bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate of progression of lung function impairment in α1-antitrypsin deficiency
Authors: Dawkins P. A. , Dawkins C. L. , Wood A. M. , Nightingale P. G. , Stockley J. A. , Stockley R. A.
Published: January 2009

The aim of the present study was to identify α1-antitrypsin (α1-AT)-deficient patients who had rapidly progressive disease.

PiZ patients (n = 101) underwent annual lung function measurements over a 3-yr period, and the results were related to factors that may influence decline.

The mean annual decline in forced expiratory volume in 1 s (FEV1) was 49.9 mL. The greatest FEV1decline occurred in the moderate severity group (FEV150–80% of the predicted value), with a mean annual decline of 90.1 mL, compared with 8.1 mL in the very severe group (FEV1<30% pred). However, annual decline in transfer coefficient of the lung for carbon monoxide (KCO) was greatest in the severe and very severe groups. When the whole group was divided into tertiles of FEV1decline, the fast tertile compared with the slow tertile had more patients with bronchodilator reversibility (BDR) (73versus41%; p = 0.010), more males (79versus56%; p = 0.048) and lower body mass index (BMI) (24.0versus26.1; p = 0.042). Logistic regression analyses confirmed that FEV1decline was independently associated with BMI, BDR, exacerbation rate and high physical component 36-item short-form health survey scores.

In PiZ α1-AT-deficient patients, FEV1decline was greatest in moderate disease, unlikeKCOdecline, which was greatest in severe disease. The FEV1decline showed associations with BDR, BMI, sex and exacerbation rate.
Effect of breastfeeding on asthma, lung function and bronchial hyperreactivity in ISAAC Phase II
Authors: Nagel G. , Büchele G. , Weinmayr G. , Björkstén B. , Chen Y-Z. , Wang H. , Nystad W. , Saraclar Y. , Bråbäck L. , Batlles-Garrido J. , Garcia-Hernandez G. , Weiland S. K. ,   the ISAAC Phase II Study Group
Published: January 2009

The association between breastfeeding and wheezing, lung function and atopy was evaluated in the International Study of Asthma and Allergy in Childhood (ISAAC) Phase II.

Cross-sectional studies were performed in 27 centres in 20 countries. Information on disease and exposure factors was collected by parental questionnaires. Data from 54,000 randomly selected school children (aged 8–12 yrs, 31,759 with skin prick testing) and a stratified subsample (n = 4,888) were used for testing the correlation of breastfeeding with bronchial hyperreactivity and lung function. Random effect models for meta-analysis were applied to calculate combined odds ratios (ORs).

Any breastfeeding was associated with less wheeze both in affluent (adjusted OR (ORadj) 0.87, 95% confidence interval (CI) 0.78–0.97) and nonaffluent countries (ORadj0.80, 95% CI 0.68–0.94). Further analyses revealed that this was true only for nonatopic wheeze in nonaffluent countries (ORadj0.69, 95% CI 0.53–0.90). Breastfeeding was not associated with atopic wheeze and objective measures of allergy in both affluent and nonaffluent countries. In contrast, breastfeeding was associated with higher predicted forced expiratory volume in one second in affluent countries only (mean ratio 1.11, 95% CI 1.02–1.20).

Breastfeeding is associated with protection against nonatopic wheeze, which becomes particularly evident in nonaffluent countries. Overall, breastfeeding was not related to any measure of allergy. These findings may explain some of the controversy regarding breastfeeding, since the direction of the association with breastfeeding depends on the predominating wheeze phenotype (e.g.atopic, nonatopic).
Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury
Authors: MacRedmond R. , Singhera G. K. , Dorscheid D. R.
Published: January 2009

Fas-mediated apoptosis of the alveolar epithelium is important in the pathogenesis of acute respiratory distress syndrome. Erythropoietin (EPO) has cytoprotective properties in other organ systems, and is relatively deficient in critical illness. This study investigates a potential role for EPO in reducing apoptosis in a model of acute lung injury.

Apoptosis was induced in human alveolar epithelial (A549) cells or normal human bronchial epithelial (NHBE) cells by Fas activation with CH-11 Fas-crosslinking antibody or by co-culture with polymorphonuclear neutrophils in a transwell system. The effect of recombinant human (rh)EPO on apoptosis was measured by poly(ADP-ribose) polymerase cleavage and cell death detection assay. The specific EPO–EPO receptor (EPOR)-mediated effect was determined using an EPO-blocking antibody or EPOR small interfering RNA.

Expression of EPOR was demonstrated in A549, NHBE and normal human alveolar epithelium. Fas- and neutrophil-mediated apoptosis of A549 and NHBE cells was inhibited by rhEPO by a specific EPO–EPOR-mediated mechanism. This anti-apoptotic effect was associated with induction of a pro-apoptotic Bcl-xL/Bax ratio.

