bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal Bipolar Cell Input Mechanisms in Giant Danio. I. Electroretinographic Analysis
Authors: Wong Kwoon Y. , Adolph Alan R. , Dowling John E.
Published: July 2004

Electroretinograms (ERGs) were recorded from the giant danio ( Danio aequipinnatus) to study glutamatergic input mechanisms onto bipolar cells. Glutamate analogs were applied to determine which receptor types mediate synaptic transmission from rods and cones to on and off bipolar cells. Picrotoxin, strychnine, and tetrodotoxin were used to isolate the effects of the glutamate analogs to the photoreceptor–bipolar cell synapse. Under photopic conditions, the group III metabotropic glutamate receptor (mGluR) antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG) only slightly reduced the b-wave, whereas the excitatory amino acid transporter (EAAT) blocker dl- threo-β-benzyl-oxyaspartate (TBOA) removed most of it. Complete elimination of the b-wave required both antagonists. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) blocked the d-wave. Under scotopic conditions, rod and cone inputs onto on bipolar cells were studied by comparing the sensitivities of the b-wave to photopically matched green and red stimuli. The b-wave was >1 log unit more sensitive to the green than to the red stimulus under control conditions. In CPPG or l-AP4 (l-(+)-2-amino-4-phosphonobutyric acid, a group III mGluR agonist), the sensitivity of the b-wave to the green stimulus was dramatically reduced and the b-waves elicited by the 2 stimuli became nearly matched. The d-wave elicited by dim green stimuli, which presumably could be detected only by the rods, was eliminated by NBQX. In conclusion: 1) cone signals onto on bipolar cells involve mainly EAATs but also mGluRs (presumably mGluR6) to a lesser extent; 2) rods signal onto on bipolars by mainly mGluR6; 3) off bipolar cells receive signals from both photoreceptor types by AMPA/kainate receptors.
Sequential Learning From Multiple Tutors and Serial Retuning of Auditory Neurons in a Brain Area Important to Birdsong Learning
Authors: Yazaki-Sugiyama Yoko , Mooney Richard
Published: July 2004

Songbirds hear many vocal models during a juvenile sensitive period, transiently imitating some while retaining imitations of others in their repertoires. Despite subsequent conflicting experiences, early experience can exert lasting effects on neural structure and function, raising the possibility that transiently expressed vocalizations or their relevant models are stored in the adult songbird's brain. One site where learned song representations could be stored is the lateral magnocellular nucleus of the anterior nidopallium (LMAN), which in the adult songbird contains neurons responsive to playback of the bird's own song (BOS) and the tutor song (TS). To test whether LMAN neurons develop and retain responses to transiently learned songs, we exposed zebra finch hatchlings [posthatch day 0 (PHD0)] to a first TS (TS1) for about 30 days, isolated them for about 30 days, then exposed them to a second TS (TS2) for 30 days starting at PHD 60. Behavioral analysis showed that PHD 60 juveniles had started to copy TS1, although this copying was transient, because the adult BOS resembled TS2 and not TS1. We found that LMAN auditory responses paralleled these behavioral changes: LMAN neurons at PHD 60 responded strongly and selectively to both the juvenile BOS and TS1, whereas LMAN neurons in adults responded to the adult BOS and TS2, but not to the transiently learned song or its model. Therefore LMAN auditory responses can be lost or overwritten as the juvenile copies a new song, suggesting that the adult LMAN does not store information about transiently learned songs or their models.
Deficits in Saccades and Fixation During Muscimol Inactivation of the Caudal Fastigial Nucleus in the Rhesus Monkey
Authors: Goffart Laurent , Chen Longtang L. , Sparks David L.
Published: July 2004

The caudal fastigial nucleus (cFN) is a major nucleus by which the cerebellum influences the accuracy of saccades. In head-restrained monkeys generating saccades from a fixation light-emitting diode (LED) toward a flashed target LED, we analyzed the effects of unilateral pharmacological inactivation of cFN on horizontal, vertical, and oblique saccades. When animals were viewing the fixation LED, usually after one or more correction saccades, the positions of the eyes were slightly offset in comparison with the positions maintained before the injection (average offset = 1.1°). The offset was ipsilateral to the injected side and did not depend on the target location. The horizontal component of all ipsilesional saccades was hypermetric and associated with a 32–42% increase in the amplitude of the deceleration displacement without significant change in the amplitude of the acceleration displacement. The horizontal component of all contralesional saccades was hypometric and associated with a decrease in the peak velocity and in the acceleration amplitude (30–35% decrease) without significant change in the deceleration amplitude. The amplitude of vertical saccades was not systematically affected, but their trajectory was always deviated toward the injected side. They missed the target with an error that depended on saccade duration or amplitude. If any, the effects of muscimol injections on the vertical component of oblique saccades were very small. The changes in fixation and the dysmetria are both viewed as consequences of an impairment in the cFN bilateral influence on the burst neurons located in the left and right brain stem.
On further strengthened Hardy‐Hilbert′s inequality
Authors: Zhongxue Lü
Published: July 2004

