bluuebunny/crossref_metadata_2025 huggingface dataset:
Knee-to-Ankle Mosaicplasty for the Treatment of Osteochondral Lesions of the Ankle Joint
Authors: Valderrabano Victor , Leumann André , Rasch Helmut , Egelhof Thomas , Hintermann Beat , Pagenstert Geert
Published: October 2009

Background

Osteochondral lesions are frequently seen in athletes after ankle injuries. At this time, osteochondral autologous transplantation (OATS, mosaicplasty) is the only surgical treatment that replaces the entire osteochondral unit in symptomatic lesions.

Purpose

To evaluate the clinical and radiological midterm to long-term outcome of ankles treated with knee-to-ankle mosaicplasty.

Study Design

Case series; Level of evidence, 4.

Methods

Clinical evaluation consisted of patient satisfaction, pain evaluation (visual analog scale [VAS]), American Orthopaedic Foot and Ankle Society (AOFAS) ankle score, sports activity score, range of motion, the radiological evaluation of magnetic resonance imaging (MRI), and single photon emission computed tomography–computed tomography (SPECT-CT) analysis of both the ankle and the knee joint.

Results

Twelve of 21 patients (mean age, 43 years; male, 8; female, 4) were available for latest follow-up (mean, 72 months). At follow-up, patients reported a satisfaction rate of good to excellent in 92% (n 5 11) and poor in 8% (n 5 1). The average VAS pain score was 3.9 (preoperative, 5.9; P 5 .02), AOFAS ankle score significantly increased from 45.9 to 80.2 points (P< .0001), sports activity score remained significantly decreased with 1.25 (preinjury level, 2.3; P 5 .035), and ankle dorsiflexion was significantly reduced (P 5 .003). Knee pain was reported in 6 patients (50%). Radiologically, recurrent lesions were found in 10 of 10 cases (100%) and some degree of cartilage degeneration and discontinuity of the subchondral bone plate in 100%.

Conclusion

Indications for mosaicplasty with a plug transfer from the knee to the talus must be considered carefully, as at midterm, moderate outcome and considerable donor-site morbidity may be found.
Friction Conditions during the Wear of Injection Mold Functional Parts in Contact with Polymer Composites
Authors: Brezinová Janette , Guzanová Anna
Published: October 2009

This article deals with the evaluation of material wear of injection molds made of aluminium alloy Alumec 89 and copper alloy Moldmax HH in friction couples with polymer materials with various filler contents. The friction relations in injection molding were simulated in an adhesion dry wear test using an Amsler machine, with an area contact of the friction couple materials. The wear intensity was evaluated by determination of friction coefficient and relative wearing by the mass loss. Surface morphology changes of evaluated alloys after wear and the thermal conditions in particular friction couples were analyzed simultaneously.
Effect of Glass Beads and Polyurethane on the Fracture Properties of Epoxy Resin
Authors: Bakar M. , Kostrzewa M.
Published: October 2009

The present work investigates the mechanical properties of conventional and hybrid composites based on epoxy resin. Diglycidyl ether of bisphenol A was used as the matrix and triethylenetetramine was used as the curing agent. Polyurethane (PUR) used was based on polyether and toluene diisocyanate. Impact strength (IS), critical stress intensity factor (Kc), tensile strength (TS) and flexural strength were evaluated as function of modifiers content. It is shown that IS is increased by approximately 120% and 200% with the addition of respectively 10 phr of glass beads (GB) or 10 phr PUR, in comparison with IS of the unmodified epoxy resin. Moreover, Kc was increased by approximately 20% with 10 phr GB and 35% with 10 phr PUR. The addition of 15 phr PUR gave compositions with 30% enhanced TS and 40% increased tensile strain at break. However, the strain at break decreased with increasing amount of GB. Hybrid composition containing 10 phr PUR and 15 phr GB exhibited the maximum tensile energy to break corresponding to 80% and 85% improvement respectively in relation to the energy at break of the virgin epoxy resin and composition with only 10 phr PUR. Infrared spectra analysis of the compositions containing PUR revealed the formation of an interpenetrating polymer network structure between the modifier and the polymer matrix
The Role and Effect of Job Satisfaction and Empowerment On Customers’ Perception of Service Quality: a Study in the Restaurant Industry
Authors: Gazzoli Gabriel , Hancer Murat , Park Yumi
Published: October 2009

