bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective population pharmacokinetics of levocetirizine in atopic children receiving cetirizine: the ETAC® study
Authors: Hussein Ziad , Pitsiu Maria , Majid Oneeb , Aarons Leon , De Longueville Marc , Stockis Armel ,   the ETAC Study Group
Published: December 2004

Aims

To evaluate the population pharmacokinetics of levocetirizine in young children receiving long‐term treatment with cetirizine.

Methods

Data were available from a randomized, double‐blind, parallel group and placebo‐controlled study of cetirizine in 343 young children between 12 and 24 months of age at entry, who were at high risk of developing asthma, but were not yet affected (ETAC® study). Infants received oral drops of cetirizine at 0.25 mg kg−1 twice daily for 18 months. Plasma concentration of the active enantiomer levocetirizine was determined in blood samples collected at months 3, 12 and 18 (1–3 samples per child). A one‐compartment open model was fitted to the data using nonlinear mixed effects modelling (NONMEM). The influence of weight, age, gender, BSA and other covariates on CL/F and V/F was evaluated.

Results

CL/F increased linearly with weight by 0.044 l h−1 kg−1 over an intercept of 0.244 l h−1, and V/F increased linearly with weight by 0.639 l kg−1. Population estimates in children with weights of 8 and 20 kg were 0.60 and 1.13 l h−1 for CL/F, and 5.1 and 12.8 l for V/F, respectively, with interpatient variabilities of 24.4% and 14.7%. Weight‐normalized estimates of CL/F and V/F were higher than in adults. The estimated relative bioavailability was 0.28 in 12% of instances of suspected noncompliance. Levocetirizine pharmacokinetics were not influenced by severe allergy or aeroallergen sensitization. Results on the effects of concomitant medications or diseases were inconclusive due to limited positive cases. AUCss, calculated in compliant subjects using posterior estimates of the final model, was 1952 (1227–3319) µg l−1 h (mean, min‐max), a value similar to that in adults after intake of 5 mg oral solution (2036 (1414–2827) µg l−1 h.

Conclusions

The model suggests that administration of levocetirizine 0.125 mg kg−1 twice daily in children 12–48 months of age or weighing 8–20 kg yields the same exposure as in adults taking the recommended dose of 5 mg once daily.
A meta‐analysis of clinical trials of paclitaxel‐ and sirolimus‐eluting stents in patients with obstructive coronary artery disease
Authors: Shafiq N. , Malhotra S. , Pandhi P. , Grover A. , Uboweja A.
Published: December 2004

Aim

This meta‐analysis was conducted to compare the effects of drug (paclitaxel and sirolimus)‐eluting stents with bare metal stents on major adverse cardiac events, restenosis rates and late loss of arterial lumen diameter in patients with obstructive coronary artery disease.

Methods

Randomized, controlled clinical trials comparing sirolimus‐ and paclitaxel‐eluting stents with bare metal stents were identified through electronic and manual search. Fixed effects method of Mantel‐Haenszel and random effects method of DerSimonian and Laird were used for computing the pooled odds ratio (OR) and 95% confidence intervals (CI) for major adverse cardiac events and restenosis rates. Standardized mean difference with 95% CI was calculated for late‐loss of arterial lumen diameter.

Results

A total of 13 studies were included in the meta‐analysis. As compared with bare metal stents, the use of sirolimus‐ and paclitaxel‐eluting stents significantly reduced the major adverse cardiac events (pooled OR 0.35; 95% CI 0.24–0.50), restenosis rates (pooled OR 0.27; 95% CI 0.15–0.47), and late loss of arterial lumen diameter (mean difference 0.57 mm, 95% CI 0.49–0.68).

Conclusion

Paclitaxel‐ and sirolimus‐eluting stents significantly reduced the incidence of major adverse cardiac events, restenosis rates, and late loss of arterial lumen diameter as compared with bare metal stents.
The effect of sepsis upon gentamicin pharmacokinetics in neonates
Authors: Lingvall M. , Reith D. , Broadbent R.
Published: December 2004

Aim

To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates.

Methods

A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C‐reactive protein and serum creatinine.

Results

The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg−1 h−1, volume of distribution (Vd) of 0.483 l kg−1 and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147 • (GA‐20) + 0.000635 • AP2) l kg−1 h−1, Vd = (0.483 +0.0656 • sepsis) l kg−1, D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%.

Conclusions

The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.
Phenotypic and functional heterogeneity of porcine blood monocytes and its relation with maturation
Authors: Chamorro Sonia , Revilla Concepción , Álvarez Belén , Alonso Fernando , Ezquerra Ángel , Domínguez Javier
Published: December 2004

Swine monocytes constitute a heterogeneous population of cells which can be divided into four subsets based on the expression of SWC3, CD14, CD163 and swine leucocyte antigen (SLA) DR markers. These subsets appear to represent different maturation stages in a pathway along which these cells up‐regulate the expression of SLA DR and CD163 antigens and reduce that of CD14. Differences in the expression of adhesion and costimulatory molecules are also patent, with a progressive increase in the expression of CD11a, wCD11R1, CD29, CD49d, CD61, CD1a and CD80/86, and a concomitant decrease in that of wCD11R2. Besides, these subsets differ in their capacity for tumour necrosis factor‐α (TNF‐α) production in response to lipopolysaccharide + interferon‐γ. The CD163+ CD14− SLA DR+ subset produces higher amounts of TNF‐α than the CD163− CD14+ SLA DR− subset, whereas CD163+ CD14+ SLA DR+ and CD163− CD14+ SLA DR+ subsets show intermediate values. CD163+ monocytes also display a higher ability to present soluble antigens to T cells than CD163− monocytes.
No mixing of granulocytes and other lymphocytes in the inflamed joints of parabiosis mice with collagen‐induced arthritis: possible in situ generation
Authors: Nishizawa Tetsuro , Kawamura Toshihiko , Izumi Nakao , Kawamura Hiroki , Fujii Katsuyuki , Abo Toru
Published: December 2004