EPO has cytoprotective properties in respiratory epithelium in anin vitromodel, which may indicate a potential therapeutic role in acute lung injury.
Validation of the COPD severity score for use in primary care: the NEREA study
Authors: Miravitlles M. , Llor C. , de Castellar R. , Izquierdo I. , Baró E. , Donado E.
Published: January 2009

Spirometry is underused for the assessment of severity of chronic obstructive pulmonary disease (COPD) in primary care (PC). Therefore, simple assessment tools are required in this setting. The aim of the present study was to validate the COPD severity score (COPDSS) for use in PC.

A multicentric study was carried out in stable COPD patients in PC. The concurrent validity of the COPDSS was evaluated by examining the association between COPDSS, COPD clinical indicators and the London Chest Activity of Daily Living (LCADL) scale, European quality of life (EuroQOL) questionnaires and Charlson comorbidity index.

A total of 837 patients with COPD were analysed (males 84.3%; mean±sdage 68±11 yrs; forced expiratory volume in one second 54.6±17.7% of the predicted value). A strong correlation was found between COPDSS and dyspnoea level and a moderate correlation between COPDSS and exacerbation number. The COPDSS discriminated between patients with varying degrees of dyspnoea (area under receiver operating characteristic (ROC) curve 0.837), and according to number of exacerbations in the last year (area under ROC curve 0.773). Higher COPDSS scores were significantly associated with lower EuroQOL scores, lower EuroQOL visual analogue scale scores and higher LCADL scores.

The present results indicate that the chronic obstructive pulmonary disease severity score is a useful and reliable tool for assessing the severity of chronic obstructive pulmonary disease in primary care.
Sex differences in emphysema phenotype in smokers without airflow obstruction
Authors: Sverzellati N. , Calabrò E. , Randi G. , La Vecchia C. , Marchianò A. , Kuhnigk J-M. , Zompatori M. , Spagnolo P. , Pastorino U.
Published: January 2009

Data on sex differences in emphysema are limited to chronic obstructive pulmonary disease. We aimed to verify whether such differences also exist in smokers without airflow obstruction, weighting their influence on the relationship between emphysema and clinical features.

We evaluated both clinical and multidetector computed tomography (MDCT) data of 1,011 heavy smokers recruited by a lung cancer screening project. MDCT scans were analysed with software allowing lobar quantification of emphysema features. For these measures, multiple regression models were applied to assess the effect of patients sex, after allowance for age, body mass index (BMI), smoking history, forced expiratory volume in 1 s (FEV1) and forced vital capacity.

The final study cohort consisted of 957 smokers without airflow obstruction. Compared with males, females exhibited an emphysema phenotype less extensive in each pulmonary lobe, characterised by smaller emphysematous areas and less concentrated in the core of the lung. However, in females, the increase of emphysema with age was more pronounced and displayed a more significant relationship with FEV1% decline; conversely, in males there was a stronger association with the decrease in BMI.

Males and females respond differently to the type and location of lung damage due to tobacco exposure. In smokers, sex influences the relationship between emphysema and clinical features.
Quality of life measured by the St George's Respiratory Questionnaire and spirometry
Authors: Weatherall M. , Marsh S. , Shirtcliffe P. , Williams M. , Travers J. , Beasley R.
Published: January 2009

The present authors aimed to determine if the criteria for the diagnosis of chronic obstructive pulmonary disease (COPD) and its classification by severity as recommended by the Global Initiative for Chronic Obstructive Lung Disease are supported by measurements of respiratory health-related quality of life.

A community-based sample of adults aged 25–75 yrs had pre- and post-bronchodilator spirometry and completed the St George's Respiratory Questionnaire (SGRQ). Loess scatter plot smoothers of the SGRQversuspost-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio and post-bronchodilator FEV1% predicted together with receiver operating characteristic (ROC) curve analysis were used to determine the relationship between spirometric variables and clinically important differences in the SGRQ score.

The scatter plot smoother and ROC curve analyses supported the value of 0.7 for post-bronchodilator FEV1/FVC ratio, which was ∼4 units higher than the nadir of the SGRQ. To represent a distance of 8 units on the SGRQ, the cut-off points for post-bronchodilator FEV1that delimit COPD severity stages were 80, 60 and 40% pred for mild, moderate and severe COPD, respectively.

To diagnose chronic obstructive pulmonary disease the use of post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio of 0.7 is supported by health-related quality of life measurements. There may be advantages in using forced expiratory volume in one second cut-off points of 80, 60 and 40% predicted for the classification of mild, moderate and severe chronic obstructive pulmonary disease, respectively, similar to the approach recommended for asthma.
Effect of bronchodilation on expiratory flow limitation and resting lung mechanics in COPD
Authors: Dellacà R. L. , Pompilio P. P. , Walker P. P. , Duffy N. , Pedotti A. , Calverley P. M. A.
Published: January 2009

Bronchodilator drugs produce variable improvements in forced expiratory volume in 1 s (FEV1), but larger changes in end-expiratory lung volume (EELV) in chronic obstructive pulmonary disease (COPD), which were suggested to be related to the presence of expiratory flow limitation (EFL) at rest.

