bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylglyoxal modifies heat shock protein 27 in glomerular mesangial cells
Authors: Padival Anoop K , Crabb John W , Nagaraj Ram H
Published: September 2003

Methylglyoxal (MGO) can modify tissue proteins through the Maillard reaction, resulting in advanced glycation end products (AGEs), which can alter protein structure and functions. Several MGO‐derived AGEs have been described, including argpyrimidine, a fluorescent product of the MGO reaction with arginine residues. We detected significant amount of argpyrimidine in rat kidney mesangial cells cultured in media containing high concentrations of glucose. Heat shock protein 27 (Hsp27) was identified by liquid chromatography tandem mass spectrometry as a major anti‐argpyrimidine immunoreactive protein. We confirmed this finding by reciprocal co‐immunoprecipitation and by Western analysis. Diabetic rats contained more argpyrimidine‐modified glomerular Hsp27 than non‐diabetic animals. Additional studies showed that MGO‐induced modification of Hsp27 decreased its binding to cytochrome c. Our results suggest that Hsp27 is a major target for MGO modification in mesangial cells.
Lipid peroxidation in skeletal muscle of obese as compared to endurance‐trained humans: a case of good vs. bad lipids?
Authors: Russell Aaron P , Gastaldi Giacomo , Bobbioni-Harsch Elisabetta , Arboit Patrizia , Gobelet Charles , Dériaz Olivier , Golay Alain , Witztum Joseph L , Giacobino Jean-Paul
Published: September 2003

Intra‐myocellular triglycerides (IMTG) accumulate in the muscle of obese and endurance‐trained (ET) humans and are considered a pathogenic factor in the development of insulin resistance, in the former. We postulate that this paradox may be associated with the peroxidation status of the IMTG. IMTG content was the same in the obese and ET subjects. The lipid peroxidation/IMTG ratio was 4.2‐fold higher in the obese subjects. Hence, obesity results in an increased level of IMTG peroxidation while ET has a protective effect on IMTG peroxidation. This suggests a link between the lipid peroxidation/IMTG ratio and insulin resistance.
Functional involvement of cathepsin W in the cytotoxic activity of NK‐92 cells
Authors: Wex Thomas , Wex Heike , Hartig Roland , Wilhelmsen Skadi , Malfertheiner Peter
Published: September 2003

Human cathepsin W (lymphopain) is a papain‐like cysteine protease of unknown function that is specifically expressed in natural killer (NK) cells and to a lesser extent in cytotoxic T cells (CTL). In order to analyze the functional importance of cathepsin W for the cytotoxic process, we investigated NK‐92 cells that have an NK cell‐like phenotype and express cathepsin W. NK‐92 cells possess strong cytotoxic activity against Jurkat and K562 cells. The cytotoxic activity of NK‐92 cells against K562 was decreased in the presence of antisense phosphorothioate oligonucleotides against the cathepsin W‐cDNA. Western blot analysis showed that the impaired cytotoxic activity of NK‐92 cells was accompanied by reduced amounts of cathepsin W in the antisense‐treated cells. In addition, co‐cultivation experiments between NK‐92 and K562 cells revealed a time‐dependent decrease of cathepsin W by Western blot and immunofluorescence analysis during the cytotoxic attack, whereas CD56 expression of NK‐92 cells was not affected. During cytotoxic attack, cathepsin W was neither targeted to K562 cells or other subcellular compartments, as shown by immunofluorescence analysis. The decrease of cathepsin W protein was associated with stable cathepsin W transcript levels. Control experiments using HT‐29 cells, which are resistant against NK‐92‐mediated cytotoxicity, showed no change of cathepsin W expression, implying that the decrease of cathepsin W in the NK‐92/K562 assay is linked to the cytotoxic process. Although the exact function of cathepsin W with respect to its enzymatic activity and its site of action still needs to be elucidated, our data demonstrate for the first time that cathepsin W is important for cellular cytotoxicity mediated by NK cells.
The carboxyl terminal 17 amino acids within Apg7 are essential for Apg8 lipidation, but not for Apg12 conjugation
Authors: Yamazaki-Sato Harumi , Tanida Isei , Ueno Takashi , Kominami Eiki
Published: September 2003

In the yeast, Saccharomyces cerevisiae, two ubiquitin‐like modifications, Apg12 conjugation with Apg5 and Apg8 lipidation with phosphatidylethanolamine, are essential for autophagy and the cytoplasm‐to‐vacuole transport of aminopeptidase I (Cvt pathway). As a unique E1‐like enzyme, Apg7 activates two modifiers (Apg12 and Apg8) in an ATP‐dependent manner and, for this activity, the carboxyl terminal 40 amino acids are essential. For a better understanding of the function of the carboxyl terminus of Apg7, we performed a sequential deletion of the region. A mutant expressing Apg7ΔC17 protein, which lacks the carboxyl 17 amino acids of Apg7, showed defects in both the Cvt pathway and autophagy. Apg8 lipidation is inhibited in the mutant, while Apg12 conjugation occurs normally. A mutant expressing Apg7ΔC13 protein showed a defect in the Cvt pathway, but not autophagy, suggesting that the activity of Apg7 for Apg8 lipidation is more essential for the Cvt pathway than for autophagy. Mutant Apg7ΔC17 protein is still able to interact with Apg8, Apg12 and Apg3, and forms a homodimer, indicating that the deletion of the carboxyl terminal 17 amino acids has little effect on these interactions and Apg7 dimerization. These results suggest that the carboxyl terminal 17 amino acids of Apg7 play a specific role in Apg8 lipidation indispensable for the Cvt pathway and autophagy.
Phosphorylase regulates the association of glycogen synthase with a proteoglycogen substrate in hepatocytes
Authors: Tavridou Anna , Agius Loranne
Published: September 2003