Empowerment, job satisfaction, and customer’s perception of service quality have been extensively researched in a multitude of industries. Although the service quality literature points out the importance of managing service quality from both customers’ and employees’ views, only a few studies have jointly considered an employee—customer research design. This study examined the answers from 474 restaurant contact employees and their 1,259 customers to determine the effects of empowerment and job satisfaction on customers’ perception of service quality. The uniqueness of this study is in its service quality variable used in the structural model. Whereas previous research based the service quality variable on the SERVQUAL conceptualization and measurement, this study conceptualized customers’ perceived service quality variable according to the “hierarchical approach” model and used the performance-only index for its measurement. Findings suggest that empowerment and job satisfaction have a significant impact on customers’ perception of service quality. Implications of the findings are discussed in detail.
Does Cultural Difference Affect Customer’s rEsponse in a Crowded Restaurant Environment? a Comparison of American Versus Chinese Customers
Authors: Kim Dae-Young , Li Wen  , Doh Kyungrok
Published: October 2009

This study focused on demonstrating cultural differences between American and Chinese people in terms of a customer’s perception of congestion and attribution in a crowded restaurant environment setting. It has been noted that culture has a substantial impact on a customer’s affection and judgment. Congestion in service environments is a critical antecedent of a customer’s evaluation of service quality. Considering the two main themes, this study examined how cultural differences play a role in explaining a customer’s attribution within the context of a crowded restaurant. Through the study of customers from two different cultures, participants’ responses regarding a similarly crowded environment in a restaurant were compared. This research reveals that cultural differences exist between the individuals from the two countries in terms of perceived congestion and customer attribution.
Vitamin E Protects Against Oxidative Damage and Learning Disability After Mild Traumatic Brain Injury in Rats
Authors: Aiguo Wu  , Zhe Ying  , Gomez-Pinilla Fernando
Published: October 2009

Background. Reactive oxygen species induce neuronal damage, and their role in reducing synaptic plasticity and function is beginning to be understood. Vitamin E is a potent reactive oxygen species scavenger, which has the potential to reduce oxidative damage encountered after traumatic brain injury (TBI). Brain-derived neurotrophic factor (BDNF) can facilitate synaptic function and support learning by modulating the CaMKII system, synapsin I, and cAMP-response element-binding protein (CREB). The elevation of superoxide dismutase (SOD) and Sir2 (silent information regulator 2) play an important role in resistance to oxidative stress. Objective. We examined the possibility that vitamin E supplemented in the diet may help counteract the effects of TBI on the molecular substrates underlying synaptic plasticity and cognitive function in the hippocampus. Methods. Rats were fed a regular diet with or without 500 IU/kg of vitamin E for 4 weeks (n = 6-8 per group) before a mild fluid percussion injury (FPI) was performed. Results. FPI increased protein oxidation as evidenced by elevated levels of protein carbonyls and reduced levels of SOD and Sir2. In addition, FPI resulted in poor performance in the Morris water maze, which was accompanied by reduced levels of BDNF and its downstream effectors on synaptic plasticity, synapsin I, CREB, and CaMKII. Supplementation of vitamin E in the diet counteracted all the observed effects of FPI. Conclusions . These results suggest that vitamin E dietary supplementation can protect the brain against the effects of mild TBI on synaptic plasticity and cognition, using molecular systems associated with the maintenance of long-term plasticity, such as BDNF and Sir2.
Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation
Authors: Nicolini Franck E. , Mauro Michael J. , Martinelli Giovanni , Kim Dong-Wook , Soverini Simona , Müller Martin C. , Hochhaus Andreas , Cortes Jorge , Chuah Charles , Dufva Inge H. , Apperley Jane F. , Yagasaki Fumiharu , Pearson Jay D. , Peter Senaka , Sanz Rodriguez Cesar , Preudhomme Claude , Giles Francis , Goldman John M. , Zhou Wei
Published: October 2009

The BCR–ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome—positive (Ph)+ acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph+ ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-α in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph+ ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.
House dust mite induces direct airway inflammationin vivo: implications for future disease therapy?
Authors: De Alba J. , Raemdonck K. , Dekkak A. , Collins M. , Wong S. , Nials A. T. , Knowles R. G. , Belvisi M. G. , Birrell M. A.
Published: October 2009

House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. HDM can evoke a direct, nonallergic inflammatory reactionin vitro. We aimed to determine whether this apparent nonallergic, inflammatory response can be observed in a more complexin vivosetting.