Collagen‐induced arthritis was evoked by an injection of lipopolysaccharide and anti‐type II collagen antibody in mice. In parallel with the onset of arthritis, granulocytes with large light scatter and a Mac‐1+ Gr‐1+ phenotype expanded in the joints of these mice. Lymphocytes with a CD3− B220+ phenotype (i.e. B220+ B cells) were the major population among lymphocyte subsets in the joints, irrespective of disease. To determine the origin of these leucocyte populations in the joints and other organs, parabiotic experiments using CBF1Ly5.1 and CBF1Ly5.2 mice were conducted in mice with and without collagen‐induced arthritis. As expected, leucocyte populations in the liver and spleen became a half‐and‐half mixture of their own cells and partner cells (e.g. ∼45% of Ly5.1+ cells in Ly5.2+ partner mice). However, such a mixture was extremely delayed in the joints and bone marrow, even in mice with arthritis. These results suggest that, because circulatory blood is not exchanged in the joints, granulocytes and other lymphocytes are generated in situ in the inflamed joints of mice with collagen‐induced arthritis or are possibly supplied by the bone marrow. It is of interest that granulocytes in the joints expanded, even without a supply from another site, namely, the synovium.
Porin of Shigella dysenteriae enhances Toll‐like receptors 2 and 6 of mouse peritoneal B‐2 cells and induces the expression of immunoglobulin M, immunoglobulin G2a and immunoglobulin A
Authors: Ray Avijit , Biswas Tapas
Published: December 2004

Porin of Shigella dysenteriae type 1 increased the mRNA levels for Toll‐like receptors TLR2 and TLR6, by 1·8‐fold and twofold, respectively, in peritoneal cavity B‐2 cells from C57BL/6 mice, implicating that the co‐expression of TLR2 and TLR6 occurs as a combinatorial repertoire in response to porin. Among the two key TLRs, TLR2 and TLR4, which are primarily responsible for recognizing the majority of bacterial products, TLR2 alone participates in porin recognition. TLR2 expression was increased on B‐2 cells, whereas the expression of TLR4 remained unaffected. Besides TLRs, mRNA for myeloid differentiation factor 88 (MyD88), an effector molecule associated with the TLR‐mediated response, was enhanced by twofold, suggesting its involvement in the activity of porin. The B‐2 cells showed a 1·8‐fold increase in mRNA expression of the signalling molecule, nuclear factor‐kappa B (NF‐κB), in the presence of porin. Porin treatment of B‐2 cells selectively up‐regulated the expression of the costimulatory molecule, CD86, by 4·4‐fold. Porin induced the cell‐surface expression of immunoglobulin (Ig)M, of IgG2a preferentially among the IgG subclasses, and of IgA, on B‐2 cells. The porin‐mediated inductions of IgG2a and IgA were augmented by interleukin‐6 on B‐2 cells, by 2·7‐ and 1·6‐fold, respectively.
Memory CD8+ T cells require CD8 coreceptor engagement for calcium mobilization and proliferation, but not cytokine production
Authors: Kerry Samantha E. , Maile Robert , Collins Edward J. , Frelinger Jeffrey A.
Published: December 2004

Memory T‐cell responses are faster and more robust than those of their naïve counterparts. The mechanisms by which memory T cells respond better to subsequent antigenic exposure remain unresolved. A portion of the more rapid response is undoubtedly the result of the increased frequency of antigen‐specific cells. In addition, there are also differences in the cells themselves with respect to their requirements for costimulation and the apparent avidity of the T cells. We used major histocompatibility complex (MHC) class I tetramers to stimulate T cells to focus on the interaction of T‐cell receptor (TCR)/MHC and CD8 in the absence of other molecules that are present on cell surfaces and so contribute to the activation of T cells by undefined mechanisms. Mutated MHC class I tetramers that are unable to engage CD8 were used to investigate the role of CD8 engagement in memory cell activation. Either wild‐type tetramers or tetramers carrying the mutation were used to stimulate both memory and naïve TCR transgenic T cells in vitro. Surprisingly, like naïve cells, memory CD8+ T cells required CD8 engagement for calcium mobilization and optimum proliferation. In contrast, the requirements for cytokine production differed. Unlike naive cells, memory cells were able to produce cytokine in the absence of CD8 engagement. This suggests both a CD8‐dependent pathway for early events and a CD8‐independent pathway for cytokine production in memory cells.
A transcriptional regulatory element in the coding sequence of the human Bcl‐2 gene
Authors: Lang Georgina , Gombert Wendy M. , Gould Hannah J.
Published: December 2004