We obtain an inequality for the weight coefficient ω(q, n)

(q > 1, 1/q + 1/q = 1, n ∈ ℕ) in the
form <π/sin(π/p) − 1/(2n1/p + (2/a)n−1/q) where 0 < a < 147/45,
as n ≥ 3; 0 < a < (1 − C)/(2C − 1), as n = 1, 2, and C is an Euler
constant. We show a generalization and improvement of Hilbert′s
inequalities. The results of the paper by Yang and Debnath are
improved.
Optical leptons
Authors: Kovachev Lubomir M.
Published: July 2004

We obtain optical vortices with classical orbital momentum
ℓ = 1 and spin j = ±1/2
as exact solutions of a system of
nonlinear Maxwell equations (NMEs). Two kinds of Kerr‐type media,
namely, those with and without linear dispersion of the electric
and the magnet susceptibility, are investigated. The electric and
magnetic fields are represented as sums of circular and linear
components. This allows us to reduce the NME to a set of
nonlinear Dirac equations (NDEs). The vortex solutions in the case
of media with dispersion admit finite energy, while the
solutions in case of media without dispersion admit infinite
energy. The amplitude equations are obtained from equations of
nonstationary optical and magnetic response (dispersion). This
includes also the optical pulses with time duration of order of
and less than the time of relaxation of the media (femtosecond
pulses). The possible generalization of NME to a higher number of
optical components and a higher number of ℓ and j is discussed.
Serial Analysis of Gene Expression: Applications in Malaria Parasite, Yeast, Plant, and Animal Studies
Authors: Tuteja Renu , Tuteja Narendra
Published: July 2004

The serial analysis of gene expression (SAGE) method is based on
the isolation of unique sequence tags from individual transcripts
and concatenation of tags serially into long DNA molecules. SAGE
is an innovative technique that offers the potential of
cataloging both the identity and relative frequencies of mRNA
transcripts in a given RNA preparation. It can quantify
low‐abundance transcripts and reliably detect relatively small
differences in transcript abundance between cell populations.
SAGE data can be used to complement studies in cases where other
gene expression methods may be more convenient or
efficient. SAGE can be used in a wide variety of applications to
identify disease‐related genes, to analyze the effect of drugs on
tissues, and to provide insights into the disease pathways. The
most important application of SAGE is the identification of
differentially expressed genes. In this review, we describe
various applications of this powerful technology in malarial
parasite, yeast, plant, and animal systems.
Survival of Human Neurofibroma in Immunodeficient Mice and Initial Results of Therapy With Pirfenidone
Authors: Babovic-Vuksanovic Dusica , Petrovic Lydia , Knudsen Bruce E. , Plummer Timothy B. , Parisi Joseph E. , Babovic Srdan , Platt Jeffrey L.
Published: July 2004

Neurofibromatosis type I is a common tumor predisposing disease
in humans. Surgical therapy can be applied only in selected
patients with resectable masses. Hence, development of new
therapies for this disease is urgent. We used human neurofibroma
implants in mice with severe combined immunodeficiency (SCID) as
a model to test the toxicity and potential efficacy of
pirfenidone, a new therapeutic agent. Two hundred twelve human
neurofibromas were transplanted into various locations in 59
experimental animals, and 30 mice with implants received oral
pirfenidone for up to six weeks. Survival of neurofibromas in
animals treated with pirfenidone was lower than in the control
group (P = .02). Tumors did not change histologic appearance or
vascularization in response to pirfenidone. Treatment with
pirfenidone, a new antifibrotic agent, inhibits survival of some
tumors without causing toxicity in animals.
5‐Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity
Authors: Hedi Harizi , Norbert Gualde
Published: July 2004

5‐lipoxygenase (5‐LO) pathway is the major source of potent
proinflammatory leukotrienes (LTs) issued from the metabolism of
arachidonic acid (AA), and best known for their roles in the
pathogenesis of asthma. These lipid mediators are mainly released
from myeloid cells and may act as physiological autocrine and
paracrine signalling molecules, and play a central role in
regulating the interaction between innate and adaptive immunity.
The biological actions of LTs including their immunoregulatory
and proinflammatory effects are mediated through extracellular
specific G‐protein‐coupled receptors. Despite their role in
inflammatory cells, such as neutrophils and macrophages, LTs may
have important effects on dendritic cells (DC)‐mediated adaptive
immunity. Several lines of evidence show that DC not only are
important source of LTs, but also become targets of their actions
by producing other lipid mediators and proinflammatory molecules.
This review focuses on advances in 5‐LO pathway biology, the
production of LTs from DC and their role on various cells of
immune system and in adaptive immunity.
African Culture and Emergent Church Forms in Ghana
Authors: Dovlo Elom
Published: June 2004