Vehicle, AlumTMor HDM (Dermatophagoides pteronyssinus5 μg,i.p.with Alum) sensitised Brown-Norway rats were challenged intratracheally with vehicle (saline), HDM (Der p10 μg) or heat-inactivated HDM on day 21. Lung function changes and the associated inflammatory response were evaluated.

Tissue and bronchoalveolar lavage from AlumTMsensitisedDer pchallenged animals exhibited strong eosinophilia and neutrophilia associated with an early release of pro-inflammatory cytokines (interleukin-13 and 1β, eotaxin and thymus and activation-regulated chemokine). This response was not attenuated by removal of HDM-associated protease activity. Interestingly, the vehicle sensitised group (no AlumTM) lacked this inflammatory response.

HDM allergen evokes nonallergic airways inflammation with an inflammatory profile similar to that of the asthmatic airway. This response, independent of the protease activity of the HDM extract, appeared to be linked to prior administration of the adjuvant AlumTMand the subsequent increase in total immunoglobulin E. This finding could have important implications in the development of future asthma therapies.
Abdominal volume contribution to tidal volume as an early indicator of respiratory impairment in Duchenne muscular dystrophy
Authors: Lo Mauro A. , D'Angelo M. G. , Romei M. , Motta F. , Colombo D. , Comi G. P. , Pedotti A. , Marchi E. , Turconi A. C. , Bresolin N. , Aliverti A.
Published: October 2009

Duchenne muscular dystrophy (DMD) is characterised by progressive loss of muscular strength that leads to an increasingly restrictive pulmonary syndrome. However, it is still not clear whether this determines alterations in the breathing pattern.

We studied: 66 DMD patients at different stages of the disease (mean±semage 12.6±0.6 yrs, range 5–22 yrs of age), subdivided into four groups according to age; and 21 age-matched healthy male controls. Spirometry, lung volumes and nocturnal oxygen saturation were measured in all DMD patients. Ventilatory pattern and chest wall volume variations were assessed by optoelectronic plethysmography during spontaneous breathing both in seated and supine positions.

Whilst in a seated position, no significant differences were found between patients and controls or between different age groups. In the supine position, the average contribution of abdominal volume change (ΔVAB) to tidal volume progressively decreased with age (p<0.001). The patients who showed nocturnal hypoxaemia showed significantly lower ΔVAB.

In conclusion, chest wall motion during spontaneous breathing in awake conditions and in supine position is an important indicator of the degree of respiratory muscle impairment in DMD. ΔVABis not only an important marker of the progression of the disease but is also an early indicator of nocturnal hypoxaemia.
Profiling hospital performance to monitor the quality of care: the case of COPD
Authors: Agabiti N. , Belleudi V. , Davoli M. , Forastiere F. , Faustini A. , Pistelli R. , Fusco D. , Perucci C. A.
Published: October 2009

Comparative outcomes data are widely used to monitor quality of care in the cardiovascular area; little is available in the respiratory field. We applied validated methods to compare hospital outcomes for chronic obstructive pulmonary disease (COPD) exacerbation.

From the hospital information system, we selected all hospital admissions for COPD exacerbation in Rome (for 2001–2005). Vital status within 30 days was obtained from the municipality mortality register. Each hospital was compared to a pool of hospitals with the lowest adjusted mortality rate (the benchmark). Age, sex and several potential clinical predictors were covariates in logistic regression analysis.

12,756 exacerbated COPD patients were analysed (mean age 74 yrs, 71% males). Diabetes, hypertension, ischaemic heart disease, heart failure and arrhythmia were the most common coexisting conditions. The average crude mortality in the benchmark group was 3.8%; in the remaining population it was 7.5% (range 5.2–17.2%). In comparison with the benchmark, the relative risk of 30-day mortality varied widely across the hospitals (range 1.5–5.9%).