We tested this concept in 42 COPD patients (FEV142.3±13.8% predicted) during spontaneous breathing before and after 5 mg nebulised salbutamol. EFL was detected by within-breath changes in respiratory system reactance measured by a multifrequency forced oscillation method, while changes in EELV were assessed by inspiratory capacity (IC). Bronchodilation (BD) increased IC (from 1.8±0.5 to 2.1±0.6 L, p<0.001) and reduced inspiration resistance (R̄insp) at 5 Hz (from 5.1±1.6 to 4.2±1.5 cmH2O·s·L−1, p<0.001).R̄inspidentified BD responders with a discriminative power of 80.1%.

In total, 20 patients were flow-limited before BD. They showed worse spirometry and higher residual volume, but significant improvements in IC were seen in all patients irrespective of flow limitation. Changes inR̄inspwere confined to flow-limited patients, as were reactance changes. BD reduced the degree of heterogeneity in the respiratory system, a change best seen with inspiratory values.

BD has complex effects on lung mechanics in COPD, and EFL affects both this and the response of some respiratory variables to treatment. However, changes in EELV are consistently seen, irrespective of the presence of flow limitation at rest.
Exhaled nitric oxide as a marker of asthma control in smoking patients
Authors: Michils A. , Louis R. , Peché R. , Baldassarre S. , Van Muylem A.
Published: January 2009

Exhaled nitric oxide fraction (FeNO), which is a reliable marker of eosinophilic airway inflammation, is partially suppressed by tobacco smoking. Consequently, its potential as a biomarker in asthma management has never been evaluated in smoking patients. In the present study, the authors tested the validity ofFeNOto predict asthma control in this population.

FeNOand the Asthma Control Questionnaire (ACQ) were recorded at least once in 411 nonsmoking (345 with at least two visits) and 59 smoking (51 with at least two visits) asthma patients.

Despite similar mean ACQ scores (1.5versus1.7),FeNOwas reduced in smoking asthmatics (18.1 ppbversus33.7 ppb). A decrease inFeNOof <20% precludes asthma control improvement in nonsmoking (negative predictive value (NPV) 78%) and in smoking patients (NPV 72%). An increase inFeNO<30% is unlikely to be associated with deterioration in asthma control in both groups of patients (NPV = 86% and 84% in nonsmoking and smoking patients, respectively).

It is concluded that, even in smokers, sequential changes inFeNOhave a relationship with asthma control. The present study is the first to indicate that cigarette smoking does not obviate the clinical value of measuringFeNOin asthma among smokers.
Predictors of poor treatment outcome in multi- and extensively drug-resistant pulmonary TB
Authors: Kliiman K. , Altraja A.
Published: January 2009

Treatment outcome in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is often unsuccessful, but the particular determinants of poor treatment outcome have remained obscure. The present authors therefore analysed treatment effectiveness and predictors of poor treatment outcome in pulmonary MDR-TB and XDR-TB in Estonia, a European country with one of the highest MDR-TB and XDR-TB rates in the world.

All culture-confirmed pulmonary MDR-TB and XDR-TB patients who started TB treatment in 2003–2005 were included. Multivariate analysis was performed on two models of predictors: 1) patients' HIV-status, demographic and socioeconomic characteristics; and 2) TB-related data.

In the 235 MDR-TB patients, the proportion of overall successful treatment outcome was 60.4%, rising to 72.8% among adherent patients. Among the 54 XDR-TB patients, these proportions were 42.6% and 50.0%, respectively. Risk factors for poor treatment outcome in MDR-TB were HIV infection, previous TB treatment, resistance to ofloxacin and positive acid-fast bacilli (AFB) smear at the start of treatment. Predictors of poor treatment outcome in XDR-TB were urban residence and positive AFB smear.

This country-wide study provides evidence that to improve treatment outcome in multidrug-resistant and extensively drug-resistant tuberculosis, special care should be taken to treat HIV-infected patients and urban residents, as well as to make efforts to diminish re-treatment cases by increasing patient adherence.
Single-dose desloratadine and montelukast and allergen-induced late airway responses
Authors: Davis B. E. , Illamperuma C. , Gauvreau G. M. , Watson R. M. , O'Byrne P. M. , Deschesnes F. , Boulet L. P. , Cockcroft D. W.
Published: January 2009

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response.

Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out.

All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy.

Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.
Phylogeny of the SNARE vesicle fusion machinery yields insights into the conservation of the secretory pathway in fungi
Authors: Kienle Nickias , Kloepper Tobias H , Fasshauer Dirk
Published: January 2009

Background

In eukaryotic cells, directional transport between different compartments of the endomembrane system is mediated by vesicles that bud from a donor organelle and then fuse with an acceptor organelle. A family of integral membrane proteins, termed soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, constitute the key machineries of these different membrane fusion events. Over the past 30 years, the yeast Saccharomyces cerevisiae has served as a powerful model organism for studying the organization of the secretory and endocytic pathways, and a few years ago, its entire set of SNAREs was compiled.

Results

Here, we make use of the increasing amount of genomic data to investigate the history of the SNARE family during fungi evolution. Moreover, since different SNARE family members are thought to demarcate different organelles and vesicles, this approach allowed us to compare the organization of the endomembrane systems of yeast and animal cells. Our data corroborate the notion that fungi generally encompass a relatively simple set of SNARE proteins, mostly comprising the SNAREs of the proto-eukaryotic cell. However, all fungi contain a novel soluble SNARE protein, Vam7, which carries an N-terminal PX-domain that acts as a phosphoinositide binding module. In addition, the points in fungal evolution, at which lineage-specific duplications and diversifications occurred, could be determined. For instance, the endosomal syntaxins Pep12 and Vam3 arose from a gene duplication that occurred within the Saccharomycotina clade.

Conclusion

Although the SNARE repertoire of baker's yeast is highly conserved, our analysis reveals that it is more deviated than the ones of basal fungi. This highlights that the trafficking pathways of baker's yeast are not only different to those in animal cells but also are somewhat different to those of many other fungi.
Identification in milk of a serum amyloid A peptide chemoattractant for B lymphoblasts
Authors: de Jesus Rodriguez Berardo , Chevaleyre Claire , Henry Gwénaële , Mollé Daniel , Virlogeux-Payant Isabelle , Berri Mustapha , Boulay François , Léonil Joëlle , Meurens François , Salmon Henri
Published: January 2009

Background

Normal mammary gland contains an extravascular population of B lymphoblasts, precursors of the immunoglobulin plasma cells that play a key role in the passive protection of neonates by secreting immunoglobulins to colostrum and milk. We investigated the presence of chemoattractants in the milk by analysing the chemoattractant activity of various fractions of this secretion. Milk chemoattractants are potentially involved in the recruitment of lymphocytes from the maternal bloodstream in lactating mammary glands.

Results

The dilution-related lymphoid cell chemoattraction of whey was associated with a < 10 kDa ultrafiltrate. Active fractions were purified by reverse-phase high performance liquid chromatography. Two peptides of 2.7 kDa (DMREANYKNSDKYFHARGNYDAA) and 1 kDa (RPPGLPDKY) were identified as fragments of the SAA protein family, tentatively identified as SAA2. Only the 2.7 kDa synthetic peptide displayed chemotactic activity, at two different optimal concentrations. At the lower concentration (3.7 nM), it attracted B-cell lymphoblasts, whereas at the higher (3.7 μM), it attracted B lymphocytes. Then, the SAA mRNA expression was analysed and we observed more SAA transcripts during lactation than gestation.

Conclusion

These data are consistent with the SAA23–45fragment being involved in preplasma B-cell recruitment to the mammary gland and resultant benefit to the neonate.
An investigation of ribosomal protein L10 gene in autism spectrum disorders
Authors: Gong Xiaohong , Delorme Richard , Fauchereau Fabien , Durand Christelle M , Chaste Pauline , Betancur Catalina , Goubran-Botros Hany , Nygren Gudrun , Anckarsäter Henrik , Rastam Maria , Gillberg I Carina , Kopp Svenny , Mouren-Simeoni Marie-Christine , Gillberg Christopher , Leboyer Marion , Bourgeron Thomas
Published: January 2009

Background

Autism spectrum disorders (ASD) are severe neurodevelopmental disorders with the male:female ratio of 4:1, implying the contribution of X chromosome genetic factors to the susceptibility of ASD. The ribosomal protein L10 (RPL10) gene, located on chromosome Xq28, codes for a key protein in assembling large ribosomal subunit and protein synthesis. Two non-synonymous mutations of RPL10, L206M and H213Q, were identified in four boys with ASD. Moreover, functional studies of mutant RPL10 in yeast exhibited aberrant ribosomal profiles. These results provided a novel aspect of disease mechanisms for autism – aberrant processes of ribosome biosynthesis and translation. To confirm these initial findings, we re-sequenced RPL10 exons and quantified mRNA transcript level of RPL10 in our samples.

Methods

141 individuals with ASD were recruited in this study. All RPL10 exons and flanking junctions were sequenced. Furthermore, mRNA transcript level of RPL10 was quantified in B lymphoblastoid cell lines (BLCL) of 48 patients and 27 controls using the method of SYBR Green quantitative PCR. Two sets of primer pairs were used to quantify the mRNA expression level of RPL10: RPL10-A and RPL10-B.

