bluuebunny/crossref_metadata_2025 huggingface dataset:
Australian parents’ needs and expectations regarding out of school hours care: A pilot study
Authors: Winefield Helen , Piteo Alicia , Kettler Lisa , Roberts Rachel , Taylor Anne , Tuckey Michelle , Denson Linley , Thomas Kay , Lamb Ian
Published: May 2011

An increasing number of working parents are making use of out of school hours care (OSHC) for their young primary-school aged children, but in Australia very little is known about how effectively these services meet parent needs. The present pilot study aimed to gather information non-directively from employed parents, first, about how OSHC use affects their workforce participation and ability to resolve the competing demands of work and family responsibilities. The second goal was to gain some idea of what parents look for in OSHC and how satisfied they feel with the service they use. Thirteen mothers answered open-ended but structured questions in a telephone interview. They expressed how vital OSHC services are in enabling them to work, but usually did not spontaneously evaluate the quality of the service. Results suggest a need for more systematic research on OSHC quality, and how it does or might contribute to parent and child well-being.
Physical activity at daycare: Childcare providers’ perspectives for improvements
Authors: Tucker Patricia , van Zandvoort Melissa M , Burke Shauna M , Irwin Jennifer D
Published: May 2011

In London, Ontario, approximately 45 percent of preschoolers are insufficiently active.With the large number of preschoolers who attend childcare (54%), and the low levels of physical activity among preschool-aged children, daycare centers may be an appropriate avenue to intervene. This study sought to collect childcare providers’ suggestions for improving physical activity during daycare hours and their perspectives regarding the feasibility of meeting the physical activity guidelines currently set out for preschoolers. This qualitative study targeted a heterogeneous sample of childcare providers (n = 54) working at YMCA daycare centers in London, Ontario. Eight focus groups were conducted. Saturation was reached by the fifth focus group; however, three additional focus groups were completed to confirm that the researchers continued hearing the same responses. Focus groups were audio-recorded and transcribed verbatim. Inductive content analysis was used to code and categorize emerging themes. Strategies were incorporated to ensure data trustworthiness. Childcare providers believed the children in their care were quite active and when asked what would be required to increase the physical activity participation among the preschoolers in their care, participants discussed: staff training/workshops; guest physical activity instructors; additional equipment and resources; and increased funds for physical activity. The majority of focus group participants also felt it was feasible for the preschoolers in their care to meet or exceed the preschooler physical activity guidelines. Developing programs and resources that are informed by childcare providers may be an effective way to target sedentary behaviors among the preschool-aged population. Accordingly, childcare providers’ suggestions of how to maximize the opportunities for physical activity during daycare hours should be considered when developing and revising childcare curriculum, resources and policies.
Individual development plans from a critical didactic perspective: Focusing on Montessori- and Reggio Emilia-profiled preschools in Sweden
Authors: Vallberg Roth Ann-Christine , Månsson Annika
Published: May 2011

Individual development plans, which are sometimes designed as ‘agreements — contracts’, can be considered the most rigid type of regulation on the individual level in the history of preschool in Sweden. Today we speak about a deregulated school. This regulation seems to have changed its character, gradually drifting from school regulation to individual and self-regulation. The study aims to map and discuss the variation of content and positions for children in the documentation from all preschools in a municipality in the south of Sweden. Documentation and individual development plans (IDP) are studied from preschools with different pedagogical profiles. Materials from Montessori- and Reggio Emilia-inspired preschools are focused on. A critical didactic perspective refers to a discussion and critical scrutiny of the structure of contents, assessment and position of children in different types of documentation. The perspective leads to questions such as: how is content constructed, and what governs the choice of content in IDPs and documentation at the institutional and individual levels? How is content related to pedagogical profile? What identities and positions are formulated for children in relation to various contents and profiles? The empirical data in the study were gathered in 2008 and comprises text in the form of governing documents on different levels: as municipal guidelines, profile descriptions on the municipality’s websites and IDP forms. Tentative results show a variation with both similar and diverse constructions of contents and positions related to pedagogical profiles.
Expanded Adult Day Program as a Transition Option From Hospital to Home
Authors: Jones Katherine R. , Tullai-McGuinness Susan , Dolansky Mary , Farag Amany , Krivanek Mary Jo , Matthews Laura
Published: May 2011

This article describes a pilot program for provision of postacute care (PAC) in an established adult day program. Demographic, clinical, utilization, and satisfaction data were abstracted retrospectively from program records; postdischarge readmission and emergency department visit data were obtained from the electronic health record. Comparative data were obtained from the health records of patients who were offered but declined the adult day program. Between 2005 and 2008, 78 patients requiring PAC were approached by the RN coordinator; 33 selected the adult day program, and 45 selected alternative destinations. The majority of patients had a neurological diagnosis, most commonly stroke. Participants and their family caregivers were highly satisfied with the program. The 30-day readmission rate for adult day program participants was significantly lower than that for nonparticipants. An expanded adult day program may represent a viable Transitional Care Model for selected patients and a feasible alternative to skilled nursing facility and home health care for PAC.
Chronic Obstructive Pulmonary Disease and Smoking Cessation
Authors: Parker Donna R. , Eaton Charles B.
Published: May 2011