A large variability in 30-day mortality after COPD exacerbation exists even considering patients’ characteristics. Although these results do not detect mechanisms related to worse outcomes, they may be useful to stimulate providers to revision and improvement of COPD care management.
Cigarette smoke induces CXCL8 production by human neutrophilsviaactivation of TLR9 receptor
Authors: Mortaz E. , Adcock I.M. , Ito K. , Kraneveld A.D. , Nijkamp F.P. , Folkerts G.
Published: October 2009

Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke is the main risk factor for the development of COPD. The characteristic changes in airway morphology, inflammatory cell infiltration and mediator expression in COPD may result from direct effects of cigarette smoke on airway cells. Toll-like receptors (TLRs) are key elements in pathogen recognition by the host immune system. Although TLRs have been intensely studied in innate immunity and infection, their critical role in noninfectious challenges has only recently emerged.

Here we investigate whether cigarette smoke induces TLR9 signalling in human neutrophils. Human neutrophils were isolated from buffy coat and exposed to cigarette smoke extract. The production of CXC chemokine ligand (CXCL)8 was measured as a functional readout and the role of TLR9 signalling was investigated. Cigarette smoke extract induced CXCL8 releaseviaTLR9 activation in neutrophils, which was confirmed in TLR9 stably transfected human embryonic kidney 293 cells. Moreover, cigarette smoke extract upregulated the expression of TLR9 and the upregulated expression was suppressed byN-acetylcysteine.

TLR9 mediates cigarette smoke-induced release of CXCL8 and this may contribute to the accumulation of neutrophils and inflammation within the airways of smokers.
Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma
Authors: Bhavsar P. , Khorasani N. , Hew M. , Johnson M. , Chung K. F.
Published: October 2009

Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone.

We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs).

PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentration-dependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method.

SD282 (10−7 M), with dexamethasone (10−6 M), caused a greater inhibition of release of IL-1β, IL-6, macrophage inflammatory protein-1α and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10−9and 10−10 M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10−8and 10−6 M) on LPS-induced IL-8 release in PBMCs from severe asthma.

Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK.
Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance
Authors: Quesnel C. , Nardelli L. , Piednoir P. , Leçon V. , Marchal-Somme J. , Lasocki S. , Bouadma L. , Philip I. , Soler P. , Crestani B. , Dehoux M.
Published: October 2009

Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS.

Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts.

Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E2compared to normal lung fibroblasts (p≤0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p≤0.01), and with a reduced duration of mechanical ventilation (p<0.001).

We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.
Diffuse alveolar haemorrhage: factors associated with in-hospital and long-term mortality
Authors: de Prost N. , Parrot A. , Picard C. , Ancel P-Y. , Mayaud C. , Fartoukh M. , Cadranel J.
Published: October 2009

Diffuse alveolar haemorrhage (DAH) is a feature of several immune and nonimmune disorders. Reported prognosis is poor, with in-hospital mortality ranging from 20% to 100%. Early identification of prognostic factors may be useful in the initiation of appropriate treatment.

We retrospectively analysed the charts of all patients referred to a university hospital for DAH between 1980 and 2008. Variables associated with in-hospital and long-term mortality were determined using a logistic regression model and the Kaplan–Meier method, respectively. Immunosuppressed patients were excluded.

Overall, 97 patients were included in the study. In-hospital mortality was 24.7%. Factors associated with in-hospital mortality were shock (OR 77.5, 95% CI 8.9–677.2), glomerular filtration rate <60 mL·min−1(OR 11.2, 95% CI 1.8–68.4) and plasmatic lactate dehydrogenase level more than twice the normal value (OR 12.1, 95% CI 1.7–84.3). Mortality among discharged patients was 16.4% with a median follow-up duration of 34 months. Factors associated with increased long-term mortality in univariate analysis were age over 60 yrs (p = 0.026), cardiovascular comorbidity (p = 0.027) and end-stage renal failure with dependence on haemodialysis (p = 0.026).

Patients with immune and nonimmune DAH had similar outcomes. Early outcome depended on nonpulmonary organ failures. Conversely, late outcome was related to age, cardiac comorbidities and the need for haemodialysis.
Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts
Authors: Kik S. V. , Franken W. P. J. , Mensen M. , Cobelens F. G. J. , Kamphorst M. , Arend S. M. , Erkens C. , Gebhard A. , Borgdorff M. W. , Verver S.
Published: October 2009

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-γ release assays (IGRAs), QuantiFERON-TB® Gold In-tube (QFT-GIT) and T-SPOT.TB®, and the tuberculin skin test (TST) in immigrants contacts.

Immigrant close contacts of sputum smear-positive TB patients were included when aged ≥16 yrs and their TST result was ≥5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease.