Changes in the glucosylation state of the glycogen primer, glycogenin, or its association with glycogen synthase are potential sites for regulation of glycogen synthesis. In this study we found no evidence for hormonal control of the glucosylation state of glycogenin in hepatocytes. However, using a modified glycogen synthase assay that separates the product into acid‐soluble (glycogen) and acid‐insoluble (proteoglycogen) fractions we found that insulin and glucagon increase and decrease, respectively, the association of glycogen synthase with an acid‐insoluble substrate. The latter fraction had a higher affinity for UDP‐glucose and accounted for between 5 and 21% of total activity depending on hormonal conditions. Phosphorylase overexpression mimicked the effect of glucagon. It is concluded that phosphorylase activation or overexpression causes dissociation of glycogen synthase from proteoglycogen causing inhibition of initiation of glycogen synthesis.
Complementation and characterization of the Pneumocystis carinii MAPK, PCM
Authors: Vohra Pawan K. , Puri Veenu , Thomas Charles F.
Published: September 2003

Mitogen‐activated protein kinase (MAPK) pathways transfer environmental signals into intracellular events such as proliferation and differentiation. Fungi utilize a specific pheromone‐induced MAPK pathway to regulate conjugation, formation of an ascus, and entry into meiosis. We have previously identified a MAPK, PCM, from the fungal opportunist Pneumocystis, responsible for causing severe pneumonia in patients with AIDS. In order to gain insight into the function of PCM, we expressed it in Saccharomyces cerevisiae deficient in pheromone signaling and tested activation and inhibition of this MAPK pathway. PCM restored pheromone signaling in S. cerevisiae fus3Δ kss1Δ mutants with α‐factor pheromone (six‐fold increase) and was not activated by osmotic stress. Signaling through this pathway decreased 2.5‐fold with 10 μM U0126, and was unaffected with SB203580. We evaluated the conditions for native PCM kinase activity isolated from Pneumocystis carinii organisms and found that 0.1 mM MgCl2, pH 6.5, temperature 30–35°C, and 10 μM ATP were optimal. The activity of PCM is significantly elevated in P. carinii trophic forms compared to cysts, implicating a role for PCM in the life cycle transition of P. carinii from trophic forms to cysts.
The gelsolin family of actin regulatory proteins: modular structures, versatile functions
Authors: McGough Amy M , Staiger Chris J , Min Jung-Ki , Simonetti Karen D
Published: September 2003

This issue ofFEBS Lettersincludes two manuscripts describing structural studies of gelsolin, the best‐characterized member of a superfamily of actin binding proteins that sever, cap, and in some cases nucleate and bundle actin filaments. The manuscripts by Narayan et al. and Irobi et al. provide snapshots of gelsolin domains activated by calcium and in complex with the actin monomer, revealing new insights into the remarkable actin regulatory activities of this versatile protein. These studies build upon nearly a quarter of a century of research on gelsolin's effects on actin dynamics and its role in normal and diseased cells. In the following minireview, we summarize the structural studies that have provided insights into gelsolin's severing and capping activities and look to the future of work on this remarkable molecule.
Evaluation of Laryngeal Function after Implantation of the Vagus Nerve Stimulation Device
Authors: Santos Perry M.
Published: September 2003

OBJECTIVES

The vagus nerve stimulation device (VNS) is used for the management of seizures. This study evaluated what effect the diameter of the vagus nerve helical electrode might have on true vocal cord (TVC) mobility. The study was prompted after 2 cases of TVC immobility. Electrode nerve compression was suspect.

METHODS

Eighteen patients underwent intraoperative vagus nerve measurement and electrode placement with subsequent voice and TVC evaluation. Electrode selection was based on vagus nerve measurements.

RESULTS

Seven patients had vagus nerves measuring less than 2 mm diameter and received the 2‐mm inner diameter electrode. Eleven patients had vagus nerves measuring more than 2 mm in diameter and received the 3‐mm inner diameter electrode. No patients experienced transient or permanent hoarseness or paresis/paralysis.