Chronic obstructive pulmonary disease (COPD) is a major and increasing cause of morbidity and mortality. Cigarette smoking is the most important risk factor for COPD, and smoking cessation is, in most cases, the most effective way of preventing the onset and progression of COPD. The purpose of the present article was to review the current state of interventions for smokers with COPD. Because 70% of smokers visit a physician annually, primary care providers play a key role in the counseling of all patients at every visit. If smoking cessation is achieved at an early stage of disease, it is associated with a decrease in pulmonary symptoms and improves prognosis and prolonged abstinence. The health benefits of smoking cessation are immediate and substantial, and interventions provided for smokers suggest that multiple modalities are needed. Smoking cessation counseling in combination with nicotine replacement therapy (NRT) appears to be the most effective modality followed by smoking cessation in combination with an antidepressant to enhance prolonged abstinence.
The Physiological Effects of Creatine Supplementation on Hydration: A Review
Authors: Sobolewski Eric J. , Thompson Brennan J. , Smith Abbie E. , Ryan Eric D.
Published: May 2011

In 1992, Harris and colleagues demonstrated that oral creatine supplementation can enhance muscle creatine stores. Since then, creatine has become an important and popular ergogenic aid for improving athletic performance with reports of up to 74% of athletes supplementing with creatine. Although many recent studies have addressed the safety concerns of creatine supplementation on hydration status in hot and humid environments, anecdotal reports still exist linking creatine usage to heat-related problems. These concerns are based on the premise that creatine is an osmotically active substance resulting in an alteration in fluid balance by increasing intracellular fluid volume and preventing fluid from entering the extracellular environment to aid in thermoregulation. However, a number studies have demonstrated that when recommended amounts of creatine are consumed, creatine does not appear to increase the risk of heat-related problems during exercise and may actually have a positive influence on core temperature and heart rate responses.
Responding to Social Signals for Response Inhibition
Authors: Wilkowski Benjamin M.
Published: May 2011

Angry facial expressions are thought to serve as signals of social correction, indicating that one person disapproves of another’s behavior and wants them to desist. If individuals respond to such signals by inhibiting disapproved-of behaviors, they should effectively reduce the prevalence of angry and aggressive encounters in their lives. Two studies tested this idea by incorporating angry and neutral expressions within a task which measures behavioral-inhibition processes. Consistent with predictions, trait anger was related to response-inhibition processes for angry but not neutral expressions; such that low trait anger individuals exhibited faster response-inhibition processes in the angry context. This effect occurred when participants were explicitly instructed to inhibit behavior in response to facial expressions (Study 1) and when expressions were presented incidentally (Study 2). The findings could not be explained in terms of more general tendencies toward aggression or impulsivity or through perceptual processes.
Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project
Authors: Delabie Jan , Holte Harald , Vose Julie M. , Ullrich Fred , Jaffe Elaine S. , Savage Kerry J. , Connors Joseph M. , Rimsza Lisa , Harris Nancy L. , Müller-Hermelink Konrad , Rüdiger Thomas , Coiffier Bertrand , Gascoyne Randy D. , Berger Françoise , Tobinai Kensei , Au Wing Y. , Liang Raymond , Montserrat Emili , Hochberg Ephraim P. , Pileri Stefano , Federico Massimo , Nathwani Bharat , Armitage James O. , Weisenburger Dennis D.
Published: May 2011

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)–cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.
Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab
Authors: Treon Steven P. , Soumerai Jacob D. , Hunter Zachary R. , Patterson Christopher J. , Ioakimidis Leukothea , Kahl Brad , Boxer Michael
Published: May 2011

CD52 is expressed on malignant cells in lymphoplasmacytic lymphoma (LPL), including IgM-secreting Waldenström macroglobulinemia (WM). We examined the activity of alemtuzumab in 28 symptomatic LPL (27 IgM and 1 IgA) patients. The median prior number of therapies for these patients was 2 (range, 0-5) and 43% had refractory disease. Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing, and also received hydrocortisone, acyclovir, and Bactrim or equivalent prophylaxis. Patients had a complete response (n = 1), a partial response (n = 9), or a MR (n = 11) for an overall and major response rate of 75% and 36%, respectively. Median serum Ig decreased from 3510 to 1460 mg/dL (P < .001 at best response). With a median follow-up of 64 months, the median time to progression was 14.5 months. Hematologic and infectious complications, including CMV reactivation, were more common in previously treated patients and were indirectly associated with 3 deaths. Long-term follow-up revealed late-onset autoimmune thrombocytopenia (AITP) in 4 patients at a median of 13.6 months after therapy, which contributed to 1 death. Alemtuzumab is an active therapy in patients with LPL, but short- and long-term toxicities need to be carefully weighed against other available treatment options. Late AITP is a newly recognized complication of alemtuzumab in this patient population. This study is registered at www.clinicaltrials.gov as NCT00142181.
Biomarkers of early respiratory effects in smoking adolescents
Authors: Van Miert E. , Sardella A. , Bernard A.
Published: May 2011

Noninvasive biomarkers can be used to evaluate airways damage caused by tobacco smoke, but studies so far have only involved adult smokers. In this study, we evaluated whether such biomarkers can detect early respiratory effects in adolescents passively or actively exposed to tobacco smoke.