We investigated the protein‐binding sites in a DNAse I hypersensitive site associated with bcl‐2 gene expression in human B cells. We mapped this hypersensitive site to the coding sequence of exon 2 of the bcl‐2 gene in the bcl‐2‐expressing REH B‐cell line. Electrophoretic mobility shift assays (EMSAs) with extracts from REH cells revealed three previously unrecognized B‐Myb‐binding sites in this sequence. The protein was identified as B‐Myb by using a specific antibody and EMSAs. Accordingly, the levels of B‐Myb and bcl‐2 proteins, and of Myb EMSA activity, were correlated over a wide range of cell lines, representing different stages of B‐cell development. Transfection of REH cells with antisense B‐myb down‐regulated EMSA activity and the level of bcl‐2, and led to the apoptosis of REH cells. Transfection of the bcl‐2‐non‐expressing RPMI 8226 cell line with a B‐Myb expression vector induced B‐Myb EMSA activity and the expression of bcl‐2. Reporter assays indicated that the HSS8 sequence containing the three B‐Myb sites may act as an enhancer when it is linked to the bcl‐2 gene promoter. Interaction of B‐Myb with HSS8 may enhance bcl‐2 gene expression by co‐operating with positive regulatory elements (e.g. previously identified B‐Myb response elements) or silencing negative response elements in the bcl‐2 gene promoter.
Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae
Authors: Wachter Andreas , Wolf Sebastian , Steininger Heike , Bogs Jochen , Rausch Thomas
Published: December 2004

The genome of Arabidopsis thaliana reveals that in this species the enzymes of glutathione biosynthesis, GSH1 and GSH2, are encoded by single genes. In silico analysis predicts proteins with putative plastidic transit peptides (TP) for both genes, but this has not been experimentally verified. Here we report a detailed analysis of the 5′ends of GSH1 and GSH2 mRNAs and demonstrate the subcellular targeting of the proteins encoded by different transcript types. GSH1 transcript analysis revealed two mRNA populations with short and long 5′‐UTRs, respectively, both including the entire TP sequence. The ratio of long/total GSH1 transcripts was subject to developmental regulation. Transient transformation experiments with reporter gene fusions, bearing long or short 5′‐UTRs, indicated an exclusive targeting of GSH1 to the plastids. Corroborating these results, endogenous and ectopically expressed GSH1 proteins were always present as a single polypeptide species with the size expected for correctly processed GSH1. Finally, the plastidic GSH1 localization was confirmed by immunocytochemistry. Similar to GSH1, multiple transcript populations were found for GSH2. However, here the prevalent shorter transcripts lacked a complete TP sequence. As expected, the large (but less abundant) transcript encoded a plastidic GSH2 protein, whereas GSH2 synthesized from the shorter transcript was targeted to the cytosol. The implications of the results for the compartmentation and regulation of GSH synthesis are discussed.
Essential role of the V‐ATPase in male gametophyte development
Authors: Dettmer Jan , Schubert Daniel , Calvo‐Weimar Olga , Stierhof York‐Dieter , Schmidt Renate , Schumacher Karin
Published: December 2004

Intracellular pH homeostasis is a prerequisite for biological processes and requires the action of proton pumps. The vacuolar H+‐ATPase (V‐ATPase) is involved in regulating pH in endomembrane compartments of all eukaryotic cells. In plants, there is an additional endomembrane proton pump, H+‐pyrophosphatase (H+‐PPase). However, the relative roles of the two types of pumps in endomembrane acidification and energization of secondary active transport are unclear. Here, we show that a strong T‐DNA insertion allele of VHA‐A, the single copy gene encoding the catalytic subunit of the Arabidopsis V‐ATPase, causes complete male and partial female gametophytic lethality. Severe changes in the morphology of Golgi stacks and Golgi‐derived vesicles in male gametophytes are the first visible symptoms of cell degeneration leading to a failure to develop mature pollen. Similar effects on Golgi morphology were observed in pollen tubes when growth was blocked by Concanamycin A, a specific V‐ATPase inhibitor. Taken together, our results suggests that V‐ATPase function is essential for Golgi organization and development of the male gametophyte.
Competition between neighboring topogenic signals during membrane protein insertion into the ER
Authors: Monné Magnus , Hessa Tara , Thissen Laura , von Heijne Gunnar
Published: December 2004

To better define the mechanism of membrane protein insertion into the membrane of the endoplasmic reticulum, we measured the kinetics of translocation across microsomal membranes of the N‐terminal lumenal tail and the lumenal domain following the second transmembrane segment (TM2) in the multispanning mouse protein Cig30. In the wild‐type protein, the N‐terminal tail translocates across the membrane before the downstream lumenal domain. Addition of positively charged residues to the N‐terminal tail dramatically slows down its translocation and allows the downstream lumenal domain to translocate at the same time as or even before the N‐tail. When TM2 is deleted, or when the loop between TM1 and TM2 is lengthened, addition of positively charged residues to the N‐terminal tail causes TM1 to adopt an orientation with its N‐terminal end in the cytoplasm. We suggest that the topology of the TM1‐TM2 region of Cig30 depends on a competition between TM1 and TM2 such that the transmembrane segment that inserts first into the ER membrane determines the final topology.
Principles behind the multifarious control of signal transduction
Authors: Hornberg Jorrit J. , Bruggeman Frank J. , Binder Bernd , Geest Christian R. , de Vaate A. J. Marjolein Bij , Lankelma Jan , Heinrich Reinhart , Westerhoff Hans V.
Published: December 2004