The author gives a review of the African Independent Churches, African Initiated Churches or Spiritual Churches, as he prefers to call them, in West Africa. He also pays attention to the relationship of these churches to the so-called mainline churches. He shows the charismatic renewal that took place in the Spiritual Churches. Furthermore Dovlo turns his eyes to the relationship between the Western mainline churches and the African mainline churches and he makes clear that between all these diff erent types of churches an intra-cultural dialogue is going on. So Dovlo concludes omit that in spite of all tensions between them all churches need each other to communicate the hope of a God who is coming.
Kolonialphantasien in der Populären Naturwissenschaft der Frühen Neuzeit
Authors: Guthke Karl
Published: June 2004

The analogy between colonization and space exploration was by no means invented by H.G. Wells in his novel about the invasion of Mars, The War of the Worlds (1897), or the science fiction in its wake. The analogy goes back to the age of the Copernican Revolution, which put the Earth on a par with other planets and thus suggested that those, too, could be inhabited by man-like creatures. Since then, popularizers of astrophysics have nurtured the notion that "we" or "they" could fill the roles of colonizers and natives, though it remained a matter of debate who had to play which role. Among those given to such contemplation we find Bruno, Kepler, Wilkins, and Huygens, along with scientifically trained literati such as Francis Godwin, Fontenelle, Swift. Together, they constitute a noteworthy phenomenon of the early modern age of discovery and conquest.
Missio Inter Gentes: Towards a New Paradigm in the Mission Theology of the Federation of Asian Bishops' Conferences (FABC)
Authors: Tan Jonathan
Published: June 2004

This essay seeks to investigate the mission theology of the Federation of Asian Bishops' Conferences (FABC) as presented in its official documents during the past three decades of its existence and evaluate its implications. In its official documents, the FABC has proceeded on the basis that the Asian milieu, with its rich diversity and plurality of religions, cultures and philosophical worldviews require a distinctively Asian approach to the proclamation of the Gospel that is sensitive to such diversity and pluralism. To this end, this essay surveys and examines the principal aspects and foundational principles of the FABC's theology of mission. It also explores the implications of the FABC's missiological approach for meeting the challenges of the task of carrying out the Christian mission in the diverse and pluralistic Asian Sitz-im-Leben, especially the FABC's consistent insistence that the Christian mission in Asia is best carried out through a threefold dialogue with the myriad of Asian religious traditions, Asian cultures and the teeming masses of Asian poor and marginalized. It then suggests that the FABC's missiological approach is best described as missio inter gentes (mission among the nations) rather than the traditional missio ad gentes (mission to the nations), because of how the FABC perceives the issue of religious pluralism in Asia and its preferred non-confrontational dialogical approach for dealing with it.
Mission or Evangelization?
Authors: Kavunkal Jacob
Published: June 2004

In this article, Indian missiologist Jacob Kavunkal notes the ongoing debate about the use of "mission" or "evangelization" to describe the task of the church in the world. One group, especially Europeans, use "mission" to designate the verbal proclamation of the gospel, and "evangelization" to designate other aspects such as social justice work, inculturation and dialogue. Another group, especially those from Latin America, define "mission" and "evangelization" in exactly the opposite way. Kavunkal argues, after a biblical and historical analysis of both terms, that the two terms should mean the same thing. However, mission or evangelization today should not be about the expansion of the church or even primarily an appeal to non-Christians. Rather, the church's evangelizing mission must be lived out in selfless service of the world, in imitation of God's own other-directed nature.
Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep
Authors: Zhou Hong , Wolberg Alisa S. , Roubey Robert A. S.
Published: June 2004

Increasing evidence suggests that autoantibodies directly contribute to hypercoagulability in the antiphospholipid syndrome (APS). One proposed mechanism is the antibody-induced expression of tissue factor (TF) by blood monocytes. Dilazep, an antiplatelet agent, is an adenosine uptake inhibitor known to block induction of monocyte TF expression by bacterial lipopolysaccharide. In the current study we characterized the effects of immunoglobulin G (IgG) from patients with APS on monocyte TF activity and investigated whether dilazep is capable of blocking this effect. IgG from 13 of 16 patients with APS significantly increased monocyte TF activity, whereas normal IgG had no effect. Time-course experiments demonstrated that APS IgG-induced monocyte TF mRNA levels were maximal at 2 hours and TF activity on the cell surface was maximal at 6 hours. Dilazep inhibited antibody-induced monocyte TF activity in a dose-dependent fashion but had no effect on TF mRNA expression. The effect of dilazep was blocked by theophylline, a nonspecific adenosine receptor antagonist. In conclusion, IgG from certain patients with APS induce monocyte TF activity. Dilazep inhibits the increased expression of monocyte TF activity at a posttranscriptional level, probably by way of its effect as an adenosine uptake inhibitor. Pharmacologic agents that block monocyte TF activity may be a novel therapeutic approach in APS.
An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients
Authors: Mitchell Michael , Dai Letian , Savidge Geoffrey , Alhaq Anwar
Published: June 2004

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)–transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.
Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood
Authors: Ingram David A. , Mead Laura E. , Tanaka Hiromi , Meade Virginia , Fenoglio Amy , Mortell Kelly , Pollok Karen , Ferkowicz Michael J. , Gilley David , Yoder Mervin C.
Published: June 2004

