bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired lung compliance andDL,CObut no restrictive ventilatory defect in sarcoidosis
Authors: Boros P.W. , Enright P.L. , Quanjer P.H. , Borsboom G.J.J.M. , Wesolowski S.P. , Hyatt R.E.
Published: April 2010

Sarcoidosis is a systemic granulomatous disease with predominant manifestation in the lungs, often presenting as interstitial lung disease. Pulmonary function abnormalities in sarcoidosis include restriction of lung volumes, reduction in diffusing capacity of the lung for carbon monoxide (DL,CO), reduced static lung compliance (CL,s) and airway obstruction. The aim of the present study was to assess various lung function indices, includingCL,sandDL,CO, as markers of functional abnormality in sarcoidosis patients.

Results from 830 consecutive patients referred for lung function tests with a diagnosis of sarcoidosis (223 in stage I, 486 in stage II and 121 in stage III) were retreospectively analysed. The mean±sdage of the patients was 40±11 yrs; 18% were active smokers and 24% were former smokers.

Normal total lung capacity was found in 772 (93%) patients. Of these cases, 24.5% had a lowCL,sand 21.5% had a lowDL,CO. At least one abnormality was observed in 39.3% of these patients, whereas, in restrictive patients, this figure was 88%. Airway obstruction was present in 11.7% of cases.

Lung volumes usually remain within the normal range and measurement of eitherCL,sorDL,COoften reveal impaired lung function in sarcoidosis patients, even when their lung volumes are still in the normal range; these two measurements provide complementary information.
Optimization algorithms for functional deimmunization of therapeutic proteins
Authors: Parker Andrew S , Zheng Wei , Griswold Karl E , Bailey-Kellogg Chris
Published: April 2010

Background

To develop protein therapeutics from exogenous sources, it is necessary to mitigate the risks of eliciting an anti-biotherapeutic immune response. A key aspect of the response is the recognition and surface display by antigen-presenting cells of epitopes, short peptide fragments derived from the foreign protein. Thus, developing minimal-epitope variants represents a powerful approach to deimmunizing protein therapeutics. Critically, mutations selected to reduce immunogenicity must not interfere with the protein's therapeutic activity.

Results

This paper develops methods to improve the likelihood of simultaneously reducing the anti-biotherapeutic immune response while maintaining therapeutic activity. A dynamic programming approach identifies optimal and near-optimal sets of conservative point mutations to minimize the occurrence of predicted T-cell epitopes in a target protein. In contrast with existing methods, those described here integrate analysis of immunogenicity and stability/activity, are broadly applicable to any protein class, guarantee global optimality, and provide sufficient flexibility for users to limit the total number of mutations and target MHC alleles of interest. The input is simply the primary amino acid sequence of the therapeutic candidate, although crystal structures and protein family sequence alignments may also be input when available. The output is a scored list of sets of point mutations predicted to reduce the protein's immunogenicity while maintaining structure and function. We demonstrate the effectiveness of our approach in a number of case study applications, showing that, in general, our best variants are predicted to be better than those produced by previous deimmunization efforts in terms of either immunogenicity or stability, or both factors.

Conclusions

By developing global optimization algorithms leveraging well-established immunogenicity and stability prediction techniques, we provide the protein engineer with a mechanism for exploring the favorable sequence space near a targeted protein therapeutic. Our mechanism not only helps identify designs more likely to be effective, but also provides insights into the interrelated implications of design choices.
Relative roles of the different Pax6 domains for pancreatic alpha cell development
Authors: Dames Petra , Puff Ramona , Weise Michaela , Parhofer Klaus G , Göke Burkhard , Götz Magdalena , Graw Jochen , Favor Jack , Lechner Andreas
Published: April 2010

Background

The transcription factor Pax6 functions in the specification and maintenance of the differentiated cell lineages in the endocrine pancreas. It has two DNA binding domains, the paired domain and the homeodomain, in addition to a C-terminal transactivation domain. The phenotype of Pax6-/- knockout mice suggests non-redundant functions of the transcription factor in the development of glucagon-expressing α-cells as this cell type is absent in the mutants. We ask the question of how the differentiation of pancreatic endocrine cells, in particular that of α-cells, is affected by selective inactivation of either one of the three major domains of Pax6.

Results

The Pax6Aey18 mutant mouse line, in which the paired domain is inactivated, showed a phenotype similar to that of Pax6-/- knockout mice with a near complete absence of glucagon-positive α-cells (0-4 cells/section; ≤1% of wt), reduced β-cell area (74% of wt) and disorganized islets. The proportion of ghrelin-positive ε-cells was expanded. In Pax6Sey-Neu mutants, which lack the transactivation domain, α-and β-cells where reduced to 25 and 40% of wt, respectively. We also studied two mouse lines with mutations in the homeodomain, Pax64Neu and Pax6132-14Neu. Neighboring amino acids are affected in the two lines and both point mutations abolish DNA binding of the classical P3 homeodomain target sequence. The pancreatic phenotype of the two mutants however was divergent. While Pax64Neu homozygotes showed a reduction of α- and β-cells to 59 and 61%, respectively, pancreatic endocrine development was unaltered in the Pax6132-14Neu mutant strain.