Results

No non-synonymous mutations were detected in our cohort. Male controls showed similar transcript level of RPL10 compared with female controls (RPL10-A, U = 81, P = 0.7; RPL10-B, U = 61.5, P = 0.2). We did not observe any significant difference in RPL10 transcript levels between cases and controls (RPL10-A, U = 531, P = 0.2; RPL10-B, U = 607.5, P = 0.7).

Conclusion

Our results suggest that RPL10 has no major effect on the susceptibility to ASD.
Certified causes of death in patients with mesothelioma in South East England
Authors: Okello Catherine , Treasure Tom , Nicholson Andrew G , Peto Julian , Møller Henrik
Published: January 2009

Background

Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.

Methods

We extracted mesothelioma registrations in the South East of England area between 2000 and 2004 from the Thames Cancer Registry database. We retained for analysis 2200 patients who had died at the time of analysis, after having excluded seven dead cases where the causes of death were not known to the cancer registry. The 2200 deaths were classified hierarchically to identify (1) mesothelioma deaths, (2) deaths certified as lung cancer deaths or (3) deaths from unspecified cancer, and (4) deaths from other causes.

Results

87% of the patients had mesothelioma mentioned on the death certificate. 6% had no mention of mesothelioma but included lung cancer as a cause of death. Another 6% had no mention of mesothelioma or lung cancer, but included an unspecified cancer as a cause of death. Lastly, 2% had other causes of death specified on the death certificate.

Conclusion

This analysis suggests that official mortality data may underestimate the true occurrence of mesothelioma by around 10%.
Development of a screening tool predicting the transition from acute to chronic low back pain for patients in a GP setting: Protocol of a multinational prospective cohort study
Authors: Melloh Markus , Aebli Nikolaus , Elfering Achim , Röder Christoph , Zweig Thomas , Barz Thomas , Herbison Peter , Hendrick Paul , Bajracharya Suraj , Stout Kirsten , Theis Jean-Claude
Published: January 2009

Background

Low back pain (LBP) is by far the most prevalent and costly musculoskeletal problem in our society today. Following the recommendations of the Multinational Musculoskeletal Inception Cohort Study (MMICS) Statement, our study aims to define outcome assessment tools for patients with acute LBP and the time point at which chronic LBP becomes manifest and to identify patient characteristics which increase the risk of chronicity.

Methods

Patients with acute LBP will be recruited from clinics of general practitioners (GPs) in New Zealand (NZ) and Switzerland (CH). They will be assessed by postal survey at baseline and at 3, 6, 12 weeks and 6 months follow-up. Primary outcome will be disability as measured by the Oswestry Disability Index (ODI); key secondary endpoints will be general health as measured by the acute SF-12 and pain as measured on the Visual Analogue Scale (VAS). A subgroup analysis of different assessment instruments and baseline characteristics will be performed using multiple linear regression models.

This study aims to examine

1. Which biomedical, psychological, social, and occupational outcome assessment tools are identifiers for the transition from acute to chronic LBP and at which time point this transition becomes manifest

2. Which psychosocial and occupational baseline characteristics like work status and period of work absenteeism influence the course from acute to chronic LBP

3. Differences in outcome assessment tools and baseline characteristics of patients in NZ compared with CH.

Discussion

This study will develop a screening tool for patients with acute LBP to be used in GP clinics to access the risk of developing chronic LBP. In addition, biomedical, psychological, social, and occupational patient characteristics which influence the course from acute to chronic LBP will be identified. Furthermore, an appropriate time point for follow-ups will be given to detect this transition. The generalizability of our findings will be enhanced by the international perspective of this study.

Trial registration

[Clinical Trial Registration Number, ACTRN12608000520336]
Clinical utility of genetic tests for inherited hypertrophic and dilated cardiomyopathies
Authors: Colombo Maria Giovanna , Botto Nicoletta , Vittorini Simona , Paradossi Umberto , Andreassi Maria Grazia
Published: January 2009

Genetic testing has become an increasingly important part of medical practice for heritable form of cardiomyopathies. Hypertrophic cardiomyopathy and about 50% of idiopathic dilatative cardiomyopathy are familial diseases, with an autosomal dominant pattern of inheritance.

Some genotype-phenotype correlations can provide important information to target DNA analyses in specific genes. Genetic testing may clarify diagnosis and help the optimal treatment strategies for more malignant phenotypes. In addition, genetic screening of first-degree relatives can help early identification and diagnosis of individuals at greatest risk for developing cardiomyopathy, allowing to focus clinical resources on high-risk family members.