In a cross-sectional study of 845 adolescents (mean age 16 yrs), we measured exhaled nitric oxide (NO) and various epithelial markers in nasal lavage fluid (NALF) and serum, including Clara cell protein (CC16) and surfactant protein (SP)-D. Information about smoking habits and potential confounders was collected by questionnaire. Four groups of equal size (n=36), of nonsmokers, passive smokers, light smokers (<5 cigarettes·day−1, median 0.08 pack-yrs) and heavy smokers (≥5 cigarettes·day−1, median 0.35 pack-yrs), were matched using an automated procedure.

The levels of exhaled NO and of CC16 in NALF were significantly decreased in the group of heavy smokers. A trend towards lower levels of CC16 in NALF was observed in passive smokers. There were no significant changes in serum CC16 and SP-D, which suggests that the deep lung epithelium had not yet been affected by smoking.

In conclusion, tobacco smoke can cause early changes in the airways of adolescents with a cumulative smoking history of <1 pack-yr.
Small airways function declines after allogeneic haematopoietic stem cell transplantation
Authors: Lahzami S. , Schoeffel R.E. , Pechey V. , Reid C. , Greenwood M. , Salome C.M. , Berend N. , King G.G.
Published: May 2011

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry.

We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (Sacin) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined.

Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by Sacinand forced expiratory volume in 1 s % predicted. 20 patients had abnormal Sacinwith normal spirometry, whereas none had airflow obstruction with normal Sacin. Sacinand LCI were the only measures to change significantly between two visits, with both worsening. Change in Sacinwas the only parameter to correlate with change in chronic graft-versus-host disease grade.

In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. Sacinmay be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.
HLA-DRB1* alleles and symptoms associated with Heerfordt's syndrome in sarcoidosis
Authors: Darlington P. , Tallstedt L. , Padyukov L. , Kockum I. , Cederlund K. , Eklund A. , Grunewald J.
Published: May 2011

Heerfordt's syndrome (HS) consists in its complete form of uveitis, parotid or salivary gland enlargement and cranial nerve palsy. The objective of the present study was to analyse if there are also links between HLA-DRB1* alleles and HS, as it is a specific phenotype of sarcoidosis.

1,000 patients with sarcoidosis, out of whom 83 had symptoms associated with HS, were included in the study together with a group of 2,000 healthy individuals from the same population, matched for sex and age. HLA-DRB1* allelic groups were determined for all individuals, and comparisons were made between different disease subgroups and between patients and healthy controls.

We found that the HLA-DRB1*04 allele was overrepresented in patients with symptoms associated with HS. 83 (8.3%) of all patients had one or more of the symptoms and 46 (55%) of them were HLA-DRB1*04 positive. 44 (55%) of the patients with ocular sarcoidosis,i.e.the most common symptom associated with HS, were HLA-DRB1*04 positive, compared with 35.9% of healthy controls (p=0.0008), and only 26.6% of the whole group of sarcoidosis patients (p<0.0001).

HLA-DRB1*04 seems to protect against overall sarcoidosis but appears to be a significant risk factor for ocular sarcoidosis as well as for other manifestations associated with HS.
Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study
Authors: Hollams E.M. , Hart P.H. , Holt B.J. , Serralha M. , Parsons F. , de Klerk N.H. , Zhang G. , Sly P.D. , Holt P.G.
Published: May 2011

Vitamin D has been linked in some studies with atopy- and asthma-associated phenotypes in children with established disease, but its role in disease inception at the community level is less clear. The aim of the present study was to investigate associations between vitamin D status and biological signatures indicative of allergy and asthma development in children aged 6 and 14 years in Perth, WA, Australia (latitude 32° S).

Serum vitamin D was assayed in 989 6-yr-olds and 1,380 14-yr-olds from an unselected community birth cohort; 689 subjects were assessed at both ages. Vitamin D levels were assessed as a risk modifier for respiratory and allergic outcomes at both ages, using previously ascertained phenotypic data. The predictive value of vitamin D levels at age 6 yrs for development of clinical phenotypes at age 14 yrs was also examined.

Serum vitamin D levels in children of both ages were negatively associated with concurrent allergic phenotypes; sex stratification revealed that this association was restricted mainly to males. Furthermore, vitamin D levels at age 6 yrs were significant predictors of subsequent atopy/asthma-associated phenotypes at age 14 yrs.