CONCLUSION

Precise vagus nerve measurements and electrode selection appear to decrease the incidence of nerve compression injury and TVC immobility.
Combined Pollicization and Toe Transfer for Thumb Reconstruction
Authors: STEINAU H. U. , LEHNHARDT M. , HOMANN H. H.
Published: September 2003

A 45-year-old orthopaedic surgeon sustained a complete thumb amputation and severe injuries to his index finger in a lawn mower accident. He was treated with a combined second toe transfer and an index finger pollicization.
Percutaneous Needle Aponeurotomy: Complications and Results
Authors: FOUCHER G. , MEDINA J. , NAVARRO R.
Published: September 2003

Recently French rheumatologists have repopularized fasciotomy using a percutaneous needle technique. This blind approach has been claimed to be plagued by numerous complications. We reviewed the charts of 211 patients treated consecutively on 261 hands and 311 fingers to assess the rate of postoperative complications. The first 100 patients were evaluated with a mean follow up of 3.2 years to assess the rate of recurrences and extension of the disease. In the whole group the mean age was 65 years and delay between onset and treatment was 6 years. Division of the cords were performed only in the palm in 165 cases, in the palm and finger in 111 and purely in the finger in 35. Complications were scarce without infection or tendon injury but one digital nerve was found injured during a second procedure. Postoperative gain was prominent at metacarpophalangeal joint level (79% versus 65% at interphalangeal level). The reoperation rate was 24%. In the group assessed at 3.2 years follow up, the recurrence rate was 58% and disease “activity” 69%. Fifty nine hands need further surgery. The ideal indication for this simple and reliable technique is an elderly patient with a bowing cord and predominant MP contracture.
Changes in Tendon Strength After Partial Cut and Effects of Running Peripheral Sutures
Authors: TAN J. , WANG B. , TAN B. , XU Y. , TANG J. B.
Published: September 2003

We performed a study to evaluate the tensile properties of partial tendon lacerations and the effects of peripheral sutures on the tendon strength. Seventy-two fresh pig flexor digitorum profundus tendons were divided equally into eight groups. Tendons in four of the groups were subjected to partial lacerations (60%, 70%, 80%, and 90%) and were not repaired. In the other four similar groups partial lacerations were repaired with running peripheral sutures. The tendons were subjected to load-to-failure tests in an Instron tensile machine to determine the initial, 1 mm, 2 mm gap formation forces and the ultimate strength. The tendons with lacerations of 80% and 90% had a remarkably lower tensile strength than those 60% and 70% lacerations. Running peripheral sutures increased the gap formation forces and the ultimate strength of all the tendons, though particularly those with 80% and 90% lacerations.
Degranulation in RBL‐2H3 cells: regulation by calmodulin pathway
Authors: Funaba Masayuki , Ikeda Teruo , Abe Matanobu
Published: September 2003

Involvement of the calmodulin pathway in Ca2+‐induced degranulation was evaluated in RBL‐2H3 mast cells. Pretreatment of RBL‐2H3 cells with a calmodulin antagonist, W‐13, blocked ionomycin‐dependent release of β‐hexosaminidase into the supernatant, although W‐13 treatment alone slightly but significantly increased the release. Ca2+/calmodulin activates various protein kinases and phosphatases including myosin‐light chain kinase (MLCK), calmodulin‐dependent protein kinases (CaMKs), and calcineurin. When RBL‐2H3 cells were pretreated with a MLCK inhibitor, ML‐7, or a CaMKs inhibitor, KN‐93, the ionomycin‐dependent release of β‐hexosaminidase into the supernatant was inhibited. In addition, pretreatment with calcineurin inhibitors, cyclosporin A and FR901725, resulted in blockage of the ionomycin‐dependent release of β‐hexosaminidase into the supernatant. Our results indicate that Ca2+/calmodulin, activated calmodulin, is indispensable for Ca2+‐induced degranulation, and that within the calmodulin pathways, at least MLCK, CaMKs and calcineurin positively regulate the release of granules initiated by increasing cytosolic Ca2+concentrations in RBL‐2H3 cells.
Evaluation of nutritional status and pathophysiology of growth retardation in patients with phenylketonuria
Authors: Dobbelaere D. , Michaud L. , Debrabander A. , Vanderbecken S. , Gottrand F. , Turck D. , Farriaux J. P.
Published: September 2003

Summary: Recent European studies have shown that growth retardation is common in people with phenylketonuria (PKU) during the first years of life while they receive a low‐phenylalanine (Phe) diet. The aims of the present study were to assess the growth of our PKU patients and to search for nutritional and hormonal explanations for the growth delay. Twenty PKU patients aged 8 months to 7 years entered the study. The design was cross‐sectional, a longitudinal study having already been performed in our centre. The following data were recorded: weight/height (W/H), height/age (H/A), and weight/age (W/A) Z‐scores; fat‐free mass (measured from bioelectrical impedometry (FFM1), and skinfold thickness (FFMA). Thyroid hormones, insulin‐like growth factor I (IGF1), insulin‐like growth factor binding protein (IGFBP3), selenium, zinc, and Phe blood levels were measured. Dietary intake was also recorded over 4 days. PKU patients were moderately but significantly shorter (H/A Z‐score varied from −2.12 to 1.61; mean −0.49) and lighter (W/A Z‐score varied from −2.58 to 1.49; mean −0.71) than the French reference population. Body composition was not different from that of controls matched for age and sex. IGF1, IGFBP3, and thyroid hormone levels were within normal range. All children received more than two‐thirds of the recommended daily allowances for energy (91%±18%) and for proteins (146%±26%). The mean daily intake of our patients was sufficient in selenium, but markedly deficient in zinc (2.4±2.2 mg/day). No correlation was found between zinc daily intake or zinc plasma levels and growth retardation. Moreover, no relation was found between the plasma Phe concentrations, protein or caloric intake and the presence of growth retardation. Our results show that growth retardation in PKU patients is not related to hormonal or caloric deficiencies. Further studies are needed to investigate the effect of various nutrient supplementation regimens (especially zinc) on the growth of PKU patients.
Airborne measurement of inorganic ionic components of fine aerosol particles using the particle‐into‐liquid sampler coupled to ion chromatography technique during ACE‐Asia and TRACE‐P
Authors: Lee Y.‐N. , Weber R. , Ma Y. , Orsini D. , Maxwell‐Meier K. , Blake D. , Meinardi S. , Sachse G. , Harward C. , Chen T.‐Y. , Thornton D. , Tu F.‐H. , Bandy A.
Published: September 2003