Of 339 immigrant contacts with TST ≥5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB®, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB®. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3–5.0%) for TST ≥10 mm, 7/184 = 3.8% (95% CI 1.7–5.9%) for TST ≥15 mm, 5/178 = 2.8% (95% CI 1.0–4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3–5.3%) for T-SPOT.TB®. Sensitivity was 100%, 88%, 63% and 75%, respectively.

The predictive values of QFT-GIT, T-SPOT.TB® and TST for progression to TB disease among immigrant close contacts were comparable.
A model of chronic lung allograft rejection in the rat
Authors: Jungraithmayr W. , Vogt P. , Inci I. , Hillinger S. , Arni S. , Korom S. , Weder W.
Published: October 2009

Bronchiolitis obliterans, the pathological hallmark of chronic pulmonary rejection, severely impacts long-term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporaryin vivomodels. Here, a model of chronic rejection is described, with sensitised recipients receiving unilateral orthotopic rat lung transplants.

Lewis rats, sensitised with skin from brown Norway rats 7 days before receiving left lung transplants from donors that were Lewis×brown Norway F1hybrids, were analysed during day 21–84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporin, and characterised histologically, immunohistochemically and by reverse transcriptase PCR.

Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles, with strong expression of smooth muscle α-actin and upregulation of mRNA for T-helper cell type-1 cytokines, smooth muscle α-actin, transforming growth factor-β and CC chemokine ligand 5, but decreased forkhead box protein P3 gene expression.

A reproducible and clinically relevant experimental set-up for progressive chronic rejection in rat pulmonary allografts is described. This model will permit better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as anin vivoset-up for testing the efficacy of novel therapeutic interventions.
Optimal positive airway pressure predicts oral appliance response to sleep apnoea
Authors: Tsuiki S. , Kobayashi M. , Namba K. , Oka Y. , Komada Y. , Kagimura T. , Inoue Y.
Published: October 2009

Patients with less severe obstructive sleep apnoea (OSA) are usually prescribed oral appliances and/or smaller optimal nasal continuous positive airway pressure (PnCPAP) in nCPAP therapy. We hypothesised that OSA patients with greaterPnCPAPwould not respond favourably to oral appliances.

Oral appliances were inserted in nCPAP users after washing-out the nCPAP effect. Follow-up polysomnography was undertaken with the adjusted oral appliance in place. The predictability ofPnCPAPwas evaluated with receiver-operating characteristic (ROC) curves.

The median baseline apnoea/hypopnoea index (AHI) was reduced with the oral appliance from 36 to 12 events·h−1in 35 patients. When responders were defined as patients showing a follow-up AHI of <5 events·h−1with >50% reduction in baseline AHI, the area under the ROC curve forPnCPAPwas 0.76. The best cut-off value ofPnCPAPturned out to be 10.5 cmH2O with a high negative predictive value (0.93) and a low negative likelihood ratio (0.18).

OSA patients with aPnCPAPof >10.5 cmH2O are unlikely to respond to oral appliance therapy. This prediction is clinically helpful to both OSA patients and medical personnel in discussing oral appliances as a temporary substitute and/or alternative for nCPAP.
Respiratory medicines for children: current evidence, unlicensed use and research priorities
Authors: Smyth A. R. , Barbato A. , Beydon N. , Bisgaard H. , de Boeck K. , Brand P. , Bush A. , Fauroux B. , de Jongste J. , Korppi M. , O’Callaghan C. , Pijnenburg M. , Ratjen F. , Southern K. , Spencer D. , Thomson A. , Vyas H. , Warris A. , Merkus P. J.
Published: October 2009

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies.

Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g.dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the β-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency.

We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.
Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis
Authors: Zappala C. J. , Latsi P. I. , Nicholson A. G. , Colby T. V. , Cramer D. , Renzoni E. A. , Hansell D. M. , du Bois R. M. , Wells A. U.
Published: October 2009

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of “marginal” changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated.

In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DL,CO) trends at 6 months were categorised as “significant” (FVC >10%;DL,CO>15%) or “marginal” (FVC 5–10%;DL,CO7.5–15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality.

In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54–5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19–4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19–4.60; p = 0.01). Marginal changes inDL,COin IPF and marginal changes in FVC andDL,COin fibrotic NSIP did not provide useful prognostic information.

Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.
Anti-apoptotic effects of Z α1-antitrypsin in human bronchial epithelial cells
Authors: Greene C. M. , Miller S. D. W. , Carroll T. P. , Oglesby I. K. , Ahmed F. , O'Mahony M. , Taggart C. C. , McElvaney N. G. , O'Neill S. J.
Published: October 2009

α1-antitrypsin (α1-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of α1-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z α1-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved.

Control, M variant α1-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-κB activation and induced expression of a selection of pro- and anti-apoptotic genes.

Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-κB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-κB. cIAP1 expression was increased in ZAATversusMAAT bronchial biopsies.

The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.
CHD5 is down-regulated through promoter hypermethylation in gastric cancer
Authors: Wang Xian , Lau Kenneth KK , So Leo KY , Lam Yun Wah
Published: October 2009

Background

Nonhistone chromosomal proteins in concert with histones play important roles in the replication and repair of DNA and in the regulation of gene expression. The deregulation of these proteins can contribute to the development of a variety of diseases such as cancer. As a nonhistone chromosomal protein, chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as the product of a novel tumor suppressor gene (TSG), promoting the transcription of p19
ink4a
and p16
arf
. The inactivation of CHD5 was achieved partly through genetic deletion since it is located in 1p36, a region frequently deleted in human tumors. In this study, we aim to study the involvement of CHD5 in gastric cancer, the second most common cancer worldwide.

Methods

CHD5 expression in a panel of gastric cancer cells were determined by quantitative RT-PCR. The methylation of CHD5 was evaluated by methylation specific PCR and bisulfite genome sequencing. The effect of CHD5 on growth of gastric cancer cells was tested by colony formation assay.

Results

CHD5 expression was down-regulated in all of gastric cancer cell lines used (100%, 7/7) and significantly restored after pharmacological demethylation. Methylation of CHD5 promoter was detected in all of seven gastric cancer cell lines and in the majority of primary gastric carcinoma tissues examined (73%, 11/15). Finally, ectopic expression of CHD5 in gastric cancer cells led to a significant growth inhibition.

Conclusion

CHD5 was a TSG epigenetically down-regulated in gastric cancer.
Characterization of the oxidative stress stimulon and PerR regulon of Campylobacter jejuni
Authors: Palyada Kiran , Sun Yi-Qian , Flint Annika , Butcher James , Naikare Hemant , Stintzi Alain
Published: October 2009

Background

During gut colonization, the enteric pathogen Campylobacter jejuni must surmount the toxic effects of reactive oxygen species produced by its own metabolism, the host immune system, and intestinal microflora. Elucidation of C. jejuni oxidative stress defense mechanisms is critical for understanding Campylobacter pathophysiology.

Results

The mechanisms of oxidative stress defense in C. jejuni were characterized by transcriptional profiling and phenotypic analysis of wild-type and mutant strains. To define the regulon of the peroxide-sensing regulator, PerR, we constructed an isogenic ΔperR mutant and compared its transcriptome profile with that of the wild-type strain. Transcriptome profiling identified 104 genes that belonged to the PerR regulon. PerR appears to regulate gene expression in a manner that both depends on and is independent of the presence of iron and/or H2O2. Mutation of perR significantly reduced motility. A phenotypic analysis using the chick colonization model showed that the ΔperR mutant exhibited attenuated colonization behavior. An analysis of changes in the transcriptome induced by exposure to H2O2, cumene hydroperoxide, or menadione revealed differential expression of genes belonging to a variety of biological pathways, including classical oxidative stress defense systems, heat shock response, DNA repair and metabolism, fatty acid biosynthesis, and multidrug efflux pumps. Mutagenic and phenotypic studies of the superoxide dismutase SodB, the alkyl-hydroxyperoxidase AhpC, and the catalase KatA, revealed a role for these proteins in oxidative stress defense and chick gut colonization.

Conclusion

This study reveals an interplay between PerR, Fur, iron metabolism and oxidative stress defense, and highlights the role of these elements in C. jejuni colonization of the chick cecum and/or subsequent survival.
Genetic effect of CysLTR2 polymorphisms on its mRNA synthesis and stabilization
Authors: Shin Jeong-Ah , Chang Hun Soo , Park Se-Min , Jang An-Soo , Park Sung Woo , Park Jong Sook , Uh Soo-Taek , Il Lim Gune , Rhim Taiyoun , Kim Mi-Kyeong , Choi Inseon S , Chung Il Yup , Park Byung Lae , Shin Hyoung Doo , Park Choon-Sik
Published: October 2009

Background

We previously demonstrated that single nucleotide polymorphism (SNP) and haplotypes were associated with aspirin hypersensitivity in asthmatics. We investigated the genetic effects of the SNPs and haplotypes on the expression of theCysLTR2gene.