General and simple principles are identified that govern signal transduction. The effects of kinase and phosphatase inhibition on a MAP kinase pathway are first examined in silico. Quantitative measures for the control of signal amplitude, duration and integral strength are introduced. We then identify and prove new principles, such that total control on signal amplitude and on final signal strength must amount to zero, and total control on signal duration and on integral signal intensity must equal −1. Collectively, kinases control amplitudes more than duration, whereas phosphatases tend to control both. We illustrate and validate these principles experimentally: (a) a kinase inhibitor affects the amplitude of EGF‐induced ERK phosphorylation much more than its duration and (b) a phosphatase inhibitor influences both signal duration and signal amplitude, in particular long after EGF administration. Implications for the cellular decision between growth and differentiation are discussed.
Interaction of the E2 and E3 components of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus
Authors: Allen Mark D. , Broadhurst R. William , Solomon Robert G. , Perham Richard N.
Published: December 2004

A 15N‐labelled peripheral‐subunit binding domain (PSBD) of the dihydrolipoyl acetyltransferase (E2p) and the dimer of a solubilized interface domain (E3int) derived from the dihydrolipoyl dehydrogenase (E3) were used to investigate the basis of the interaction of E2p with E3 in the assembly of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus. Thirteen of the 55 amino acids in the PSBD show significant changes in either or both of the 15N and 1H amide chemical shifts when the PSBD forms a 1 : 1 complex with E3int. All of the 13 amino acids reside near the N‐terminus of helix I of PSBD or in the loop region between helix II and helix III. 15N backbone dynamics experiments on PSBD indicate that the structured region extends from Val129 to Ala168, with limited structure present in residues Asn126 to Arg128. The presence of structure in the region before helix I was confirmed by a refinement of the NMR structure of uncomplexed PSBD. Comparison of the crystal structure of the PSBD bound to E3 [Mande SS, Sarfaty S, Allen MD, Perham RN & Hol WGJ (1996) Structure4, 277–286] with the solution structure of uncomplexed PSBD described here indicates that the PSBD undergoes almost no conformational change upon binding to E3. These studies exemplify and validate the novel use of a solubilized, truncated protein domain in overcoming the limitations of high molecular mass on NMR spectroscopy.
Asthma phenotypes in Niue Islanders
Authors: ABBOTT William G. H. , WINSHIP Ingrid M. , WILSHER Margaret L. , NILAU Malama , TUKUITONGA Colin F.
Published: December 2004

Objective:  The aim of this study was to identify asthma phenotypes in patients of Niue Island ancestry that might be suitable for susceptibility gene mapping studies.

Methodology:  Two hundred and sixteen Niue Islanders with physician‐diagnosed asthma that was not secondary to other medical conditions were recruited through community organisations. Fifty‐one of the subjects with asthma were resident on Niue Island and 165 in New Zealand. Each subject was interviewed and tested for atopy, serum [IgE] (5% quantile, median, 95% quantile) and lung function.

Results:  There were two groups of subjects defined by an age of onset of asthma less than 12 years of age (childhood‐onset, boys:girls 64:65) and greater than 12 years of age (adult‐onset, men:women 11:76). A positive response (wheal > 3 mm) to at least one aeroallergen was seen in 181 patients, with 168/181 (92.8%) responding to house dust mite. Twenty‐eight subjects with asthma were non‐atopic (no detectable wheal) and the atopy status of seven subjects with asthma could not be determined (wheal < 3 mm). In childhood‐onset asthma, serum IgE levels were higher (P < 0.0001) in subjects with atopic than in subjects with non‐atopic asthma. In adult‐onset asthma, serum IgE levels were higher (P < 0.0001) in subjects with atopic asthma than in either subjects with non‐atopic asthma or matched non‐atopic subjects without asthma. The asthma phenotypes in Niue Island and New Zealand residents were similar.

Conclusions:  Both atopic and non‐atopic asthma phenotypes exist in Niue Islanders resident in Niue and New Zealand. The potential for mapping asthma susceptibility genes in this isolated population is discussed.
Occult bronchial foreign body aspiration in adults: analysis of four cases
Authors: YILMAZ Adnan , AKKAYA Esen , DAMADOGLU Ebru , GUNGOR Sinem
Published: December 2004

Abstract:  Occult tracheobronchial foreign body aspirations are infrequently seen in adults because there is usually a high index of suspicion. Occult foreign bodies can remain undetected for months to years and often are misdiagnosed. The aim of this paper is to report the cases of four adult patients with occult bronchial foreign body aspiration. None of the patients had a previous history of aspiration. One patient had been misdiagnosed as having asthma. One was thought to have tuberculosis, while unresolved pneumonia was present in another. A CXR showed the presence of a foreign body in only one patient because it was metallic. The foreign bodies included a stone, a tooth fragment, a bone fragment, and a needle. The foreign bodies were removed using a rigid bronchoscope in two patients and via a surgical procedure in the other two. In conclusion, tracheobronchial foreign body aspiration should always be taken into consideration in the differential diagnosis of radiographic lesions or chronic respiratory symptoms that are poorly explained, even in the absence of a previous history of aspiration.
Prediction equations for pulmonary function values in healthy young Iranians aged 8–18 years
Authors: BOSKABADY Mohammad Hossein , TASHAKORY Abulghasem , MAZLOOM Reza , GHAMAMI Gity
Published: December 2004

Objective:  Pulmonary function test (PFT) variables are dependent on height, age and gender. In addition, there is evidence of PFT variation in different ethnic groups. Prediction equations for PFT from a healthy, non‐smoking, urban young population in the city of Mashhad (north‐east Iran) have been derived.