Eight inorganic ions in fine aerosol particles (Dp < 1.3 μm) were measured on board the NCAR C130 and NASA P‐3B aircraft during the 2001 Aerosol Characterization Experiment (ACE)‐Asia and the Transport and Chemical Evolution over the Pacific (TRACE‐P) experiments, respectively. Concentrations of NH4+, SO42−, NO3−, Ca2+, K+, Mg2+, Na+, and Cl− were determined using a particle‐into‐liquid sampler coupled to ion chromatography (PILS‐IC) technique at a 4‐min resolution and a limit of detection <0.05 μg m−3. The maximum total ion concentrations observed on the C130 and the P‐3B were 27 μg m−3 and 84 μg m−3, respectively. During ACE‐Asia, NH4+ and SO42− dominated, with the dust‐derived Ca2+ contributing nearly equally as SO42− in mixing ratios. The sea‐salt‐derived Na+ and Cl− were comparable to biomass‐burning tracer K+, showing >1 ppbv only in the top 1% sample population. During TRACE‐P, NH4+ dominated, followed by SO42−, Cl−, Na+, NO3−, Ca2+, and K+, in decreasing order of importance. In addition to a sea‐salt origin, Cl− showed a source in urban emissions possibly related to biofuel combustion. Both sea salt and dust contributed to Mg2+. In both experiments, NH4+, SO42−, NO3−, and CO were strongly correlated, indicating that combustion was the dominant source of these species and that NH3 and other alkaline materials were in sufficient supply to neutralize H2SO4. The [NH4+] to ([NO3−] + 2[SO42−]) ratio was ∼0.70 in the two campaigns, with deviations found only in volcano plumes, whereby SO42− was found to correlate with SO2. Charge balance of the ions showed both positive and negative deviations whose magnitudes, ∼30%, provide estimates of the lower limits of unmeasured ions. Elevated NO3− and Ca2+ coexist mainly under polluted conditions, suggesting the importance of sequestering HNO3 by mineral dust.
Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis
Authors: KOKKOLA ARTO , KOSUNEN TIMO U. , PUOLAKKAINEN PAULI , SIPPONEN PENTTI , HÄRKÖNEN MATTI , LAXÉN FRANK , VIRTAMO JARMO , HAAPIAINEN REIJO , RAUTELIN HILPI
Published: September 2003

Background. Only a few reported studies focus on the natural history and course of advanced and severe chronic atrophic gastritis. Methods. In this study we followed 47 men (mean age 62 years) with advanced (moderate or severe) Helicobacter pylori‐positive atrophic corpus gastritis. Duration of endoscopic follow‐up was 6 years and follow‐up based on serum levels of pepsinogen I and antibodies to H. pylori covered a period of 10 years. None of the patients was treated for H. pylori infection prior to end of follow‐up. Results. The median H. pylori antibody titre declined (IgG from 4000 to 1300; IgA from 200 to 50) in the study population, and 11 men (23%) converted to seronegative (p=0.0005, Fisher's exact test). There was a small but significant (p=0.0004, Page's test) declining trend in mean atrophy score of the corpus during follow‐up (from 2.5 to 2.2). However, no significant changes were observed in grade of atrophy or intestinal metaplasia of the antral mucosa or in grade of intestinal metaplasia in the corpus. The mean SPGI level remained at the initial low level during the entire follow‐up. Conclusions. H. pylori antibodies disappear spontaneously within 10 years in almost one fourth of patients with advanced atrophic corpus gastritis. The disappearance of H. pylori antibodies is accompanied by no or more than a mild improvement of the gastric mucosa.
Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus in systemic and nonoral infections in Finland
Authors: PAJU SUSANNA , CARLSON PETTERI , JOUSIMIES‐SOMER HANNELE , ASIKAINEN SIRKKA
Published: September 2003

The oral cavity is the ecological niche for Actinobacillus actinomycetemcomitans and Haemophilus aphrophilus, but occasionally they cause severe nonoral infections. In this study we present 20 systemic or nonoral infections due to A. actinomycetemcomitans and H. aphrophilus, comprising all isolates of these species forwarded to and stored in Finnish reference laboratories during the years 1988–2000. The time from specimen collection to correct species identification was 9.3 days for A. actinomycetemcomitans and 10.7 days for H. aphrophilus. A. actinomycetemcomitans strains represented serotypes a, b, c, and d. Arbitrarily primed PCR distinguished four A. actinomycetemcomitans and six H. aphrophilus genotypes. Antimicrobial susceptibility testing with benzylpenicillin, amoxicillin, tetracycline, metronidazole, azithromycin, and trovafloxacin showed generally good activities against the present strains, and the susceptibility patterns closely resembled those of oral strains. The prolonged time to recover and identify A. actinomycetemcomitans and H. aphrophilus from systemic and nonoral infections may delay the correct diagnosis of the patient, but the good antimicrobial efficacies of antimicrobial agents against these pathogens give a good prognosis for the patients and advance the treatment of severe infections caused by these fastidious organisms of oral origin.
Blm3 is part of nascent proteasomes and is involved in a late stage of nuclear proteasome assembly
Authors: Fehlker Marion , Wendler Petra , Lehmann Andrea , Enenkel Cordula
Published: September 2003