Methods

We measured CysLTR2 protein and mRNA expression in EB virus-infected B cell lines from asthmatics havinght1+/+andht2+/+. A gel retardation assay was used to identify nuclear protein binding to the c.-819 promoter site. The function of promoter and 3'-UTR were assessed using pGL3 luciferase and pEGFP reporter system, respectively.

Results

We found that the expression of CysLTR2 protein was higher in B cell lines of asthmatics havinght2+/+than in those havinght1+/+. PMA/ionomycin induced higher mRNA expression of CysLTR2 in B cell lines fromht2+/+asthmatics than those fromht1+/+asthmatics. A nuclear protein from the B cell lines showed stronger DNA binding affinity with a probe containingc.-819T thanone containingc.-819G. The luciferase activity of thec.-819Ttype ofCysLTR2promoter was higher than that of thec.-819Gtype. EGFP expression was higher in the EGFP-c.2078T3'-UTR fusion construct than in thec.2078Cconstruct.

Conclusion

The sequence variants ofCysLTR2may affect its transcription and the stability of its mRNA, resulting in altered expression of CysLTR2 protein, which in turn causes some asthmatics to be susceptible to aspirin hypersensitivity.
Managing insecticide resistance in malaria vectors by combining carbamate-treated plastic wall sheeting and pyrethroid-treated bed nets
Authors: Djènontin Armel , Chabi Joseph , Baldet Thierry , Irish Seth , Pennetier Cédric , Hougard Jean-Marc , Corbel Vincent , Akogbéto Martin , Chandre Fabrice
Published: October 2009

Background

Pyrethroid resistance is now widespread in Anopheles gambiae, the major vector for malaria in sub-Saharan Africa. This resistance may compromise malaria vector control strategies that are currently in use in endemic areas. In this context, a new tool for management of resistant mosquitoes based on the combination of a pyrethroid-treated bed net and carbamate-treated plastic sheeting was developed.

Methods

In the laboratory, the insecticidal activity and wash resistance of four carbamate-treated materials: a cotton/polyester blend, a polyvinyl chloride tarpaulin, a cotton/polyester blend covered on one side with polyurethane, and a mesh of polypropylene fibres was tested. These materials were treated with bendiocarb at 100 mg/m2 and 200 mg/m2 with and without a binding resin to find the best combination for field studies. Secondly, experimental hut trials were performed in southern Benin to test the efficacy of the combined use of a pyrethroid-treated bed net and the carbamate-treated material that was the most wash-resistant against wild populations of pyrethroid-resistant An. gambiae and Culex quinquefasciatus.

Results

Material made of polypropylene mesh (PPW) provided the best wash resistance (up to 10 washes), regardless of the insecticide dose, the type of washing, or the presence or absence of the binding resin. The experimental hut trial showed that the combination of carbamate-treated PPW and a pyrethroid-treated bed net was extremely effective in terms of mortality and inhibition of blood feeding of pyrethroid-resistant An. gambiae. This efficacy was found to be proportional to the total surface of the walls. This combination showed a moderate effect against wild populations of Cx. quinquefasciatus, which were strongly resistant to pyrethroid.

Conclusion

These preliminary results should be confirmed, including evaluation of entomological, parasitological, and clinical parameters. Selective pressure on resistance mechanisms within the vector population, effects on other pest insects, and the acceptability of this management strategy in the community also need to be evaluated.
Biochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase
Authors: Dar Mohd J , Monel Blandine , Krishnan Lavanya , Shun Ming-Chieh , Di Nunzio Francesca , Helland Dag E , Engelman Alan
Published: October 2009

Background

The 18 residue tail abutting the SH3 fold that comprises the heart of the C-terminal domain is the only part of HIV-1 integrase yet to be visualized by structural biology. To ascertain the role of the tail region in integrase function and HIV-1 replication, a set of deletion mutants that successively lacked three amino acids was constructed and analyzed in a variety of biochemical and virus infection assays. HIV-1/2 chimers, which harbored the analogous 23-mer HIV-2 tail in place of the HIV-1 sequence, were also studied. Because integrase mutations can affect steps in the replication cycle other than integration, defective mutant viruses were tested for integrase protein content and reverse transcription in addition to integration. The F185K core domain mutation, which increases integrase protein solubility, was furthermore analyzed in a subset of mutants.