Methodology:  Prediction equations for normal pulmonary function were derived from 336 healthy, non‐smoking subjects, including 187 males (height 103–188.5 cm) and 149 females (height 104–183 cm) aged 8–18 years. The subjects underwent measurement of spirometric flow and volume. The following variables were measured: FVC, FEV1, maximal mid‐expiratory flow (MMEF), PEF, maximal expiratory flow at 75, 50 and 25% of the FVC (MEF75, MEF50, and MEF25, respectively), tidal volume (VT), inspiratory reserve volume (IRV), expiratory reserve volume (ERV), inspiratory capacity (IC), and vital capacity (VC). Regression analysis using height and age as independent variables was applied to provide predicted values for both genders.

Results:  There were positive correlations for each pulmonary function variable with height and age. The largest positive correlations were found for FEV1 with height and age, in both genders. Comparison of PFT variables derived from the equations obtained in the present study showed significant differences to those calculated from several previously published equations (P < 0.001 for most variables). For example, the values of FVC and FEV1 derived from the equations obtained in the present study were 2.83 ± 0.99 and 2.50 ± 0.89 for males, and 2.41 ± 0.54 and 2.19 ± 0.53 for females, while the values derived from the equations of the European Community for Steel and Coal study were 3.12 ± 1.06 and 2.62 ± 0.89 for males and 2.79 ± 0.67 and 3.35 ± 0.57 for females, respectively.

Conclusions:  A set of PFT reference values and prediction equations for both genders has been derived using a relatively large, healthy, non‐smoking Iranian young population, and has generated results that differ from several other prediction equations.
Causes and management of pleural fibrosis
Authors: HUGGINS John T , SAHN Steven A
Published: December 2004

Abstract:  The development of pleural fibrosis follows severe pleural space inflammation which is typically associated with an exudative pleural effusion. The response of the mesothelial cell to injury and its ability, along with the basement membrane, to maintain its integrity, is vital in determining whether there is normal healing or pleural fibrosis. The formation of a fibrinous intrapleural matrix is critical to the development of pleural fibrosis. This matrix is the result of disordered fibrin turnover, whereby fibrin formation is up‐regulated and fibrin dissolution is down‐regulated. Cytokines, such as TGF‐β and TNF‐α, facilitate the fibrin matrix formation. A complete understanding of the pathogenesis of pleural fibrosis and why abnormal pleural space remodeling occurs in some and not in others, remains unknown. Clinically significant pleural fibrosis requires involvement of the visceral pleura. Isolated parietal pleural fibrosis, as with asbestos pleural plaques, does not cause restriction or respiratory impairment. The causes of visceral pleural fibrosis include asbestos‐associated diffuse pleural thickening, coronary bypass graft surgery, pleural infection (including tuberculous pleurisy), drug‐induced pleuritis, rheumatoid pleurisy, uraemic pleurisy, and haemothorax. Systemic and intrapleural corticosteroids administered during the initial presentation of rheumatoid pleurisy in small series may decrease the incidence of pleural fibrosis. Several randomised control trials using corticosteroids in tuberculous pleurisy have not shown efficacy in reducing residual pleural fibrosis. Decortication is effective in treating symptomatic patients regardless of the cause of pleural fibrosis as long as chronicity has been documented and significant underlying parenchymal disease has been excluded.
A new asthma spacer device to improve compliance in children: a pilot study
Authors: CHANEY Gervase , CLEMENTS Barry , LANDAU Lou , BULSARA Max , WATT Paul
Published: December 2004

Objective:  This pilot study was designed to compare the acceptance, ease of use, and effects on compliance between currently used spacer devices and the Funhaler—a new small volume spacer device designed to improve adherence to asthma medication in children.

Methodology:  A matched questionnaire‐based survey was conducted by two interviews of each caregiver by the same person. A total of 32 children were randomly recruited from seven clinics spanning widely differing socioeconomic and geographical areas of Perth, Western Australia. Preschool children taking regular inhaled asthma medication using an existing low volume spacer device and aged between 1.5 and 6 years, took part in the pilot study. Parents completed two matched questionnaires. The first questionnaire was completed at the beginning of the study and the second after 2 weeks’ use of the Funhaler spacer. Data collected related primarily to ease of use of the devices, child and parental compliance, and treatment attitudes. During the study, parents were also called at random on one occasion to ascertain whether they had attempted to medicate their child the previous day.

Results:  Using the Funhaler incentive spacer device, parents reported significantly more success at medicating their children (22/30 always successful) in comparison to using their existing spacer device (3/30). Parental adherence to prescribed frequency and the delivery technique of children were also improved. The children also showed improved satisfaction and willingness to use the device and parents’ attitude towards medicating their children was improved with the Funhaler spacer device.