Emerging evidence to support the use of endothelial progenitor cells (EPCs) for angiogenic therapies or as biomarkers to assess cardiovascular disease risk and progression is compelling. However, there is no uniform definition of an EPC, which makes interpretation of these studies difficult. Although hallmarks of stem and progenitor cells are their ability to proliferate and to give rise to functional progeny, EPCs are primarily defined by the expression of cell-surface antigens. Here, using adult peripheral and umbilical cord blood, we describe an approach that identifies a novel hierarchy of EPCs based on their clonogenic and proliferative potential, analogous to the hematopoietic cell system. In fact, some EPCs form replatable colonies when deposited at the single-cell level. Using this approach, we also identify a previously unrecognized population of EPCs in cord blood that can achieve at least 100 population doublings, replate into at least secondary and tertiary colonies, and retain high levels of telomerase activity. Thus, these studies describe a clonogenic method to define a hierarchy of EPCs based on their proliferative potential, and they identify a unique population of high proliferative potential-endothelial colony-forming cells (HPP-ECFCs) in human umbilical cord blood. (Blood. 2004;104:2752-2760)
Interstitial lung disease in a baby with ade novomutation in the SFTPC gene
Authors: Brasch F. , Griese M. , Tredano M. , Johnen G. , Ochs M. , Rieger C. , Mulugeta S. , Müller K.M. , Bahuau M. , Beers M.F.
Published: July 2004

Mutations in the surfactant protein C gene (SFTPC) were recently reported in patients with interstitial lung disease.

In a 13‐month-old infant with severe respiratory insufficiency, a lung biopsy elicited combined histological patterns of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Immunohistochemical and biochemical analyses showed an intra-alveolar accumulation of surfactant protein (SP)‐A, precursors of SP‐B, mature SP‐B, aberrantly processed proSP‐C, as well as mono- and dimeric SP‐C.

Sequencing of genomic DNA detected ade novoheterozygous missense mutation of the SFTPC gene (g.1286T>C) resulting in a substitution of threonine for isoleucine (I73T) in the C‐terminal propeptide. At the ultrastructural level, abnormal transport vesicles were detected in type‐II pneumocytes. Fusion proteins, consisting of enhanced green fluorescent protein and wild-type or mutant proSP‐C, were used to evaluate protein traffickingin vitro. In contrast to wild-type proSP‐C, mutant proSP‐C was routed to early endosomes when transfected into A549 epithelial cells.

In contrast to previously reported mutations, the I73T represents a new class of surfactant protein C gene mutations, which is marked by a distinct trafficking, processing, palmitoylation, and secretion of the mutant and wild-type surfactant protein C. This report heralds the emerging diversity of phenotypes associated with the expression of mutant surfactant C proteins.
Older individuals have increased oro-nasal breathing during sleep
Authors: Madronio M.R. , Di Somma E. , Stavrinou R. , Kirkness J.P. , Goldfinch E. , Wheatley J.R. , Amis T.C.
Published: July 2004

Breathing route during sleep has been studied very little, however, it has potential importance in the pathophysiology of sleep disordered breathing.

Using overnight polysomnography, with separate nasal and oral thermocouple probes, data were obtained from 41 subjects (snorers and nonsnorers; 25 male and 16 female; aged 20–66 yrs). Awake, upright, inspiratory nasal resistance (Rn) was measured using posterior rhinomanometry. Each 30‐s sleep epoch (not affected by apnoeas/hypopnoeas) was scored for presence of nasal and/or oral breathing.

Overnight, seven subjects breathed nasally, one subject oro-nasally and the remainder switched between nasal and oro-nasal breathing. Oral‐only breathing rarely occurred. Nasal breathing epochs were 55.79 (69.78) per cent of total sleep epochs (%TSE; median (interquartile range)), a value not significantly different to that for oro-nasal (TSE: 44.21 (68.66)%). Oro-nasal breathing was not related to snoring, sleep stage, posture, body mass index, height, weight, Rn (2.19 (1.77) cm H2O·L−1·sec−1) or sex, but was positively associated with age. Subjects ≥40 yrs were approximately six times more likely than younger subjects to spend >50% of sleep epochs utilising oro-nasal breathing.

Ageing is associated with an increasing occurrence of oro-nasal breathing during sleep.
Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms
Authors: Gunnbjörnsdóttir M.I. , Omenaas E. , Gíslason T. , Norrman E. , Olin A‐C. , Jõgi R. , Jensen E.J. , Lindberg E. , Björnsson E. , Franklin K. , Janson C. ,   on behalf of the RHINE study group
Published: July 2004

Several studies have identified obesity as a risk factor for asthma in both children and adults. An increased prevalence of asthma in subjects with gastro-oesophageal reflux (GOR) and obstructive sleep apnoea syndrome has also been reported. The aim of this investigation was to study obesity, nocturnal GOR and snoring as independent risk factors for onset of asthma and respiratory symptoms in a Nordic population.

In a 5–10 yr follow-up study of the European Community Respiratory Health Survey in Iceland, Norway, Denmark, Sweden and Estonia, a postal questionnaire was sent to previous respondents.