This paper provides a concise overview of the genetic etiology as well as the clinical utilities and limitations of genetic testing for the heritable cardiomyopathies.
Biopsychosocial approaches to a patient with vomiting of 10 years' duration – a case of temporal lobe epilepsy
Authors: Mutsuura Hiromi , Fukunaga Mikihiko , Kanbara Kenji , Yagyu Takami , Yamamoto Kazumi , Kitamura Kana , Ban Ikumi , Nakai Yoshihide
Published: January 2009

Background

Vomiting is commonly encountered in clinical medicine. When organic gastrointestinal, metabolic, and brain diseases are ruled out, many cases are considered to be functional. We experienced an adult patient with epilepsy whose main symptom was vomiting. Biopsychosocial approaches were needed to control the symptoms.

Case presentation

A 26-year-old female with a 10-year history of persistent vomiting was found to have temporal lobe epilepsy (TLE). Throughout this time, during which the vomiting had become part of a vicious cycle, her epilepsy was poorly controlled by medication. Biopsychosocial approaches were employed successfully and the patient subsequently undertook training to become a home-helper, started a job, and was able to leave her parents' house and live independently. All of her symptoms resolved after she became self-sufficient.

Discussion

Vomiting without impaired consciousness is seldom considered to be a manifestation of epilepsy. Difficulty in recording an electroencephalogram (EEG) because of the presence of persistent vomiting delayed the diagnosis. The improvement of symptoms was thought to have been due to the patient's emotional stabilization and physical improvement, which may have stabilized the limbic system.

Conclusion

When an illness persists for many years and conditioning and a vicious cycle occur secondarily, systematic biopsychosocial approaches are needed in addition to general treatment. Also, secondary symptoms make the diagnosis more difficult when efforts at treatment are ineffective.
Central retinal artery occlusion and non-arteritic anterior ischemic optic neuropathy associated with an overlap syndrome: a case report
Authors: Lima Verônica C , Prata Tiago S , Liebmann Jeffrey M , Ritch Robert
Published: January 2009

Introduction

An "overlap syndrome" is defined as the sequential appearance over time of two or more risk factors for glaucomatous damage. The appearance of a new risk factor can alter the course and prognosis of previously stable disease. Exfoliation syndrome is a leading cause of glaucoma and is associated with vascular disease. We report a case of central retinal artery occlusion and non-arteritic anterior ischemic optic neuropathy in a patient with overlap syndrome.

Case presentation

An 87-year-old woman with longstanding stable primary open-angle glaucoma developed bilateral exfoliation syndrome, after which her intraocular pressure became uncontrolled and her glaucomatous damage progressed rapidly. She also developed ischemic arterial events in both eyes.

Conclusion

The case presented here shows that overlap syndromes can lead to rapid, irreversible vision impairment. To the best of our knowledge, this is the first reported case of central retinal artery occlusion and non-arteritic anterior ischemic optic neuropathy in a patient with overlap syndrome.
Minimally invasive treatment of patients with bronchobiliary fistula: a case series
Authors: Aydin Unal , Yazici Pinar , Tekin Fatih , Ozutemiz Omer , Coker Ahmet
Published: January 2009

Introduction

Bronchobiliary fistula is an uncommon complication secondary to hepatobiliary surgery. Bilioptysis is a pathognomic finding for bronchobiliary fistulas. Diagnosis may be easily established in the light of clinical history, which can be aided by imaging studies to pinpoint the exact location. Some diagnostic procedures such as endoscopic retrograde cholangiopancreatectomy are also useful for treatment.

Case presentation

We present three Turkish patients with bronchobiliary fistula secondary to previous hepatic surgery due to hydatid cyst in two, a 19-year-old and a 47-year-old man, and iatrogenic trauma of the common bile duct by endoscopy in a 35-year-old man. All of the patients were successfully treated by minimally invasive methods including percutaneous drainage and endoscopic retrograde cholangiopancreatography.

Conclusion

We suggest that bronchobiliary fistula could be managed through conservative treatment methods which do not require in-hospital follow-up, particularly in uncomplicated cases. Otherwise, surgical management can be unavoidable.
Chest pain and ST-segment elevation in a patient with polymyositis: a case report
Authors: Stougiannos Pavlos N , Mytas Dimitrios Z , Katsaros Andreas A , Kakkavas Apostolos T , Androulakis Aristides E , Kallikazaros Ioannis E , Chrissos Dimitrios N
Published: January 2009

Background

Cardiac involvement in patients with polymyositis is well-documented and includes myocarditis, coronary arteritis, pericarditis, valvular dysfunction and arrhythmias.

Case report

There are only few reports of acute myocarditis in patients with polymyositis and, although it usually follows a chronic, mild course, it may occasionally become life-threatening. We describe the case of a 36-year-old young woman suffering from polymyositis who presented with clinical signs and symptoms mimicking an ST Elevation Acute Coronary Syndrome. The atypical features of the pain, the young age of the woman, the lack of significant cardiovascular risk factors and the medical history of an autoimmune disease, led us to reconsider our initial diagnosis towards the presence of focal myocarditis.