Conclusions:  Use of a novel, incentive spacer device (Funhaler) appeared to be associated with increased success and fewer problems in medicating children, improved child and parental adherence, and a more positive attitude towards treatment, suggesting that more extensive long‐term efficacy trials with the device are warranted.
Glutathione‐S‐transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma
Authors: TAMER Lülüfer , ÇALIKOĞLU Mukadder , ATES Nurcan Aras , YILDIRIM Hatice , ERCAN Bahadir , SARITAS Emel , ÜNLÜ Ali , ATIK Ugur
Published: December 2004

Objectives:  Asthma is a complex multifactorial disease with an obvious genetic predisposition, immunological aberration, and involvement of noxious environmental factors. Polymorphisms of the glutathione‐S‐transferase (GST) genes are known risk factors for some environmentally‐related diseases. In the present study, the hypothesis that polymorphisms in the GSTT1, GSTM1 and GSTP1 genes are associated with atopic and nonatopic asthma was examined.

Methodology:  The study population consisted of 103 unrelated healthy individuals and 101 patients with bronchial asthma (64 atopic, 37 nonatopic). Asthma was diagnosed according to the American Thoracic Society statement. Genotyping of polymorphisms in the GSTT1, GSTM1 and GSTP1 genes was performed using real time polymerase chain reaction with a Light Cycler instrument and hybridization probes in combination with the Light Cycler DNA master hybridization probes kit.

Results:  Patients with atopic asthma (34.4%) had a higher prevalence of the GSTT1 null genotype than the nonatopic asthma patients (13.5%; OR = 3.83; 95% CI, 1.24–11.78). Asthma patients (63.4%) had a higher prevalence of the GSTM1 null genotype than the control group (40.8%; OR = 2.34; 95% CI, 1.31–4.20). Subjects with the GSTP1 homozygous Val/Val genotype had a 3.55‐fold increased risk of having atopic asthma compared to nonatopic asthma (OR = 3.55; 95% CI, 1.10–12.56).

Conclusions:  These results suggest that the GSTT1 and GSTM1 null genotypes and the GSTP1 Val/Val polymorphism may play important roles in asthma pathogenesis. It is possible that intermediate electrophilic metabolites, arising in the first phase of detoxification, are not metabolized by GST enzymes in asthmatic patients and are not excreted. These intermediate metabolites may damage cells and generate oxidative stress, and so contribute to the pathogenesis of asthma.
Augmentation mammoplasty and ‘silicone‐osis’
Authors: Englert H. , Joyner E. , Thompson M. , Garcia H. , Chambers P. , Horner D. , Hunt C. , Makaroff J. , O'Connor H. , Russell N. , March L.
Published: December 2004

Background: Claims have been made that breast augmentation induces a previously unrecognized disease (‘silicone‐osis’).

Aims: To confirm the existence of ‘silicone‐osis’, qualify and quantify its characteristics.

Methods: In this population‐based retrospective cohort study, the health status of 458 female Sydney residents who had augmentation mammoplasty for cosmetic reasons (‘augmentation mammoplasty‐exposed’ or ‘exposed’ cohort) between 1979 and 1983 was compared with the health status of 687 female Sydney residents who had non‐silicone‐associated plastic surgery (‘augmentation mammoplasty‐nonexposed’ or ‘non‐exposed’ cohort). Both groups were matched for age (± 5 years), year of plastic surgery (± 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised dummy symptoms to assess reporting bias, as well as symptoms and symptom clusters from a comprehensive 78‐symptom list.

Results: Dummy variables were not over‐reported by the exposed cohort. The following individual symptoms developed more commonly in the exposed cohort after index plastic surgery: ‘memory loss/confusion’, ‘altered bowel habit’, ‘chest pain made worse by deep breathing’, ‘shortness of breath after walking up 10 steps’‘breast pain’, ‘sweating mainly at night’ and ‘tunnel vision’. Of eight identified symptom clusters, three were rejected as biologically unimportant: ‘joint swelling of the bunion joint’, ‘haemorrhoids’ and ‘breast lumps’ (the latter two occurring more commonly in the non‐exposed cohort). In contrast, five symptom clusters were thought to have potential biological importance and occurred more commonly in the exposed cohort. The symptom ‘night sweats’ was common to all five clusters, and comprised the sole symptom in one instance. The other four multisymptom clusters were also characterized by ‘low energy’ (lethargy) and ‘pins and needles’, whereas ‘breast pain’, ‘impaired memory’, ‘muscle pain’ and ‘reflux’, occurred in three of the four clusters.

Conclusion: Cluster analysis suggested the existence of a multisystem disorder occurring more commonly in the exposed cohort and characterized by night sweats, lethargy, breast pain, impaired mentation, reflux, paraesthesiae, hand muscle weakness and myalgia. The argument against this being a new disease entity −‘silicone‐osis’− however, was its presence, albeit at lower frequency, in the silicone‐unexposed cohort. Thus this study did not confirm the existence of a new disease entity ‘silicone‐osis’ uniquely and causally associated with silicone exposure. The possible interpretations of these findings are discussed. (Intern Med J 2004; 34: 668−676)
Tumour necrosis factor inhibitors: risks and benefits in patients with rheumatoid arthritis
Authors: Roberts L. , McColl G. J.
Published: December 2004