A total of 16,191 participants responded to the questionnaire. Reported onset of asthma, wheeze and night-time symptoms as well as nocturnal GOR and habitual snoring increased in prevalence along with the increase in body mass index (BMI). After adjusting for nocturnal GOR, habitual snoring and other confounders, obesity (BMI >30) remained significantly related to the onset of asthma, wheeze and night-time symptoms. Nocturnal GOR was independently related to the onset of asthma and in addition, both nocturnal GOR and habitual snoring were independently related to onset of wheeze and night-time symptoms.

This study adds evidence to an independent relationship between obesity, nocturnal gastro-oesophageal reflux and habitual snoring and the onset of asthma and respiratory symptoms in adults.
Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease
Authors: O'Donnell D.E. , Voduc N. , Fitzpatrick M. , Webb K.A.
Published: July 2004

This study examined the effects of bronchodilator-induced reductions in lung hyperinflation on breathing pattern, ventilation and dyspnoea during exercise in chronic obstructive pulmonary disease (COPD). Quantitative tidal flow/volume loop analysis was used to evaluate abnormalities in dynamic ventilatory mechanics and their manipulation by a bronchodilator.

In a randomised double-blind crossover study, 23 patients with COPD (mean±sem forced expiratory volume in one second 42±3% of the predicted value) inhaled salmeterol 50 µg or placebo twice daily for 2 weeks each. After each treatment period, 2 h after dose, patients performed pulmonary function tests and symptom-limited cycle exercise at 75% of their maximal work-rate.

After salmeterolversusplacebo at rest, volume-corrected maximal expiratory flow rates increased by 175±52%, inspiratory capacity (IC) increased by 11±2% pred and functional residual capacity decreased by 11±3% pred. At a standardised time during exercise, salmeterol increased IC, tidal volume (VT), mean inspiratory and expiratory flows, ventilation, oxygen uptake (V'O2) and carbon dioxide output. Salmeterol increased peak exercise endurance,V'O2and ventilation by 58±19, 8±3 and 12±3%, respectively. Improvements in peakV'O2correlated best with increases in peakVT; increases in peakVTand resting IC were interrelated. The reduction in dyspnoea ratings at a standardised time correlated with the increasedVT.

Mechanical factors play an important role in shaping the ventilatory response to exercise in chronic obstructive pulmonary disease. Bronchodilator-induced lung deflation reduced mechanical restriction, increased ventilatory capacity and decreased respiratory discomfort, thereby increasing exercise endurance.
Parameters associated with persistent airflow obstruction in chronic severe asthma
Authors: Bumbacea D. , Campbell D. , Nguyen L. , Carr D. , Barnes P.J. , Robinson D. , Chung K.F.
Published: July 2004

The significance of severe airflow obstruction in severe asthma is unclear. The current study determined whether severe airflow obstruction is related to inflammatory or structural changes in the airways.

Patients with severe asthma from a tertiary referral clinic were divided into two groups according to their postbronchodilator forced expiratory volume in one second (FEV1): severe persistent airflow limitation (FEV1<50% predicted; group S; n=37) and no obstruction (FEV1>80% pred; group N; n=29). Smoking history, atopic status, lung function tests, exhaled NO, blood eosinophil count, quality of life scores using St George's Respiratory Questionnaire and high resolution computed tomography (HRCT) of the lungs were assessed.

Patients from group S were older and had longer disease duration. There was no difference in smoking history, atopic status, hospital admissions, quality of life scores and amount of treatment with inhaled or oral corticosteroids. Exhaled NO and peripheral blood eosinophils were higher in group S (21.0±2.4versus12.8±2.3 ppb; 0.41±0.06versus0.15±0.03×109cells·L−1, respectively). HRCT scores for bronchial wall thickening and dilatation were higher in group S with no differences in air trapping. Peripheral blood eosinophilia and bronchial wall thickening on HRCT scan were the only parameters significantly and independently associated with persistent airflow obstruction.

Patients with severe asthma and irreversible airflow obstruction had longer disease duration, a greater inflammatory process and more high resolution computed tomography airway abnormalities suggestive of airway remodelling, despite being on similar treatments and experiencing equivalent impairment in quality of life.
Proteasome inhibitors modulate chemokine production in lung epithelial and monocytic cells
Authors: Gerber A. , Heimburg A. , Reisenauer A. , Wille A. , Welte T. , Bühling F.
Published: July 2004

Proteasome inhibition has become a target for antitumour and anti-inflammatory therapy. The present study investigated the influence of cysteine proteinase and proteasome inhibitors on chemokine production in lung epithelial cells and monocytic cells.

The lung carcinoma cell lines A549, SK‐MES, NCI‐H727, virus-transformed bronchial epithelial cell line BEAS‐2B, primary lung epithelial cells, and the acute monocytic leukaemia cell lines Mono-Mac‐6 and THP‐1 were incubated with proteasome (N‐acetyl‐L‐leucyl‐L‐leucyl‐L‐norleucinal (ALLN), β‐lactone) or cysteine proteinase inhibitor (L‐trans-Epoxysuccinyl-Leu‐3‐methylbutylamide-ethyl ester) and the influence on chemokine production (interleukin‐8: IL‐8, monocyte chemoattractant protein‐1, RANTES) was quantified at protein and mRNA levels.