In an unselected community setting, children (particularly males) with inadequate vitamin D are at increased risk of developing atopy, and subsequently bronchial hyperresponsiveness (BHR) and asthma. In a large unselected cohort, males with inadequate vitamin D at 6 and 14 yrs of age had increased atopy and BHR. Low vitamin D at age 6 yrs was a predictor of atopy and asthma at 14 yrs of age.
Association of the transfer coefficient of the lung for carbon monoxide with emphysema progression in male smokers
Authors: Mohamed Hoesein F.A.A. , Zanen P. , van Ginneken B. , van Klaveren R.J. , Lammers J-W.J.
Published: May 2011

A decreased transfer coefficient of the lung for carbon monoxide (KCO) is associated with emphysema. We evaluated whether in heavy smokers, baselineKCOwas associated with the progression of computed tomography (CT)-detected emphysema, and the progression of airflow limitation.

Heavy smokers, mean±sd41.3±18.7 pack-yrs, participating in a lung cancer screening trial underwent diffusion testing and CT scanning of the lungs. CT scanning was repeated after median (25th–75th percentile) 2.8 (2.7–3.0) yrs and emphysema was assessed by lung densitometry using the 15th percentile. The association betweenKCOat baseline with progression of emphysema and lung function decline was assessed by multiple linear regression, correcting for baseline CT-quantified emphysema severity and forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), age, height, body mass index, pack-yrs and smoking status (current or former smoker).

522 participants aged 60.1±5.4 yrs were included. Mean±sd15th percentile was -938±19, absolute FEV1/FVC was 71.6±9% andKCOwas 1.23±0.25, which is 81.8±16.5% of predicted. By interpolation, a onesd(0.25) lowerKCOvalue at baseline predicted a 1.6 HU lower 15th percentile and a 0.78% lower FEV1/FVC after follow-up (p<0.001).

A lower baselineKCOvalue is independently associated with a more rapid progression of emphysema and airflow limitation in heavy smokers.
Patterns of airway disease and the clinical diagnosis of asthma in the Busselton population
Authors: Musk A.W. , Knuiman M. , Hunter M. , Hui J. , Palmer L.J. , Beilby J. , Divitini M. , Mulrennan S. , James A.
Published: May 2011

The aim of this study was to examine how objective measures related to lung function cluster in the general population and how the patterns relate to asthma and bronchitis as diagnosed by a doctor (DDA and DDB, respectively).

A cross-sectional survey of an age-stratified random general population sample of 1,969 adults from the electoral register of Busselton (Australia) was performed in 2005–2007. Respiratory symptoms, DDA ever, DDB ever, recent wheezing and smoking history, together with anthropometric measurements, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), methacholine challenge or bronchodilator response, exhaled nitric oxide (eNO), skin-prick tests to common allergens, and blood eosinophil and neutrophil counts were studied. Cluster analysis (variables sex, age, atopy, FEV1% predicted, FEV1/FVC, airway hyperresponsiveness, eNO, log eosinphil count, log neutrophil count and body mass index) was used to identify phenotypic patterns.

Seven clusters (subjects with DDA and DDB, respectively) were identified: normal males (n=467; 7 and 13%), normal females (n=477; 12 and 18%), obese females (n=250; 16 and 28%), atopic younger adults (n=330; 21 and 17%), atopic adults with high eNO (n=130; 30 and 25%), atopic males with reduced FEV1(n=103; 33 and 32%) and atopic adults with bronchial hyperreactivity (n=212; 40 and 26%).

The clinical diagnosis of asthma (ever) and bronchitis (ever) is not specific for any of the clustering patterns of airway abnormality.
Efficacy of pleurodesis for malignant pleural effusions in breast cancer patients
Authors: Hirata T. , Yonemori K. , Hirakawa A. , Shimizu C. , Tamura K. , Ando M. , Katsumata N. , Tanimoto M. , Fujiwara Y.
Published: May 2011

This study retrospectively compared long-term outcomes between two groups of breast cancer patients with malignant pleural effusion (MPE): those receiving only systemic therapy (ST) and those receiving ST following initial pleurodesis (P-ST).

We identified 180 breast cancer patients from the National Cancer Center Hospital (Tokyo, Japan) database who had received ST and P-ST as an initial treatment for MPE between 1997 and 2008 for study inclusion. Pleural progression-free survival (PPFS) was defined as the time from ST in the ST group and from pleurodesis in the P-ST group to the first observation of pleural progression or death from any cause.

Of the 180 patients, 78 received ST and 102 received P-ST after MPE diagnosis. Median duration of follow-up was 12.7 months (range 0.9–80.1 months). Median PPFS for the ST group and the P-ST group was 4.1 and 8.5 months, respectively. The difference in PPFS between the two groups was statistically significant (p<0.001) and the hazard ratio after adjusting for prognostic factors in the P-ST group relative to the ST group was 0.24.