Results

Purified proteins were assessed for in vitro levels of 3' processing and DNA strand transfer activities whereas HIV-1 infectivity was measured using luciferase reporter viruses. Deletions lacking up to 9 amino acids (1-285, 1-282, and 1-279) displayed near wild-type activitiesin vitroand during infection. Further deletion yielded two viruses, HIV-11-276and HIV-11-273, that displayed approximately two and 5-fold infectivity defects, respectively, due to reduced integrase function. Deletion mutant HIV-11-270and the HIV-1/2 chimera were non-infectious and displayed approximately 3 to 4-fold reverse transcription in addition to severe integration defects. Removal of four additional residues, which encompassed the C-terminal β strand of the SH3 fold, further compromised integrase incorporation into virions and reverse transcription.

Conclusion

HIV-11-270, HIV-11-266, and the HIV-1/2 chimera were typed as class II mutant viruses due to their pleiotropic replication defects. We speculate that residues 271-273 might play a role in mediating the known integrase-reverse transcriptase interaction, as their removal unveiled a reverse transcription defect. The F185K mutation reduced thein vitroactivities of 1-279 and 1-276 integrases by about 25%. Mutant proteins 1-279/F185K and 1-276/F185K are therefore highlighted as potential structural biology candidates, whereas further deleted tail variants (1-273/F185K or 1-270/F185K) are less desirable due to marginal or undetectable levels of integrase function.
Ocular disorders as the prevailing manifestations of antiphospholipid syndrome: a case series
Authors: Tsironi Evangelia , Gatselis Nikolaos , Kotoula Maria G , Zachou Kalliopi , Pefkianaki Maria , Zacharaki Fani , Chatzoulis Dimitrios Z , Dalekos George N
Published: October 2009

Introduction

Antiphospholipid syndrome is an autoimmune disorder characterized by either a history of vascular thrombosis (one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ) or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The systemic features of the syndrome are characterized by large variability depending on the affected organ(s). Among them, neurological and behavioural disturbances, dermatological features as livedo reticularis and renal, ocular, liver or valvular heart manifestations have been reported in antiphospholipid syndrome patients. However, studies on the frequency and clinical presentation of the ocular manifestations as the prevailing (first) sign of antiphospholipid syndrome in patients suffering from "unexplained" ocular disease are missing. Herein, we present three cases suffering from unexplained ocular disease as first manifestation of antiphospholipid syndrome.

Case presentation

All the three patients were referred to our department because of unexplained ocular features from the anterior or posterior segment and unexplained neuro-ophthalmologic symptoms. The first patient had bilateral retinal occlusive disease, the second and the third patient had unilateral nonarteritic anterior ischemic optic neuropathy with macular oedema. Moderate to high levels of antiphospholipid antibodies were detected in all of them at baseline as well as 6 to 12 weeks after initial testing confirming the presence of antiphospholipid antibodies. Anticoagulant treatment with acenocoumarol was instituted resulting in stabilization and/or improvement of ocular signs in all of them.

Conclusion

Due to the important diagnostic and therapeutic implications of antiphospholipid syndrome, the possibility of ocular features as the first clinical manifestation of antiphospholipid syndrome should be kept in mind of the physicians particularly in patients with no evident risk factors for ocular disease. In this case, prompt anticoagulant treatment and close follow-up seem to be essential for vision salvation and stabilization.
Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers
Authors: Neuhausen Susan L , Brummel Sean , Ding Yuan Chun , Singer Christian F , Pfeiler Georg , Lynch Henry T , Nathanson Katherine L , Rebbeck Timothy R , Garber Judy E , Couch Fergus , Weitzel Jeffrey , Narod Steven A , Ganz Patricia A , Daly Mary B , Godwin Andrew K , Isaacs Claudine , Olopade Olufunmilayo I , Tomlinson Gail , Rubinstein Wendy S , Tung Nadine , Blum Joanne L , Gillen Daniel L
Published: October 2009

Introduction

Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.

Methods

A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.

Results

Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.

Conclusions

This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.