Proteasomes are multisubunit proteases that are responsible for regulated proteolysis. The degradation of the proteasomal maturation factor, named Ump1 in yeast, completes the autocatalytic processing of inactive precursor complexes into the proteolytically active core particle (CP) of the proteasome. We have identified Blm3, a conserved nuclear protein, as a new component of Ump1‐associated precursor complexes. A lack of Blm3 resulted in an increased rate of precursor processing and an accelerated turnover of Ump1, which suggests that Blm3 prevents premature activation of proteasomal CPs. On the basis of biochemical fractionation experiments combined with in vivo localization studies, we propose that Blm3 joins nascent CPs inside the nucleus to coordinate late stages of proteasome assembly in yeast.
Esomeprazole administered through a nasogastric tube provides bioavailability similar to oral dosing
Authors: Sostek M. B. , Chen Y. , Skammer W. , Winter H. , Zhao J. , Andersson T.
Published: September 2003

Aim : To determine if nasogastric tube administration of the enteric‐coated pellets from an opened esomeprazole capsule provides bioavailability similar to oral dosing with the intact capsule.

Methods : A randomized, single‐centre, open‐label, two‐period crossover pharmacokinetic study consisting of two 5‐day dosing periods separated by a 7‐ to 14‐day washout period was conducted. Healthy subjects between the ages of 18 and 50 years received esomeprazole 40 mg once daily either orally as an intact capsule, or as a suspension of the enteric‐coated pellets from an opened capsule in water through a nasogastric tube.

Results : In 47 evaluable subjects, the 90% confidence intervals were 0.87–1.08 and 0.93–1.25 for the geometric mean of the ratio of nasogastric tube administration relative to administration of the intact capsule for the area under the plasma concentration–time curve and for maximum plasma concentration, respectively, on day 1, demonstrating bioequivalence. Oral and nasogastric administration also demonstrated similar bioavailabilities on day 5. Esomeprazole was well tolerated regardless of the mode of administration.

Conclusions : Nasogastric tube administration of the enteric‐coated pellets from an opened esomeprazole 40 mg capsule provides bioavailability similar to oral dosing. Administration of the contents of an opened esomeprazole 40 mg capsule in water through a nasogastric tube is a practical alternative for patients with feeding tubes who require effective gastric acid suppression, but cannot swallow an oral preparation.
Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome
Authors: Corazziari E. , Bytzer P. , Delvaux M. , Holtmann G. , Malagelada J. R. , Morris J. , Muller‐Lissner S. , Spiller R. C. , Tack J. , Whorwell P. J.
Published: September 2003

Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations.

This consensus report highlights the following points.

(a) A 4‐week period is considered to be adequate to assess drug efficacy for the control of symptoms.

(b) For the cyclic and non‐life‐threatening nature of the disease, a long‐term study of 4–6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients.

(c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow‐up period prolonged for a sufficient time (4–8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post‐treatment benefit.

(d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on‐demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome.

(e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome.

(f)  The main efficacy outcome of the treatment should be based on one primary end‐point.

(g) The primary efficacy end‐point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms.

(h) A 50% improvement in the primary efficacy end‐point seems to be a reasonable definition of a responder.
Meta‐analysis: comparative efficacy of different proton‐pump inhibitors in triple therapy for Helicobacter pylori eradication
Authors: Vergara M. , Vallve M. , Gisbert J. P. , Calvet X.
Published: September 2003

Background : It is not known whether certain proton‐pump inhibitors are more efficacious than others when used in triple therapy for Helicobacter pylori eradication.

Aim : To compare the efficacy of different proton‐pump inhibitors in triple therapy by performing a meta‐analysis.

Methods : A MEDLINE search was performed. Abstracts of the European Helicobacter pylori Study Group and the American Gastroenterological Association congresses from 1996 to 2002 were also examined. Randomized studies with at least two branches of triple therapy that differed only in terms of type of proton‐pump inhibitor were included in a meta‐analysis using Review Manager 4.1.

Results : Fourteen studies were included. Intention‐to‐treat cure rates were similar for omeprazole and lansoprazole: 74.7% vs. 76%, odds ratio (OR) 0.91 [95% confidence interval (CI) 0.69–1.21] in a total of 1085 patients; for omeprazole and rabeprazole: 77.9% vs. 81.2%, OR 0.81 (95% CI 0.58–1.15) in a total of 825 patients; for omeprazole and esomeprazole: 87.7% vs. 89%, OR 0.89 (95% CI 0.58–1.35) in 833 patients; and for lansoprazole and rabeprazole: 81% vs. 85.7%, OR 0.77 (95% CI 0.48–1.22) in 550 patients.