Our results suggest that the efficacy of P-ST may be superior to that of ST alone with respect to local control of pleural effusions in breast cancer patients.
Properties of the COPD assessment test in a cross-sectional European study
Authors: Jones P.W. , Brusselle G. , Dal Negro R.W. , Ferrer M. , Kardos P. , Levy M.L. , Perez T. , Soler Cataluña J.J. , van der Molen T. , Adamek L. , Banik N.
Published: May 2011

A short, easy-to-use health status questionnaire is needed in the multidimensional assessment of chronic obstructive pulmonary disease (COPD) in routine practice.

The performance of the eight-item COPD assessment test (CAT) was analysed in 1,817 patients from primary care in seven European countries. The CAT has a scoring range of 0–40 (high score representing poor health status).

Mean CAT scores indicated significant health status impairment that was related to severity of airway obstruction, but within each Global Initiative for Obstructive Lung Disease stage (I to IV) there was a wide range of scores (I: 16.2±8.8; II: 16.3±7.9; III: 19.3±8.2; and IV: 22.3±8.7; IversusII, p = 0.88; IIversusIII, p<0.0001; IIIversusIV, p = 0.0001). CAT scores showed relatively little variability across countries (within ±12% of the mean across all countries). Scores were significantly better in patients who were stable (17.2±8.3)versusthose suffering an exacerbation (21.3±8.4) (p<0.0001); and in patients with no (17.3±8.1) or one or two (16.6±8.2)versusthree or more (19.7±8.5) comorbidities (p<0.0001 for both). The CAT distinguished between classes of other impairment measures and was strongly correlated with the St George’s Respiratory Questionnaire (r = 0.8, p<0.0001).

The CAT is a simple and easy-to-use questionnaire that distinguishes between patients of different degrees of COPD severity and appears to behave the same way across countries.
Development of a decision tree to assess the severity and prognosis of stable COPD
Authors: Esteban C. , Arostegui I. , Moraza J. , Aburto M. , Quintana J.M. , Pérez-Izquierdo J. , Aizpiri S. , Capelastegui A.
Published: May 2011

The aim of this study was to develop and validate a new method: a classification and regression tree (CART) based on easily accessible measures to predict mortality in patients with stable chronic obstructive pulmonary disease (COPD).

This was a prospective study of two independent prospective cohorts: a derivation cohort with 611 recruited patients and a validation cohort with 348 patients, all followed for 5 yrs. CART analysis was used to predict 5-yr mortality risk using the following covariates from the derivation cohort: age, % predicted forced expiratory volume in 1 s (FEV1), dyspnoea, physical activity, general health and number of hospital admissions for COPD exacerbations in the previous 2 yrs.

Age (≥75 or <75 yrs) provided the first branch of the COPD-CART. The highest mortality risk (0.74) was seen in patients >75 yrs of age with higher levels of dyspnoea and FEV1<50% pred. Patients with the lowest risk of 5-yr mortality (0.04) were <55 yrs of age with FEV1>35% pred and one or no recent hospitalisations for COPD exacerbations.

A simple decision tree that uses variables commonly gathered by physicians can provide a quick assessment of the severity of the disease, as measured by the risk of 5-yr mortality.
Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis
Authors: Sahoo D.H. , Bandyopadhyay D. , Xu M. , Pearson K. , Parambil J.G. , Lazar C.A. , Chapman J.T. , Culver D.A.
Published: May 2011

Leflunomide has been reported as an alternative therapy in sarcoidosis. However, the published data are limited.

We performed a retrospective chart review of the tolerance and effects of leflunomide therapy in patients with sarcoidosis.

76 patients were included. The most common reasons for initiation were progression of disease or failure of other immunomodulator therapy. Side-effects attributable to leflunomide were noted in 34% of subjects, prompting discontinuation in 17%. The lungs were a target of therapy in 33 (44%) and extrapulmonary organs were a target in 45 (59%). The mean±sdchange in forced vital capacity in the 6 months prior to leflunomide was −0.1±0.3 L, and it was +0.09±0.3 L in the following 6 months (p=0.01). For extrapulmonary target organ response, 51% had a good response and 32% a partial response. The median corticosteroid dose at initiation was 10 mg (interquartile range 5–20) mg at baseline, and 0 (0–10) mg at the 6-month follow-up (p<0.001).

Leflunomide is a viable alternative agent for pulmonary and extrapulmonary sarcoidosis. Leflunomide appears to facilitate reduction of steroid dose and can be considered as monotherapy or as add-on therapy in cases of progressive disease.
Escherichia coli genome-wide promoter analysis: Identification of additional AtoC binding target elements
Authors: Pilalis Eleftherios , Chatziioannou Aristotelis A , Grigoroudis Asterios I , Panagiotidis Christos A , Kolisis Fragiskos N , Kyriakidis Dimitrios A
Published: May 2011

Background

Studies on bacterial signal transduction systems have revealed complex networks of functional interactions, where the response regulators play a pivotal role. The AtoSC system of E. coli activates the expression of atoDAEB operon genes, and the subsequent catabolism of short-chain fatty acids, upon acetoacetate induction. Transcriptome and phenotypic analyses suggested that atoSC is also involved in several other cellular activities, although we have recently reported a palindromic repeat within the atoDAEB promoter as the single, cis-regulatory binding site of the AtoC response regulator. In this work, we used a computational approach to explore the presence of yet unidentified AtoC binding sites within other parts of the E. coli genome.