Inhibition of proteasome activity by ALLN and β‐lactone resulted in significantly increased IL‐8 secretion (5‐ to 22‐fold). Cysteine proteinase inhibitors did not influence chemokine production. The simultaneous rise in IL‐8 mRNA was caused by an increased half-life of mRNA and increased RNA synthesis. Moreover, analysis of transcription factor activation revealed induction of activator protein‐1 (c‐Jun) activity by proteasome inhibition, whereas nuclear factor‐κB (p50 and p65) was not activated. The significant increase in IL‐8 production after proteasome inhibition was also observed in primary lung epithelial cells and in monocytic cells. In addition, the secreted IL‐8 was biologically active as shown by the neutrophil chemotaxis assay.

In conclusion, it was shown that proteasome inhibitors stimulate interleukin‐8 secretion in lung epithelial cells and monocytic cells, thus recruiting neutrophils.
Relevance of assessing quadriceps endurance in patients with COPD
Authors: Coronell C. , Orozco‐Levi M. , Méndez R. , Ramírez‐Sarmiento A. , Gáldiz J.B. , Gea J.
Published: July 2004

The aims of this study were to investigate whether the impairment in endurance of limb muscles is a general finding in chronic obstructive pulmonary disease (COPD) patients, affecting even those with mild-to-moderate disease or relatively normal physical activity. In addition, this study aimed to determine the physiopathology of exhaustion in local endurance tests and whether the reduction in quadriceps endurance can be predicted from muscle strength measurements.

A total of 75 volunteers were assigned to one of two groups according to pulmonary function tests: COPD patients or healthy age-matched controls. Functional assessment included both quadriceps strength (maximum voluntary contraction (QMVC)), and quadriceps endurance (contractions against a load equivalent to 10% QMVCuntil task failure or for up to a limiting time of 30 min (QTlim)).

COPD patients showed a decrease of ∼43% in QMVCand ∼77% in QTlimcompared with controls. Task failure occurred only in COPD patients and was due to muscle fatigue, since limiting symptoms were associated with a decrease in the median frequency of quadriceps electromyographical signal and a reversible decrease in QMVC. The impairment in skeletal muscle endurance was present even in patients with mild-to-moderate airflow obstruction and individuals with relatively normal physical activity, and was irrespective of lung function variables, anthropometrical data or quadriceps strength.

Peripheral muscle endurance was impaired in chronic obstructive pulmonary disease patients, even in those with relatively normal physical activity and mild-to-moderate airflow obstruction. This impairment associated with an early onset of muscle fatigue and could not be predicted from the severity of the disease or the reduction in quadriceps strength.
STAT4 activation in smokers and patients with chronic obstructive pulmonary disease
Authors: Di Stefano A. , Caramori G. , Capelli A. , Gnemmi I. , Ricciardolo F.L. , Oates T. , Donner C.F. , Chung K.F. , Barnes P.J. , Adcock I.M.
Published: July 2004

Activation of the transcription factor signal transducer and activator of transcription (STAT)‐4 is critical for the differentiation of T‐helper 1 cells/type‐1 cytotoxic T‐cells and the production of interferon (IFN)‐γ.

Expression of STAT4, phospho‐STAT4, IFN‐γ and T‐box expressed in T‐cells (T‐bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)‐derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59±16% predicted), 14 smokers with normal lung function (FEV1106±12% pred) and 12 nonsmoking subjects (FEV1111±14% pred), was examined by immunohistochemistry and immunocytochemistry.

In bronchial biopsies of COPD patients, the number of submucosal phospho‐STAT4+ cells was increased (240 (22–406)versus125 (0–492)versus29 (0–511) cells·mm−2) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho‐STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN‐γ+ cells. Similar results were seen in BAL (2.8 (0.2–5.9)versus1.03 (0.09–1.6)versus0.69 (0–2.3) lymphocytes·mL−1×103). In all smokers who underwent lavage, phospho‐STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNγ+ lymphocytes. T‐bet expression was not altered in bronchial biopsies and BAL‐derived lymphocytes between the three groups.

In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T‐helper 1 cell/type‐1 cytotoxic T‐cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.
Area deprivation predicts lung function independently of education and social class
Authors: Shohaimi S. , Welch A. , Bingham S. , Luben R. , Day N. , Wareham N. , Khaw K‐T.
Published: July 2004

The cross-sectional association between socioeconomic status (at both the individual and area-based level) and lung function, as measured by forced expiratory volume in one second, in a large population-based cohort was investigated.

The study population consisted of 22,675 males and females aged 39–79 yrs. They were recruited from the general community in Norfolk, UK using general practice age/sex registers, as part of the European Prospective Investigation into Cancer (EPIC-Norfolk).

It was found that being in a manual occupational social class, having no educational qualifications and living in a deprived area all independently predicted significantly lower lung function, even after controlling for smoking habit.

