiral selector

Charged cyclodextrin-mediated capillary electrophoretic methods (capillary zone electrophoresis [CZE] and isotachophoresis [ITP]) in a hydrodynamically closed separation system with suppressed electroosmotic flow and UV absorbance photometric detection (for CZE) or conductivity detection (for ITP) were developed for a highly effective separation and quantitation of dimethindene enantiomers in various pharmaceutical formulations (solution, gel, capsules). Optimized electrolyte systems were based on low-mobility buffer constituents (epsilon-aminocaproic acid, beta-alanine, potassium acetate, acetic acid), negatively charged (at pH > 4.5) carboxyethyl-beta-cyclodextrin (CE-beta-CD), serving as chiral selector, and methylhydroxyethylcellulose, serving as an electroosmotic flow suppressor. Complete enantioseparations of dimethindene in the presence of low concentrations of CE-beta-CD (2.5 mg/ml in CZE, 6.0 mg/ml in ITP) clearly indicated a role of charge of this chiral selector in enantioresolution. It also outlined the potential of charged CD-derivatives as chiral selectors for various CE techniques. The proposed methods were successfully validated, appraising parameters of sensitivity, linearity, precision, accuracy/recovery, and robustness, and then, they were applied to pharmaceutical samples. Consistent results obtained by both CE methods indicate their usefulness for routine use.     

Immunogenicity of peptides of measles virus origin and influence of adjuvants

Epitope-based peptide antigens have been under development for protection against measles virus. The immunogenicity of five peptides composed of the same B cell epitope (BCE) (H236-250 of the measles virus hemagglutinin), and different T cell epitopes of measles virus fusion protein (F421-435, F256-270, F288-302) and nucleoprotein (NP335-345) was studied in mice (subcutaneous immunisation). The adjuvant effects of peptidoglycan monomer (PGM), Montanide ISA 720 and 206 were also investigated. Results showed basic differences in peptide immunogenicity that were consistent with already described structural differences. PGM elevated peptide-specific IgG when applied together with four of five tested peptides. A strong synergistic effect was observed after co-immunisation of mice with a mixture containing all five chimeric peptides in small and equal amounts. Results revealed for the first time that immunisation with several peptides having the common BCE generated significantly higher levels of both anti-peptide and anti-BCE IgG in comparison to those obtained after immunisation with a single peptide in much higher quantity. Further improvement of immune response was obtained after incorporation of such a peptide mixture into oil-based adjuvants.     

Reduction in non-glomerular renal clearance of the caffeine metabolite 1-methylxanthine by probenecid

OBJECTIVE: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. METHODS: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. RESULTS: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. CONCLUSIONS: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.     

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Purpose

We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1*15 haplotype in healthy volunteers.

Methods

In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n?=?6), with CYP2C19*1/*1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n?=?4), with CYP2C19 EM and homozygous (n?=?3) or heterozygous for SLCO1B1*15 (n?=?1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3–14 and twice-daily oral doses of 500 mg clarithromycin on study days 11–14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).

Results

Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (C_max) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and C_max by 27 % (n?=?10, both p?<?0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.

Conclusions

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.     

Recovery in Austria: mental health trialogue

The active involvement of service users and relatives and friends is essential for the development of recovery-orientated mental health practice and research. However, accepting each other as equally entitled experts is still a challenge. In trialogue groups users, carers and friends and mental health workers meet regularly in an open forum that is located on 'neutral terrain' - outside any therapeutic, familial or institutional context - with the aim of discussing the experiences and consequences of mental health problems and ways forward. Trialogues offer new possibilities for gaining knowledge and insights and developing new ways of communicating beyond role stereotypes. They also function as the basis and starting point for trialogic activities on different levels, e.g. serving on quality control boards or teaching in trialogic teams, and different topics, e.g. a task force on stigma busting or a work group on trauma and psychosis. In German-speaking countries well over a hundred trialogue groups are regularly attended by altogether about 5,000 people. International interest and experiences are growing fast. Trialogues facilitate a discrete and independent form of acquisition and production of knowledge and drive relevant changes in forms of communication as well as in structures.