Results

Through the implementation of a computational de novo motif detection workflow, a set of candidate motifs was generated, representing putative AtoC binding targets within the E. coli genome. In order to assess the biological relevance of the motifs and to select for experimental validation of those sequences related robustly with distinct cellular functions, we implemented a novel approach that applies Gene Ontology Term Analysis to the motif hits and selected those that were qualified through this procedure. The computational results were validated using Chromatin Immunoprecipitation assays to assess the in vivo binding of AtoC to the predicted sites. This process verified twenty-two additional AtoC binding sites, located not only within intergenic regions, but also within gene-encoding sequences.

Conclusions

This study, by tracing a number of putative AtoC binding sites, has indicated an AtoC-related cross-regulatory function. This highlights the significance of computational genome-wide approaches in elucidating complex patterns of bacterial cell regulation.
Resistance to organic hydroperoxides requires ohr and ohrR genes in Sinorhizobium meliloti
Authors: Fontenelle Catherine , Blanco Carlos , Arrieta Morgane , Dufour Virginie , Trautwetter Annie
Published: May 2011

Background

Sinorhizobium meliloti is a symbiotic nitrogen-fixing bacterium that elicits nodules on roots of host plants Medicago sativa. During nodule formation bacteria have to withstand oxygen radicals produced by the plant. Resistance to H2O2 and superoxides has been extensively studied in S. meliloti. In contrast resistance to organic peroxides has not been investigated while S. meliloti genome encodes putative organic peroxidases. Organic peroxides are produced by plants and are highly toxic. The resistance to these oxygen radicals has been studied in various bacteria but never in plant nodulating bacteria.

Results

In this study we report the characterisation of organic hydroperoxide resistance gene ohr and its regulator ohrR in S. meliloti. The inactivation of ohr affects resistance to cumene and ter-butyl hydroperoxides but not to hydrogen peroxide or menadione in vitro. The expression of ohr and ohrR genes is specifically induced by organic peroxides. OhrR binds to the intergenic region between the divergent genes ohr and ohrR. Two binding sites were characterised. Binding to the operator is prevented by OhrR oxidation that promotes OhrR dimerisation. The inactivation of ohr did not affect symbiosis and nitrogen fixation, suggesting that redundant enzymatic activity exists in this strain. Both ohr and ohrR are expressed in nodules suggesting that they play a role during nitrogen fixation.

Conclusions

This report demonstrates the significant role Ohr and OhrR proteins play in bacterial stress resistance against organic peroxides in S. meliloti. The ohr and ohrR genes are expressed in nodule-inhabiting bacteroids suggesting a role during nodulation.
The temporal and spatial expression pattern of the LGI1 epilepsy predisposition gene during mouse embryonic cranial development
Authors: Silva Jeane , Wang Guanghu , Cowell John K
Published: May 2011

Background

Mutations in the LGI1 gene predispose to a rare, hereditary form of temporal epilepsy. Currently, little is known about the temporal and spatial expression pattern of Lgi1 during normal embryogenesis and so to define this more clearly we used a transgenic mouse line that expresses GFP under the control of Lgi1 cis-regulatory elements.

Results

During embryonic brain growth, high levels of Lgi1 expression were found in the surface ectoderm, the neuroepithelium, mesenchymal connective tissue, hippocampus, and sensory organs, such as eye, tongue, and the olfactory bulb. Lgi1 was also found in the cranial nerve nuclei and ganglia, such as vestibular, trigeminal, and dorsal ganglia. Expression of Lgi1 followed an orchestrated pattern during mouse development becoming more subdued in areas of the neocortex of the mid- and hind-brain in early postnatal animals, although high expression levels were retained in the choroid plexus and hippocampus. In late postnatal stages, Lgi1 expression continued to be detected in many areas in the brain including, hippocampus, paraventricular thalamic nuclei, inferior colliculus, and the cerebral aqueduct. We also showed that Lgi1-expressing cells co-express nestin, DCX, and beta-III tubulin suggesting that Lgi1-expressing cells are migratory neuroblasts.

Conclusion

These observations imply that Lgi1 may have a role in establishing normal brain architecture and neuronal functions during brain development suggesting that it may be involved in neurogenesis and neuronal plasticity, which become more specifically defined in the adult animal.
Operationalizing frailty among older residents of assisted living facilities
Authors: Freiheit Elizabeth A , Hogan David B , Strain Laurel A , Schmaltz Heidi N , Patten Scott B , Eliasziw Misha , Maxwell Colleen J
Published: May 2011

Background

Frailty in later life is viewed as a state of heightened vulnerability to poor outcomes. The utility of frailty as a measure of vulnerability in the assisted living (AL) population remains unexplored. We examined the feasibility and predictive accuracy of two different interpretations of the Cardiovascular Health Study (CHS) frailty criteria in a population-based sample of AL residents.