The influence of area-deprivation on lung function, independent of individual socioeconomic status and of individual smoking habit, suggests that apart from targeting individuals who are at high-risk, such as smokers, environmental determinants also need to be examined when considering measures to improve respiratory health.
Tuberculosis in HIV‐infected persons in the context of wide availability of highly active antiretroviral therapy
Authors: Girardi E. , Antonucci G. , Vanacore P. , Palmieri F. , Matteelli A. , Iemoli E. , Carradori S. , Salassa B. , Bruna Pasticci M. , Raviglione M.C. , Ippolito G. ,   the GISTA-SIMIT Study Group
Published: July 2004

Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV‐infected persons. Nonetheless, HIV‐associated tuberculosis continues to occur in countries where HAART is widely used.

To identify the characteristics of HIV‐infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999–2000. These patients represent 0.7% of the 40,413 HIV‐infected patients cared for in the clinical units participating in this current study.

From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells·mm−3versus100 cells·mm−3, and 109 cells·mm−3, respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded.

Failure of tuberculosis control interventions (e.g.noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV‐associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment.
CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis
Authors: Inoue T. , Fujishima S. , Ikeda E. , Yoshie O. , Tsukamoto N. , Aiso S. , Aikawa N. , Kubo A. , Matsushima K. , Yamaguchi K.
Published: July 2004

Pulmonary fibrosis is caused by various known and unknown aetiologies, but the key pathogenic mechanisms are still ill-defined. Chemokines are a large family of chemotactic cytokines that play pivotal roles in various inflammatory diseases.

In the present study, the roles of chemokines in a rat model of radiation pneumonitis/pulmonary fibrosis were examined.

Accumulation of inflammatory cells and pneumonitis were observed on day 28, and diffuse alveolar wall thickening with extensive fibrosis was observed on day 56. In addition to the previously reported CCL2 (macrophage chemoattractant protein‐1) induction, selective upregulation of CCL22 (macrophage-derived chemokine) and CCL17 (thymus and activation-regulated chemokine) were demonstrated for the first time in the irradiated lung tissues. Immunohistochemically, it was demonstrated that CCL22 and CCL17 were localised primarily to alveolar macrophages, whereas their receptor CC chemokine receptor 4 (CCR4) was detected on alveolar lymphocytes and macrophages. On further analysis of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and sarcoidosis, elevated levels of CCL22, but not of CCL17, were observed in the idiopathic pulmonary fibrosis patients.

Since these two chemokines play pivotal roles in various type‐2 T‐helper cell-dominant diseases, it was speculated that CCL22, and probably CCL17, are involved in the pathophysiology of radiation pneumonitis/pulmonary fibrosis and idiopathic pulmonary fibrosis through the recruitment of CC chemokine receptor 4‐positive type‐2 T‐helper cells and alveolar macrophages.
Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis
Authors: Kakugawa T. , Mukae H. , Hayashi T. , Ishii H. , Abe K. , Fujii T. , Oku H. , Miyazaki M. , Kadota J. , Kohno S.
Published: July 2004

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. The present study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone attenuates the bleomycin (BL)‐induced overexpression of HSP47 in the lungs.

Male ICR mice were intravenously injected with BL or saline (SA). Pirfenidone or control drug (CD) was administered 14 days after commencement of BL or SA, and continued throughout the course of the experiment. The mice were randomly divided into three experimental groups: 1) SA‐treated with CD (SA group); 2) BL‐treated with CD (BL group); and 3) BL‐treated with pirfenidone (pirfenidone group).

Lungs of the pirfenidone group showed a marked reduction of fibrotic lesions compared with the corresponding BL group. Immunohistochemical studies showed that BL treatment significantly increased the number of macrophages, myofibroblasts, HSP47‐positive type II pneumocytes and HSP47‐positive interstitial spindle-shaped cells. Treatment with pirfenidone significantly reduced the number of these cells compared with the corresponding BL group. Furthermore, treatment with pirfenidone significantly suppressed the BL‐induced increase of the positive ratio of HSP47 and α‐smooth muscle actin to interstitial spindle-shaped cells.

The present study results showed that pirfenidone inhibited heat shock protein 47‐positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis.
Atypical pathogens and respiratory tract infections
Authors: Blasi F.
Published: July 2004

The atypical respiratory pathogensChlamydia pneumoniae,Mycoplasma pneumoniaeandLegionella pneumophilaare now recognised as a significant cause of acute respiratory-tract infections, implicated in community-acquired pneumonia, acute exacerbations of chronic bronchitis, asthma, and less frequently, upper respiratory-tract infections.

Chronic infection withC. pneumoniaeis common among patients with chronic obstructive pulmonary disease and may also play a role in the natural history of asthma, including exacerbations. The lack of a gold standard for diagnosis of these pathogens still handicaps the current understanding of their true prevalence and role in the pathogenesis of acute and chronic respiratory infections.

While molecular diagnostic techniques, such as polymerase chain reaction, offer improvements in sensitivity, specificity and rapidity over culture and serology, the need remains for a consistent and reproducible diagnostic technique, available to all microbiology laboratories.