Conclusion : The efficacy of various proton‐pump inhibitors seems to be similar when used for H. pylori eradication in standard triple therapy.
Inter‐individual variability in levels of human microsomal protein and hepatocellularity per gram of liver
Authors: Wilson Z. E. , Rostami‐Hodjegan A. , Burn J. L. , Tooley A. , Boyle J , Ellis S. W. , Tucker G. T.
Published: September 2003

Aims  To determine levels of microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of human liver and their interindividual variability.

Methods  Triplicate liver samples were used to determine values of MPPGL (n = 20) and HPGL (n = 7) after accounting for the fractional loss of microsomal protein or hepatocytes during processing. Repeated measurements from each liver sample allowed the estimation of true interindividual variability in MPPGL and HPGL using ANOVA.

Results  The value of MPPGL ranged from 26 to 54 mg g−1 (meangeo= 33 mg g−1). The value of HPGL ranged from 65 to 185 × 106 cells g−1 (meangeo= 107 × 106 cells g−1).

Conclusions  There is significant interindividual variability in MPPGL, which has implications for the accurate extrapolation of in vitro data on drug metabolism to predict in vivo metabolic clearance.
Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions
Authors: Kokwaro Gilbert O. , Ogutu Bernhards R. , Muchohi Simon N. , Otieno Godfrey O. , Newton Charles R. J. C.
Published: September 2003

Aims  Phenobarbital is commonly used to treat status epilepticus in resource‐poor countries. Although a dose of 20 mg kg−1 is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15‐mg kg−1 intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus.

Methods  Twelve children (M/F: 11/1), aged 7–62 months, received a loading dose of phenobarbital (15 mg kg−1) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg−1 at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx® fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l−1 for 72 h.

Results  All the children achieved plasma concentrations above 15 mg l−1 by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, ∞) ]: 4259 (3169, 5448) mg l−1.h, : 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg−1 h−1, Vss: 0.8 (0.7, 0.9) l kg −1, CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9–27.9) mg l−1. Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg−1 followed by two maintenance doses of 2.5 mg kg−1 at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l−1 for 72 h.

Conclusions  Phenobarbital, given as an i.v. loading dose, 15 mg kg−1, achieves maximum plasma concentrations of greater than 15 mg l−1 with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg−1 at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15–20 mg l−1 for 72 h, and may be a suitable regimen for treatment of convulsions in these children.
Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma
Authors: Currie Graeme P. , Lima John J. , Sylvester Jim E. , Lee Daniel K. C. , Cockburn Wendy J. R. , Lipworth Brian J
Published: September 2003

Aim  Cysteinyl leukotrienes are important pro‐inflammatory mediators in the pathogenesis of asthma, while leukotriene C4 synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild‐type (A) polymorphism of this enzyme.

Methods  We carried out a retrospective analysis of 8 randomised, placebo‐controlled trials performed in our department in mild‐to‐moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils.

Results  For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) (n = 78): 2.21 and 2.07‐fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36‐fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold‐differences of 1.07 (95%CI 0.63–1.81) and 1.02 (95%CI 0.70–1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes.

Conclusion  Polymorphisms of leukotriene C4 synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists in mild‐to‐moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide.
Blood‐mediated scavenging of cerebrospinal fluid glutamate
Authors: Gottlieb Miroslav , Wang Yin , Teichberg Vivian I.
Published: September 2003

The maintenance of brain extracellular glutamate (Glu) at levels below its excitotoxic threshold is performed by Glu transporters present on glia and neurons as well as on brain capillary endothelial cells which remove brain Glu into blood. The feasibility of accelerating the naturally occurring brain‐to‐blood Glu efflux was studied using paradigms based on the fate of Glu present in the cerebrospinal fluid or infused into the brain ventricles and monitored before, during, and after decreasing blood Glu levels with pyruvate and oxaloacetate, the respective Glu co‐substrates of the blood resident enzymes glutamate–pyruvate transaminase and glutamate–oxaloacetate transaminase. Results from cerebroventricular perfusions with [3H]Glu, intracerebroventricular injections of [3H]Glu, and measurements of the basal CSF Glu levels point out to the same conclusion that the intravenous administration of pyruvate and oxaloacetate which decreases blood Glu levels accelerates the brain‐to‐blood Glu efflux. We conclude that the brain extracellular Glu levels can be controlled in part by the blood Glu levels. The results may provide not only a rational explanation for the inhibition of Glu release and neuroprotective effects of parentally administered pyruvate in hemorrhagic shock and forebrain ischemia but could also outline a potential strategy for the removal of excess Glu in various neurodegenerative disorders.
Signal transduction pathways in mouse microglia N‐11 cells activated by advanced glycation endproducts (AGEs)
Authors: Dukic‐Stefanovic Sladjana , Gasic‐Milenkovic Jovana , Deuther‐Conrad Winnie , Münch Gerald
Published: September 2003