Conclusion

We describe our diagnostic approach and comment on our speculations and decisions about the treatment of such a life threatening event.
Expiratory automatic endotracheal tube compensation reduces dynamic hyperinflation in a physical lung model
Authors: Haberthür Christoph , Mehlig Annekathrin , Stover John F , Schumann Stefan , Möller Knut , Priebe Hans-Joachim , Guttmann Josef
Published: January 2009

Introduction

The effect of expiratory endotracheal tube (ETT) resistance on dynamic lung inflation is unknown. We hypothesized that ETT resistance causes dynamic lung hyperinflation by impeding lung emptying. We further hypothesized that compensation for expiratory ETT resistance by automatic tube compensation (ATC) attenuates dynamic lung hyperinflation.

Methods

A ventilator equipped with the original ATC mode and operating in a pressure-targeted mode was connected to a physical lung model that consists of four equally sized glass bottles filled with copper wool. Inspiratory pressure, peak expiratory flow, trapped lung volume and intrinsic positive end-expiratory pressure (PEEP) were assessed at combinations of four inner ETT diameters (7.0, 7.5, 8.0 and 8.5 mm), four respiratory rates (15, 20, 25 and 30/minute), three inspiratory pressures (3.0, 4.5 and 6.0 cmH2O) and four lung compliances (113, 86, 58 and 28 ml/cmH2O). Intrinsic PEEP was measured at the end of an expiratory hold manoeuvre.

Results

At a given test lung compliance, inspiratory pressure and ETT size, increasing respiratory rates from 15 to 30/minutes had the following effects: inspiratory tidal volume and peak expiratory flow were decreased by means of 25% (range 0% to 51%) and 11% (8% to 12%), respectively; and trapped lung volume and intrinsic PEEP were increased by means of 25% (0% to 51%) and 26% (5% to 45%), respectively (all P < 0.025). At otherwise identical baseline conditions, introduction of expiratory ATC significantly attenuated (P < 0.025), by approximately 50%, the respiratory rate-dependent decreases in inspiratory tidal volume and the increases in trapped lung volume and intrinsic PEEP.

Conclusions

In a lung model of pressure-targeted ventilation, expiratory ETT resistance caused dynamic lung hyperinflation during increases in respiratory rates, thereby reducing inspiratory tidal volume. Expiratory ATC attenuated these adverse effects.
Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys
Authors: Swarbrick Michael M. , Havel Peter J. , Levin Arthur A. , Bremer Andrew A. , Stanhope Kimber L. , Butler Madeline , Booten Sheri L. , Graham James L. , McKay Robert A. , Murray Susan F. , Watts Lynnetta M. , Monia Brett P. , Bhanot Sanjay
Published: January 2009

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.
Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice
Authors: Riant Elodie , Waget Aurélie , Cogo Haude , Arnal Jean-François , Burcelin Rémy , Gourdy Pierre
Published: January 2009

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.
Torcetrapib Induces Aldosterone and Cortisol Production by an Intracellular Calcium-Mediated Mechanism Independently of Cholesteryl Ester Transfer Protein Inhibition
Authors: Hu Xiao , Dietz Jessica D. , Xia Chunsheng , Knight Delvin R. , Loging William T. , Smith Andrew H. , Yuan Haodan , Perry David A. , Keiser Joan
Published: January 2009

ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib’s effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.
Liver X Receptor Ligands Suppress Ubiquitination and Degradation of LXRα by Displacing BARD1/BRCA1
Authors: Kim Kang Ho , Yoon Jeong Min , Choi A Hyun , Kim Woo Sik , Lee Gha Young , Kim Jae Bum
Published: January 2009

Liver X receptor (LXR) is a ligand-activated transcription factor that plays important roles in cholesterol and lipid homeostasis. However, ligand-induced posttranslational modification of LXR is largely unknown. Here, we show that ligand-free LXRα is rapidly degraded by ubiquitination. Without ligand, LXRα interacts with an ubiquitin E3-ligase protein complex containing breast and ovarian cancer susceptibility 1 (BRCA1)-associated RING domain 1 (BARD1). Interestingly, LXR ligand represses ubiquitination and degradation of LXRα, and the interaction between LXRα and BARD1 is inhibited by LXR ligand. Consistently, T0901317, a synthetic LXR ligand, increased the level of LXRα protein in liver. Moreover, overexpression of BARD1/BRCA1 promoted the ubiquitination of LXRα and reduced the recruitment of LXRα to the target gene promoters, whereas BARD1 knockdown reversed such effects. Taken together, these data suggest that LXR ligand prevents LXRα from ubiquitination and degradation by detaching BARD1/BRCA1, which might be critical for the early step of transcriptional activation of ligand-stimulated LXRα through a stable binding of LXRα to the promoters of target genes.
The cell migration molecule UNC-53/NAV2 is linked to the ARP2/3 complex by ABI-1
Authors: Schmidt Kristopher L. , Marcus-Gueret Nancy , Adeleye Adetayo , Webber Jordan , Baillie David , Stringham Eve G.
Published: January 2009