Methods

CHS frailty criteria were operationalized using two different approaches in 928 AL residents from the Alberta Continuing Care Epidemiological Studies (ACCES). Risks of one-year mortality and hospitalization were estimated for those categorized as frail or pre-frail (compared with non-frail). The prognostic significance of individual criteria was explored, and the area under the ROC curve (AUC) was calculated for select models to assess the utility of frailty in predicting one-year outcomes.

Results

Regarding feasibility, complete CHS criteria could not be assessed for 40% of the initial 1,067 residents. Consideration of supplementary items for select criteria reduced this to 12%. Using absolute (CHS-specified) cut-points, 48% of residents were categorized as frail and were at greater risk for death (adjusted risk ratio [RR] 1.75, 95% CI 1.08-2.83) and hospitalization (adjusted RR 1.54, 95% CI 1.20-1.96). Pre-frail residents defined by absolute cut-points (48.6%) showed no increased risk for mortality or hospitalization compared with non-frail residents. Using relative cut-points (derived from AL sample), 19% were defined as frail and 55% as pre-frail and the associated risks for mortality and hospitalization varied by sex. Frail (but not pre-frail) women were more likely to die (RR 1.58 95% CI 1.02-2.44) and be hospitalized (RR 1.53 95% CI 1.25-1.87). Frail and pre-frail men showed an increased mortality risk (RR 3.21 95% CI 1.71-6.00 and RR 2.61 95% CI 1.40-4.85, respectively) while only pre-frail men had an increased risk of hospitalization (RR 1.58 95% CI 1.15-2.17). Although incorporating either frailty measure improved the performance of predictive models, the best AUCs were 0.702 for mortality and 0.633 for hospitalization.

Conclusions

Application of the CHS criteria for frailty was problematic and only marginally improved the prediction of select adverse outcomes in AL residents. Development and validation of alternative approaches for detecting frailty in this population, including consideration of female/male differences, is warranted.
Associations of common polymorphisms in GCKR with type 2 diabetes and related traits in a Han Chinese population: a case-control study
Authors: Ling Yan , Li Xiaomu , Gu Qian , Chen Hongyan , Lu Daru , Gao Xin
Published: May 2011

Background

Several studies have shown that variants in the glucokinase regulatory protein gene (GCKR) were associated with type 2 diabetes and dyslipidemia. The purpose of this study was to examine whether tag single nucleotide polymorphisms (SNPs) in the GCKR region were associated with type 2 diabetes and related traits in a Han Chinese population and to identify the potential mechanisms underlying these associations.

Methods

We investigated the association of polymorphisms in the GCKR gene with type 2 diabetes by employing a case-control study design (1118 cases and 1161 controls). Four tag SNPs (rs8179206, rs2293572, rs3817588 and rs780094) with pairwise r2 > 0.8 and minor allele frequency > 0.05 across the GCKR gene and its flanking regions were studied and haplotypes were constructed. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using a MassARRAY platform.

Results

The G alleles of GCKR rs3817588 and rs780094 were associated with an increased risk of type 2 diabetes after adjustment for year of birth, sex and BMI (OR = 1.24, 95% CI 1.08-1.43, p = 0.002 and OR = 1.22, 95% CI 1.07-1.38, p = 0.002, respectively). In the non-diabetic controls, the GG carriers of rs3817588 and rs780094 were nominally associated with a lower plasma triglyceride level compared to the AA carriers after adjustment for year of birth, sex and BMI (p for trend = 0.00004 and 0.03, respectively). Furthermore, the association of rs3817588 with plasma triglyceride level was still significant after correcting for multiple testing.

Conclusions

The rs3817588 A/G polymorphism of the GCKR gene was associated with type 2 diabetes and plasma triglyceride level in the Han Chinese population.
A 115-bp MethyLight assay for detection of p16 (CDKN2A) methylation as a diagnostic biomarker in human tissues
Authors: Zhou Jing , Cao Jie , Lu Zheming , Liu Hongwei , Deng Dajun
Published: May 2011

Background

p16 Methylation is a potential biomarker for prediction of malignant transformation of epithelial dysplasia. A probe-based, quantitative, methylation-specific PCR (MSP) called MethyLight may become an eligible method for detecting this marker clinically. We studied oral mucosa biopsies with epithelial dysplasia from 78 patients enrolled in a published 4-years' followup cohort, in which cancer risk for patients with p16 methylation-positive dysplasia was significantly higher than those without p16 methylation (by 150-bp MSP and bisulfite sequencing; +133 ~ +283, transcription starting site, +1). The p16 methylation status in samples (N = 102) containing sufficient DNA was analyzed by the 70-bp classic (+238 ~ +307) and 115-bp novel (+157 ~ +272) MethyLight assays, respectively.