Deposition of cross‐linked insoluble protein aggregates such as amyloid plaques is characteristic for Alzheimer's disease. Microglial activation by these extracullar deposits has been proposed to play a crucial role in functional degeneration as well as cell death of neurones. A sugar‐derived post‐translational modification of long‐lived proteins, advanced glycation endproducts (AGEs), activate specific signal transduction pathways, resulting in the up‐regulation of various pro‐inflammatory signals such as cytokines [interleukin‐6 (IL‐6), tumour necrosis factor‐alpha (TNF‐α)] and inducible nitric oxide synthase (iNOS). Our goal was to study AGE‐activated signal transduction pathways involved in the induction of pro‐inflammatory effectors in the murine microglial cell line N‐11. Chicken egg albumin‐AGE (CEA‐AGE), used as model AGE, induces nitric oxide (NO), TNF‐α and IL‐6 production. The AGE receptor, RAGE, and the transcription factor, nuclear factor kappa B (NF‐κB), appear to be involved in all pathways, since a neutralizing RAGE antibody and a peptide inhibiting NF‐κB translocation down‐regulated NO, TNF‐α and IL‐6 production. NO and TNF‐α, but not IL‐6 production appear to be regulated independently, since NOS inhibitors did not decrease TNF‐α secretion and a neutralizing TNF‐α antibody did not reduce NO production, while employment of NOS inhibitors reduced significantly the secretion of IL‐6. Inhibition of the MAP‐kinase‐kinase (MEK) and phosphatidylinositol 3‐kinase (PI3K) pathway, but not that of mitogen‐activated protein kinase‐p38 (MAPK‐p38), reduced NO, TNF‐α and IL‐6 significantly, suggesting that simultaneous activation of the first two pathways is necessary for the AGE‐induced induction of these pro‐inflammatory stimuli.
Dopamine‐dependent increases in phosphorylation of cAMP response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures of rat striatum
Authors: Chartoff Elena H. , Papadopoulou Maria , Konradi Christine , Carlezon William A.
Published: September 2003

Chronic morphine leads to compensatory up‐regulation of cAMP signaling pathways in numerous brain regions. One potential consequence of up‐regulated cAMP signaling is increased phosphorylation of cAMP response element binding protein (CREB), a transcription factor that may regulate neuroadaptations related to morphine dependence. Altered gene expression within the nucleus accumbens (NAc), a ventral component of the striatum that receives substantial dopaminergic input, may play a role in some of the motivational aspects of opiate withdrawal. To determine if morphine withdrawal leads to increased CREB phosphorylation in striatal tissues, we examined the effects of naloxone‐precipitated morphine withdrawal on CREB phosphorylation in primary cultures of rat striatal neurons. Precipitated morphine withdrawal was associated with enhanced dopamine‐, SKF 82958 (D1 receptor agonist)‐, and forskolin‐induced CREB phosphorylation. During precipitated withdrawal, D1 receptor‐mediated CREB phosphorylation was dependent on cAMP‐dependent protein kinase (PKA). Precipitated withdrawal also led to up‐regulation of c‐fos mRNA in response to SKF 82958. CREB protein levels were not altered by acute or chronic morphine. These results suggest that D1 receptor‐mediated signal transduction is enhanced during morphine withdrawal. Furthermore, they are consistent with in vivo evidence suggesting that increased CREB activation in portions of the striatum (e.g. the NAc) is related to dysphoric states associated with drug withdrawal.
TAK1‐mediated induction of nitric oxide synthase gene expression in glial cells
Authors: Bhat Narayan R. , Shen Qin , Fan Fan
Published: September 2003

Inflammatory cell signaling leading to transcriptional activation is primarily mediated by signal transduction via mitogen‐activated protein kinase (MAPK) and NFκB pathways. A common upstream kinase that signals the activation of these pathways is TGFβ–activated kinase 1 (TAK1), which itself becomes activated in response to cytokines and upon engagement of a class of cell surface receptors involved in innate immunity, that is Toll‐like receptors (TLRs) by bacterial and viral pathogens. This study directly tests the role of TAK1 in the induction of inducible nitric oxide (NO) synthase (iNOS) in glial cells, which represent immune‐regulatory cells of the CNS, by transient transfection assays. Transfection of C‐6 glia, primary astrocytes and a rat microglial cell line with TAK1 (but not its inactive form) along with its activator protein, TAK1‐binding protein 1 (TAB1) resulted in a marked stimulation of a co‐transfected rat iNOS promoter‐reporter construct (iNOS‐Luc). TAK1‐induced iNOS‐Luc activity was substantially inhibited by pharmacological inhibitors of the known downstream kinases, p38 MAPK and JNK (SB203580 and SP620125), and was almost completely blocked by co‐expression of a phosphorylation mutant of IκB. TAK1/TAB1 also induced the production of NO and the expression of iNOS in microglial cells in a p38 MAPK‐, JNK‐ and NFκB‐dependent manner. The results of these studies provide evidence for an important role for TAK1‐mediated intracellular signaling, via p38 MAPK, JNK and NFκB, in the transcriptional activation of iNOS in glial cells.
Micropipe evolution in silicon carbide
Authors: Gutkin Mikhail Yu. , Sheinerman Alexander G. , Argunova Tatyana S. , Mokhov Evgeniy N. , Ho Je Jung , Hwu Yeukuang , Tsai Wen-Li , Margaritondo Giorgio
Published: September 2003