The shape changes that are required to position a cell to migrate or grow out in a particular direction involve a coordinated reorganization of the actin cytoskeleton. Although it is known that the ARP2/3 complex nucleates actin filament assembly, exactly how the information from guidance cues is integrated to elicit ARP2/3-mediated remodeling during outgrowth remains vague. Previous studies have shown that C. elegans UNC-53 and its vertebrate homolog NAV (Neuronal Navigators) are required for the migration of cells and neuronal processes. We have identified ABI-1 as a novel molecular partner of UNC-53/NAV2 and have found that a restricted calponin homology (CH)domain of UNC-53 is sufficient to bind ABI-1. ABI-1 and UNC-53 have an overlapping expression pattern, and display similar cell migration phenotypes in the excretory cell, and in mechanosensory and motoneurons. Migration defects were also observed after RNAi of proteins known to function with abi-1 in actin dynamics, including nck-1, wve-1 and arx-2. We propose that UNC-53/NAV2, through its CH domain, acts as a scaffold that links ABI-1 to the ARP2/3 complex to regulate actin cytoskeleton remodeling.
Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities
Authors: Kawakami Yasuhiko , Uchiyama Yukako , Rodriguez Esteban Concepcion , Inenaga Toshiaki , Koyano-Nakagawa Naoko , Kawakami Hiroko , Marti Merce , Kmita Marie , Monaghan-Nichols Paula , Nishinakamura Ryuichi , Izpisua Belmonte Juan Carlos
Published: January 2009

The genetic mechanisms that regulate the complex morphogenesis of generating cartilage elements in correct positions with precise shapes during organogenesis, fundamental issues in developmental biology, are still not well understood. By focusing on the developing mouse limb, we confirm the importance of transcription factors encoded by the Sall gene family in proper limb morphogenesis, and further show that they have overlapping activities in regulating regional morphogenesis in the autopod. Sall1/Sall3 double null mutants exhibit a loss of digit1 as well as a loss or fusion of digit2 and digit3, metacarpals and carpals in the autopod. We show that Sall activity affects different pathways, including the Shh signaling pathway, as well as the Hox network. Shh signaling in the mesenchyme is partially impaired in the Sall mutant limbs. Additionally, our data suggest an antagonism between Sall1-Sall3 and Hoxa13-Hoxd13. We demonstrate that expression of Epha3 and Epha4 is downregulated in the Sall1/Sall3double null mutants, and, conversely, is upregulated in Hoxa13 and Hoxd13 mutants. Moreover, the expression of Sall1 and Sall3 is upregulated in Hoxa13 and Hoxd13 mutants. Furthermore, by using DNA-binding assays, we show that Sall and Hox compete for a target sequence in the Epha4 upstream region. In conjunction with the Shh pathway, the antagonistic interaction between Hoxa13-Hoxd13 and Sall1-Sall3 in the developing limb may contribute to the fine-tuning of local Hox activity that leads to proper morphogenesis of each cartilage element of the vertebrate autopod.
The molecular genetics of intrahepatic cholestasis of pregnancy
Authors: Dixon P H , Williamson C
Published: January 2009

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, causes maternal pruritus and liver impairment, and may be complicated by spontaneous preterm labour, fetal asphyxial events and intrauterine death. Our understanding of the aetiology of this disease has expanded significantly in the last decade due to a better understanding of the role played by genetic factors. In particular, advances in our knowledge of bile homeostasis has led to the identification of genes that play a considerable role in susceptibility to ICP. In this review we consider these advances and discuss the disease in the context of bile synthesis and metabolism, focusing on the genetic discoveries that have shed light on the molecular aetiology and pathophysiology of the condition.
Weakness in pregnancy – expect the unexpected
Authors: Furara S , Maw M , Khan F , Powell K
Published: January 2009

Guillain-Barré syndrome (GBS) is rare in pregnancy with an incidence estimated to be between 1.2 and 1.9 cases per 100,000 people annually, and it is generally accepted that it carries a high maternal risk. Delayed diagnosis is common because the initial non-specific symptoms may mimic changes in pregnancy. GBS should be considered in any pregnant patient complaining of muscle weakness, general malaise, tingling of the fingers and respiratory discomfort. This case aims to highlight the importance of early diagnosis, allowing prompt initiation of the immunomodulatory treatments which have been shown to improve outcome alongside multidisciplinary care.