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and can, if left untreated, result in significant disability and early death. It is also associated with large direct and indirect costs to the individual and to society. Early and aggressive disease modifying anti‐rheumatic drug (DMARD) treatment of patients at risk of erosive disease has improved the outcome in the majority, but not all, RA patients. Tumour necrosis factor (TNF) appears to be a key mediator of the inflammatory and destructive process in RA, and consequently inhibitors of TNF action have been tested in randomized controlled trials in patients with RA. The results of these studies have suggested that TNF inhibitors are potent DMARD particularly when combined with methotrexate. They appear well tolerated with the commonest adverse events related to their parenteral route of administration, and the serious but rare side‐effects being various infections, notably tuberculosis, multiple sclerosis, and worsening of cardiac failure. Treatment costs are high and range from $15 000 to $25 000 per patient per year. Etanercept, adalimumab and infliximab have recently been subsidised under the Pharmaceutical Benefits Scheme in Australia for patients with severe DMARD‐resistant RA. The availability of TNF inhibitors in RA represents a significant advance in the treatment of patients with severe RA. (Intern Med J 2004; 34: 687−693)
Using marine reserves to estimate fishing mortality
Authors: Willis Trevor J. , Millar Russell B.
Published: December 2004

The proportion of a fish stock that is killed by fishing activity is often calculated as the catch divided by the estimated stock biomass. However, stock biomass is notoriously difficult to estimate reliably, and moreover, the catch may be uncertain or misreported and does not include losses due to discarding. In all too many fisheries, these difficulties have lead to underestimates of total fishing mortality and the commercial demise of the fishery. No‐take marine reserves eliminate fishing mortality from within their boundaries and, for species that exhibit seasonal migratory behaviour, comparison of reserves with fished areas can provide direct estimates of the proportion killed by fishing. For an important exploited species in New Zealand, seasonal changes in density of sub‐legal fish at three marine reserves were similar in both reserve and adjacent non‐reserve areas. However, this result did not hold for legal‐size fish, and the difference in seasonal change between reserved and non‐reserved areas was used to obtain direct estimates of the total localized fishing mortality in the non‐reserve area over 6‐month periods. Estimates of the percentage of legal‐size fish killed by fishing ranged from 70 to 96%. These results demonstrate an unanticipated practical benefit from marine reserves that goes beyond their ecological role.
Bacterial traits, organism mass, and numerical abundance in the detrital soil food web of Dutch agricultural grasslands
Authors: Mulder Christian , Cohen Joel E. , Setälä Heikki , Bloem Jaap , Breure Anton M.
Published: December 2004

This paper compares responses to environmental stress of the ecophysiological traits of organisms in the detrital soil food webs of grasslands in the Netherlands, using the relationship between average body massMand numerical abundanceN. The microbial biomass and biodiversity of belowground fauna were measured in 110 grasslands on sand, 85 of them farmed under organic, conventional and intensive management. Bacterial cell volume and abundance and electrophoretic DNA bands as well as bacterial activity in the form of either metabolic quotient (qCO2) or microbial quotient (Cmic/Corg) predicted the response of microorganisms to stress. For soil fauna, the logarithm of body mass log(M) was approximately linearly related to the logarithm of numerical abundance log(N) with slope near −1, and the regression slope and the proportion of predatory species were lower in intensive agroecosystems (more reduced substrates with higher energy content). Linear regression of log(N) on log(M) had slope not far from −3/4. The approach to monitoring data illustrated in this paper could be useful in assessing land‐use quality.
A Panel Data Analysis of the Effects of Wages, Standard Hours and Unionization on Paid Overtime Work in Britain
Authors: Kalwij Adriaan S. , Gregory Mary
Published: December 2004

This study examines the effects of the basic wage rate, standard working hours and unionization on paid overtime work in Britain by using individual level data from the New Earnings Survey over the period 1975–2001. For this purpose we estimate a panel data model. We show that to obtain consistent estimates it is important to allow for both the censoring of paid overtime hours at 0 and for correlations between the explanatory variables and unobserved individual-specific effects. The main empirical results are that a reduction in standard hours increases both the incidence of overtime and overtime hours, whereas an increase in the wage rate decreases the incidence of overtime but brings a small increase in overtime hours for those working overtime. For men the effects are stronger than for women. Union coverage is of minor empirical importance. The occupation and industry structure of employment has shifted from high to lower overtime jobs. Taken together, these economic variables can explain almost half of the changing incidence of overtime for men, and most of the change in overtime hours worked by women, but are less successful in explaining the changes in overtime hours worked by men or the incidence of overtime for women.
Sjögren's syndrome: the diagnostic potential of early oral manifestations preceding hyposalivation/xerostomia
Authors: Mignogna M. D. , Fedele S. , Russo L. Lo , Muzio L. Lo , Wolff A.
Published: December 2004

Sjögren's syndrome (SS) is a systemic autoimmune exocrinopathy that affects mainly the salivary and lacrimal glands, leading to progressive reduction in saliva and tear flow. Although the underlying immuno‐mediated glandular destruction is thought to develop slowly over several years, a long delay from the start of the symptoms to final diagnosis has been frequently reported. A limited knowledge concerning SS natural history is among the major causes of the actual diagnostic delay. Although very few studies have been focused on the analysis of SS early clinical onset, a series of oral features preceding xerostomia/hyposalivation development in patients eventually diagnosed as having SS have been reported. Sialochemistry alterations, salivary gland swelling, early dental loss and sialorrhea have been observed before the onset of typical signs and symptoms (namely xerostomia and/or hyposalivation), which usually lead to SS clinical presentation and diagnosis. Here we suggest, after evaluating available data, that the traditional ‘untouchable’ association between SS and xerostomia/hyposalivation might probably be reconsidered, and that astute clinicians should not underestimate the possible presence or development of SS in patients without xerostomia/hyposalivation and presenting these atypical early oral features.
Are Parents Investing Less Time in Children? Trends in Selected Industrialized Countries
Authors: Gauthier Anne H. , Smeeding Timothy M. , Furstenberg Frank F.
Published: December 2004