Micropipe bundling and twisting in SiC crystals was revealed using synchrotron x-ray phase sensitive radiography. The computer simulation of micropipe evolution during the crystal growth suggests that the bundled and twisted micropipes arise under the influence of stress fields from other neighboring micropipes. The annihilation of twisted dipoles is attributed to their transformation into semiloops. Reactions of micropipe coalescence lead to the generation of micropipes and/or the annihilation of initial micropipes, resulting in the decrease in their average density.
Recording and readout mechanisms of super-resolution near-field structure disk with a silver oxide mask layer
Authors: Her Yung-Chiun , Lan Yuh-Chang , Hsu Wei-Chih , Tsai Song-Yeu
Published: September 2003

The chemical decomposition of AgOx sandwiched between two ZnS–SiO2 protective layers was an irreversible process. We confirmed that a hollow Ag cylinder, or ring, serving as an aperture, was formed and small Ag particles were precipitated in the center region during the recording process. The small aperture can significantly reduce the laser spot size during the readout process and the strong near-field interaction between precipitated Ag particles and subwavelength marks can effectively enhance the readout signal. That clarifies both the super-resolution effect and the near-field interaction in the super-resolution near-field structure disk.
Two stage oxidation in epitaxial Ni (111)/GaN (0001) thin films
Authors: Kang H. C. , Seo S. H. , Jang H. W. , Kim D. H. , Noh D. Y.
Published: September 2003

We present the oxidation process of epitaxial Ni (111)/GaN (0001) thin films studied by in situ synchrotron x-ray scattering, scanning electron microscopy, and transmission electron microscopy. By monitoring the evolution of the Ni (111) Bragg reflection, we reveal that two distinct oxidation processes occur. Initially, a continuous NiO layer of about 50 Å thickness is formed on the surface of Ni. The planar oxide layer saturates immediately and passivates the film from further surface oxidation. From this stage, the oxidation proceeds by means of the growth of surface oxide islands. The Ni atoms diffuse out through the defect sites running vertically through the initial oxide layer to form the oxide islands. Voids are generated underneath the oxide layer in this process. The oxide in the second stage grows logarithmically in time with the activation energy of about 0.15 eV.
Current-induced precessional magnetization reversal
Authors: Schumacher H. W. , Chappert C. , Sousa R. C. , Freitas P. P.
Published: September 2003

We report magnetization reversal in microscopic current-in-plane spin valves by ultrashort current pulses through the device. Current densities of the order of 1011 A/m2 with pulse durations as short as 120 ps reliably and reversibly switch the cell’s free-layer magnetization. Variations of the pulse parameters reveal the full signature of precessional switching, which is triggered by the transverse magnetic field generated by the device current. This current switching mode allows for the design of a two-terminal nonvolatile magnetic memory cell combining ultrafast access times and high magnetoresistive readout.
High sensitive detection of near-infrared absorption by surface plasmon resonance
Authors: Ikehata Akifumi , Li Xiaoling , Itoh Tamitake , Ozaki Yukihiro , Jiang Jian-Hui
Published: September 2003

In this letter we report on an operative method for high sensitive measurement of near-infrared absorption based on a surface plasmon resonance (SPR) technique. By coupling with the SPR of a gold film, an absorption band of water near 5173 cm−1 assigned to a combination of the stretching and bending modes of OH groups is enhanced over 100 times compared with a case without the gold film. In addition, positive and negative enhancements of an absorption depending on the thickness of a gold film were observed as predicted by H. Kano et al. [Appl. Opt. 33, 5166 (1994)]. These experimental results are mathematically well reproduced by use of Fresnel multiple-reflection theory.
Current–voltage and reverse recovery characteristics of bulk GaN p-i-n rectifiers
Authors: Irokawa Y. , Luo B. , Kim Jihyun , LaRoche J. R. , Ren F. , Baik K. H. , Pearton S. J. , Pan C.-C. , Chen G.-T. , Chyi J.-I. , Park S. S. , Park Y. J.
Published: September 2003

p-i-n rectifiers were fabricated on epitaxial layers grown on free-standing GaN substrates. The forward turn-on voltage, VF was ∼5 V at 300 K and displayed a positive temperature coefficient. The specific on-state resistance (RON) was ∼5 mΩ cm2 at 300 K, with an ideality factor of ∼2 and activation energy for low forward current density of ∼1.6 eV. This is consistent with carrier recombination in the space charge region via a midgap deep level. The figure-of-merit, VB2/RON, where VB is the reverse breakdown voltage, was 0.32 MW cm−2. The reverse recovery time was ⩽600 ns at 300 K. The improved forward characteristics relative to previous heteroepitaxial p-i-n GaN rectifiers show the advantages of employing a GaN substrate to make a true vertical transport geometry device.
Narrow features in metals at the interfaces between different etch resists
Authors: Sundar Vikram C. , Aizenberg Joanna
Published: September 2003

The ability to create structures on length scales below 100 nm easily is a challenging feat. We report here a facile technique for the fabrication of such structures in gold (Au) with feature sizes smaller than 50 nm, utilizing two families of Au etch resists in conjunction. The first resist family consists of self-assembled monolayers (SAMs) of alkane thiols on Au, which provide substantial resistance against cyanide etch solutions. The second class consists of metals deposited on the surface of Au, which also provide similar resistance of the Au film to CN etchants but are not conducive for the formation of SAMs. Selective etching is initiated at the interface between these resists, proceeds into the Au layer, and results in narrow trenches in the Au film. Our protocol allows for the sequential removal of both resists and thus permits the creation of planar Au surfaces with well-defined sub-50-nm etch patterns.