Results

p16 Methylation was detectable in 75 samples using the classic MethyLight assay. The methylated-p16 positive rate and proportion of methylated-p16 by the MethyLight in MSP-positive samples were higher than those in MSP-negative samples (positive rate: 37/44 vs. 38/58, P=0.035, two-sided; proportion [median]: 0.78 vs. 0.02, P < 0.007). Using the published results of MSP as a golden standard, we found sensitivity, specificity, and accuracy for this MethyLight assay to be 70.5%, 84.5%, and 55.0%, respectively. Because amplicon of the classic MethyLight procedure only partially overlapped with the MSP amplicon, we further designed a 115-bp novel MethyLight assay in which the amplicon on the sense-strand fully overlapped with the MSP amplicon on the antisense-strand. Using the 115-bp MethyLight assay, we observed methylated-p16 in 26 of 44 MSP-positive samples and 2 of 58 MSP-negative ones (P = 0.000). These results were confirmed with clone sequencing. Sensitivity, specificity, and accuracy using the 115-bp MethyLight assay were 59.1%, 98.3%, and 57.4%, respectively. Significant differences in the oral cancer rate were observed during the followup between patients (≥60 years) with and without methylated-p16 as detected by the 115-bp MethyLight assay (6/8 vs. 6/22, P = 0.034, two-sided).

Conclusions

The 115-bp MethyLight assay is a useful and practical assay with very high specificity for the detection of p16 methylation clinically.
Genes Associated With Prognosis After Surgery For Malignant Pleural Mesothelioma Promote Tumor Cell Survival In Vitro
Authors: Gordon Gavin J , Bueno Raphael , Sugarbaker David J
Published: May 2011

Background

Mesothelioma is an aggressive neoplasm with few effective treatments, one being cytoreductive surgery. We previously described a test, based on differential expression levels of four genes, to predict clinical outcome in prospectively consented mesothelioma patients after surgery. In this study, we determined whether any of these four genes could be linked to a cancer relevant phenotype.

Methods

We conducted a high-throughput RNA inhibition screen to knockdown gene expression levels of the four genes comprising the test (ARHGDIA, COBLL1, PKM2, TM4SF1) in both a human lung-derived normal and a tumor cell line using three different small inhibitory RNA molecules per gene. Successful knockdown was confirmed using quantitative RT-PCR. Detection of statistically significant changes in apoptosis and mitosis was performed using immunological assays and quantified using video-assisted microscopy at a single time-point. Changes in nuclear shape, size, and numbers were used to provide additional support of initial findings. Each experiment was conducted in triplicate. Specificity was assured by requiring that at least 2 different siRNAs produced the observed change in each cell line/time-point/gene/assay combination.

Results

Knockdown of ARHGDIA, COBLL1, and TM4SF1 resulted in 2- to 4-fold increased levels of apoptosis in normal cells (ARHGDIA only) and tumor cells (all three genes). No statistically significant changes were observed in apoptosis after knockdown of PKM2 or for mitosis after knockdown of any gene.

Conclusions

We provide evidence that ARHGDIA, COBLL1, and TM4SF1 are negative regulators of apoptosis in cultured tumor cells. These genes, and their related intracellular signaling pathways, may represent potential therapeutic targets in mesothelioma.
Genotypic tropism testing by massively parallel sequencing: qualitative and quantitative analysis
Authors: Däumer Martin , Kaiser Rolf , Klein Rolf , Lengauer Thomas , Thiele Bernhard , Thielen Alexander
Published: May 2011

Background

Inferring viral tropism from genotype is a fast and inexpensive alternative to phenotypic testing. While being highly predictive when performed on clonal samples, sensitivity of predicting CXCR4-using (X4) variants drops substantially in clinical isolates. This is mainly attributed to minor variants not detected by standard bulk-sequencing. Massively parallel sequencing (MPS) detects single clones thereby being much more sensitive. Using this technology we wanted to improve genotypic prediction of coreceptor usage.

Methods

Plasma samples from 55 antiretroviral-treated patients tested for coreceptor usage with the Monogram Trofile Assay were sequenced with standard population-based approaches. Fourteen of these samples were selected for further analysis with MPS. Tropism was predicted from each sequence with geno2pheno[coreceptor].

Results

Prediction based on bulk-sequencing yielded 59.1% sensitivity and 90.9% specificity compared to the trofile assay. With MPS, 7600 reads were generated on average per isolate. Minorities of sequences with high confidence in CXCR4-usage were found in all samples, irrespective of phenotype. When using the default false-positive-rate of geno2pheno[coreceptor](10%), and defining a minority cutoff of 5%, the results were concordant in all but one isolate.

Conclusions

The combination of MPS and coreceptor usage prediction results in a fast and accurate alternative to phenotypic assays. The detection of X4-viruses in all isolates suggests that coreceptor usage as well as fitness of minorities is important for therapy outcome. The high sensitivity of this technology in combination with a quantitative description of the viral population may allow implementing meaningful cutoffs for predicting response to CCR5-antagonists in the presence of X4-minorities.