Trends in parental time invested in children since the 1960s are examined in 16 industrialized countries using time‐use survey data. Despite the time pressures that confront today's families, parents appear to be devoting more time to children than they did 40 years ago. Results also suggest that mothers continue to devote more time to childcare than fathers, but the gender gap has been reduced. The consistency of these results across countries suggests a global trend toward an increase in parental time investment in children. Multivariate analysis of trends in parental time by type of activity was undertaken for Canada. It revealed a significant increase in parental time even after controlling for changes in the demographic composition of the population during the past few decades.
bHLH Transcription Factor Olig1 Is Required to Repair Demyelinated Lesions in the CNS
Authors: Arnett Heather A. , Fancy Stephen P. J. , Alberta John A. , Zhao Chao , Plant Sheila R. , Kaing Sovann , Raine Cedric S. , Rowitch David H. , Franklin Robin J. M. , Stiles Charles D.
Published: December 2004

Olig1 and Olig2 are closely related basic helix-loop-helix (bHLH) transcription factors that are expressed in myelinating oligodendrocytes and their progenitor cells in the developing central nervous system (CNS). Olig2 is necessary for the specification of oligodendrocytes, but the biological functions of Olig1 during oligodendrocyte lineage development are poorly understood. We show here that Olig1 function in mice is required not to develop the brain but to repair it. Specifically, we demonstrate a genetic requirement for Olig1 in repairing the types of lesions that occur in patients with multiple sclerosis.
Translation of DNA Signals into Polymer Assembly Instructions
Authors: Liao Shiping , Seeman Nadrian C.
Published: December 2004

We developed a DNA nanomechanical device that enables the positional synthesis of products whose sequences are determined by the state of the device. This machine emulates the translational capabilities of the ribosome. The device has been prototyped to make specific DNA sequences. The state of the device is established by the addition of DNA set strands. There is no transcriptional relationship between the set strands and the product strands. The device has potential applications that include designer polymer synthesis, encryption of information, and use as a variable-input device for DNA-based computation.
Clues from Fe Isotope Variations on the Origin of Early Archean BIFs from Greenland
Authors: Dauphas Nicolas , van Zuilen Mark , Wadhwa Meenakshi , Davis Andrew M. , Marty Bernard , Janney Philip E.
Published: December 2004

Archean rocks may provide a record of early Earth environments. However, such rocks have often been metamorphosed by high pressure and temperature, which can overprint the signatures of their original formation. Here, we show that the early Archean banded rocks from Isua, Akilia, and Innersuartuut, Greenland, are enriched in heavy iron isotopes by 0.1 to 0.5 per mil per atomic mass unit relative to igneous rocks worldwide. The observed enrichments are compatible with the transport, oxidation, and subsequent precipitation of ferrous iron emanating from hydrothermal vents and thus suggest that the original rocks were banded iron formations (BIFs). These variations therefore support a sedimentary origin for the Akilia banded rocks, which represent one of the oldest known occurrences of water-laid deposits on Earth.
Optimized for Chewing
Authors: Rybczynski Natalia
Published: December 2004

Dental Functional Morphology
How Teeth Work. by Peter W. Lucas. Cambridge University Press, Cambridge, 2004. 371 pp. $130, £75. ISBN 0-521-56236-8.

Lucas builds his account of the function and evolution of mammalian teeth around considerations of how teeth adapt to diet (in particular, around analyses of how food particles fracture).
The Cytoplasmic Tail Slows the Folding of Human Immunodeficiency Virus Type 1 Env from a Late Prebundle Configuration into the Six-Helix Bundle
Authors: Abrahamyan Levon G. , Mkrtchyan Samvel R. , Binley James , Lu Min , Melikyan Grigory B. , Cohen Fredric S.
Published: December 2004

Effects of the cytoplasmic tail (CT) of human immunodeficiency virus type 1 Env on the process of membrane fusion were investigated. Full-length Env (wild type [WT]) and Env with its CT truncated (ΔCT) were expressed on cell surfaces, these cells were fused to target cells, and the inhibition of fusion by peptides that prevent Env from folding into a six-helix bundle conformation was measured. For both X4-tropic and R5-tropic Env proteins, ΔCT induced faster fusion kinetics than did the WT, and peptides were less effective at inhibiting ΔCT-induced fusion. We tested the hypothesis that the inhibitory peptides were less effective at inhibiting ΔCT-induced fusion because ΔCT folds more quickly into a six-helix bundle. Early and late intermediates of WT- and ΔCT-induced fusion were captured, and the ability of peptides to block fusion when added at the intermediate stages was quantified. When added at the early intermediate, the peptides were still less effective at inhibiting ΔCT-induced fusion but they were equally effective at preventing WT- and ΔCT-induced fusion when added at the late intermediate. We conclude that for both X4-tropic and R5-tropic Env proteins, the CT facilitates conformational changes that allow the trimeric coiled coil of prebundles to become optimally exposed. But once Env does favorably expose its coiled coil to inhibitory peptides, the CT hinders subsequent folding into a six-helix bundle. Because of this facilitation of maximal exposure and hindrance of bundle formation, the coiled coil is optimally exposed for a longer time for WT than for ΔCT. This accounts for the greater peptide inhibition of WT-induced fusion.