Current treatment guidelines for community-acquired pneumonia recognise the importance of atypical respiratory pathogens in its aetiology, for which macrolides are considered suitable first-line agents. The value of atypical coverage in antibiotic therapy for acute exacerbations of chronic bronchitis and exacerbations of asthma is less clear, while there is no evidence to suggest that atypical pathogens should be covered in antibiotic treatment of upper respiratory-tract infections.
Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease
Authors: Hopkinson N.S. , Man W.D‐C. , Dayer M.J. , Ross E.T. , Nickol A.H. , Hart N. , Moxham J. , Polkey M.I.
Published: July 2004

Prospective data to support the hypothesis that corticosteroids are a significant cause of muscle weakness in patients with chronic obstructive pulmonary disease (COPD) are lacking.

The authors studied respiratory and quadriceps muscle function, using both volitional techniques and magnetic nerve stimulation, as well as measuring metabolic parameters during incremental cycle ergometry, in 25 stable COPD patients. The forced expiratory volume in one second was 37.6±21.4 % predicted, before and after a 2‐week course ofo.d.prednisolone 30 mg. Quadriceps strength was also assessed in 15 control patients on two occasions.

Only two patients met the British Thoracic Society definition of steroid responsiveness. There was no change either in sniff transdiaphragmatic pressure (pre: 96.8±19.7 cmH2O; post: 98.6±22.4 cmH2O) or in twitch transdiaphragmatic pressure elicited by bilateral anterolateral magnetic phrenic-nerve stimulation (pre: 16.8±9.1 cmH2O; post: 17.9±10 cmH2O). Quadriceps twitch force did not change significantly either in the steroid group (pre: 9.5±3.1 kg; post: 8.9±3.7 kg) or in the control patients (pre: 8.1±2.7 kg; post: 7.9±2.2 kg). There were no changes in either peak or isotime ventilatory and metabolic parameters during exercise.

In conclusion, in stable patients with chronic obstructive pulmonary disease, a 2‐week course of 30 mg prednisolone daily does not cause significant skeletal muscle dysfunction or alter metabolic parameters during exercise.
Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders
Authors: Perkins Diana O. , Lieberman Jeffrey A. , Gu Hongbin , Tohen Mauricio , McEvoy Joseph , Green Alan I. , Zipursky Robert B. , Strakowski Stephen M. , Sharma Tonmoy , Kahn René S. , Gur Raquel , Tollefson Gary
Published: June 2004

Background

Duration of untreated psychosis (DUP) may contribute to the observed heterogeneity of the treatment response in first-episode schizophrenia.

Aims

To examine the relationship of DUP and premorbid function with clinical outcomes following up to 2 years of antipsychotic treatment.

Method

For a subsample (n= 191) of subjects participating in a clinical trial, DUP and premorbid function were prospectively compared with clinical response to olanzapine or haloperidol.

Results

Shorter DUP and good premorbid function each independently are associated with better clinical response, including improvement in overall psychopathology and negative symptoms. Premorbid function also is associated with positive symptom, social and vocational outcomes.

Conclusions

Earlier antipsychotic treatment is associated with better outcomes in first-episode schizophrenia. Poor premorbid function could indicate an illness subtype less likely to respond to antipsychotic treatment regardless of when it is instituted.
From CHI to CHAI: what a difference an ‘A’ makes
Authors: Griffiths Hugh
Published: July 2004

When the National Health Service (NHS) was born in 1948, there was no specific agenda for clinical quality, which was assumed to be inherent in the system. The received wisdom was that good professional training with self-regulation and appropriate opportunities for ongoing professional development all inevitably added up to high-quality health care. Unfortunately, as we now know, this was not and is not true. What quality initiatives there were tended to be disconnected, with duplication, inefficiency and complicated processes all too often the result. Understanding of the relationships between structures, processes and outcomes improved in the 1970s, but in the 1980s, effort was arguably constrained by a prominent emphasis on organisational performance and cost containment.
Consultant psychiatrists' working patterns: is a progressive approach the key to staff retention?
Authors: Mears Alex , Pajak Sarah , Kendall Tim , Katona Cornelius , Medina Jibby , Huxley Peter , Evans Sherrill , Gately Claire
Published: June 2004

Aims and Method

The aim of the study was to explore how different styles of working relate to measures of occupational pressure experienced by consultant psychiatrists. A questionnaire was sent to a random sample of 500 consultant psychiatrists enquiring about work patterns, roles and responsibilities; it also contained validated tools, including the 12-item General Health Questionnaire.

Results

A total of 185 usable questionnaires were returned; an adjusted response rate of 41%. More ‘progressive’ styles of working were found to be linked with less occupational pressure on consultant psychiatrists. Three scales were derived: positive workload pattern, clarity of role and perceived support.

Clinical Implications

Alterations in working style may be helpful in combating occupational stress, and therefore in reducing attrition in the psychiatric workforce. Consultants and their teams should give consideration to reviewing their roles and patterns of working.