Conclusions

We show that inactivation of the Pax6 paired domain leads to a more severe phenotype with regards to the differentiation of pancreatic α-cells than the loss of the transactivation domain. The analysis of two different homeodomain mutants suggests that the binding of Pax6 to P3 homeodomain consensus sequences is not required for α-cell development. It rather seems that the homeodomain has a modulating role in Pax6 function, possibly by facilitating a PH0-like binding confirmation on paired domain target genes like proglucagon. This function is differentially affected by the two homeodomain mutations analyzed in this study.
Identification of copy number variations and common deletion polymorphisms in cattle
Authors: Bae Joon Seol , Cheong Hyun Sub , Kim Lyoung Hyo , NamGung Suk , Park Tae Joon , Chun Ji-Yong , Kim Jason Yongha , Pasaje Charisse Flerida A , Lee Jin Sol , Shin Hyoung Doo
Published: April 2010

Background

Recently, the discovery of copy number variation (CNV) led researchers to think that there are more variations of genomic DNA than initially believed. Moreover, a certain CNV region has been found to be associated with the onset of diseases. Therefore, CNV is now known as an important genomic variation in biological mechanisms. However, most CNV studies have only involved the human genome. The study of CNV involving other animals, including cattle, is severely lacking.

Results

In our study of cattle, we used Illumina BovineSNP50 BeadChip (54,001 markers) to obtain each marker's signal intensity (Log R ratio) and allelic intensity (B allele frequency), which led to our discovery of 855 bovine CNVs from 265 cows. For these animals, the average number of CNVs was 3.2, average size was 149.8 kb, and median size was 171.5 kb. Taking into consideration some overlapping regions among the identified bovine CNVs, 368 unique CNV regions were detected. Among them, there were 76 common CNVRs with > 1% CNV frequency. Together, these CNVRs contained 538 genes. Heritability errors of 156 bovine pedigrees and comparative pairwise analyses were analyzed to detect 448 common deletion polymorphisms. Identified variations in this study were successfully validated using visual examination of the genoplot image, Mendelian inconsistency, another CNV identification program, and quantitative PCR.

Conclusions

In this study, we describe a map of bovine CNVs and provide important resources for future bovine genome research. This result will contribute to animal breeding and protection from diseases with the aid of genomic information.
A scenario of mitochondrial genome evolution in maize based on rearrangement events
Authors: Darracq Aude , Varré Jean-Stéphane , Touzet Pascal
Published: April 2010

Background

Despite their monophyletic origin, animal and plant mitochondrial genomes have been described as exhibiting different modes of evolution. Indeed, plant mitochondrial genomes feature a larger size, a lower mutation rate and more rearrangements than their animal counterparts. Gene order variation in animal mitochondrial genomes is often described as being due to translocation and inversion events, but tandem duplication followed by loss has also been proposed as an alternative process. In plant mitochondrial genomes, at the species level, gene shuffling and duplicate occurrence are such that no clear phylogeny has ever been identified, when considering genome structure variation.

Results

In this study we analyzed the whole sequences of eight mitochondrial genomes from maize and teosintes in order to comprehend the events that led to their structural features, i.e. the order of genes, tRNAs, rRNAs, ORFs, pseudogenes and non-coding sequences shared by all mitogenomes and duplicate occurrences. We suggest a tandem duplication model similar to the one described in animals, except that some duplicates can remain. This model enabled us to develop a manual method to deal with duplicates, a recurrent problem in rearrangement analyses. The phylogenetic tree exclusively based on rearrangement and duplication events is congruent with the tree based on sequence polymorphism, validating our evolution model.

Conclusions

This study suggests more similarity than usually reported between plant and animal mitochondrial genomes in their mode of evolution. Further work will consist of developing new tools in order to automatically look for signatures of tandem duplication events in other plant mitogenomes and evaluate the occurrence of this process on a larger scale.
Evolutionary conservation of essential and highly expressed genes in Pseudomonas aeruginosa
Authors: Dötsch Andreas , Klawonn Frank , Jarek Michael , Scharfe Maren , Blöcker Helmut , Häussler Susanne
Published: April 2010

Background

The constant increase in development and spread of bacterial resistance to antibiotics poses a serious threat to human health. New sequencing technologies are now on the horizon that will yield massive increases in our capacity for DNA sequencing and will revolutionize the drug discovery process. Since essential genes are promising novel antibiotic targets, the prediction of gene essentiality based on genomic information has become a major focus.

Results

In this study we demonstrate that pooled sequencing is applicable for the analysis of sequence variations of strain collections with more than 10 individual isolates. Pooled sequencing of 36 clinicalPseudomonas aeruginosaisolates revealed that essential and highly expressed proteins evolve at lower rates, whereas extracellular proteins evolve at higher rates. We furthermore refined the list of experimentally essentialP. aeruginosagenes, and identified 980 genes that show no sequence variation at all. Among the conserved nonessential genes we found several that are involved in regulation, motility and virulence, indicating that they represent factors of evolutionary importance for the lifestyle of a successful environmental bacterium and opportunistic pathogen.

Conclusion

The detailed analysis of a comprehensive set ofP. aeruginosagenomes in this study clearly disclosed detailed information of the genomic makeup and revealed a large set of highly conserved genes that play an important role for the lifestyle of this microorganism. Sequencing strain collections enables for a detailed and extensive identification of sequence variations as potential bacterial adaptation processes, e.g., during the development of antibiotic resistance in the clinical setting and thus may be the basis to uncover putative targets for novel treatment strategies.
Gauging knowledge of developmental milestones among Albertan adults: a cross-sectional survey
Authors: Rikhy Shivani , Tough Suzanne , Trute Barry , Benzies Karen , Kehler Heather , Johnston David W
Published: April 2010

Background

Parental knowledge of child development has been associated with more effective parenting strategies and better child outcomes. However, little is known about what adults who interact with children under the age of 14 years know about child development.

Methods

Between September 2007 and March 2008, computer assisted telephone interviews were completed with 1443 randomly selected adults. Adults were eligible if they had interacted with a child less than 14 years of age in the past six months and lived in Alberta, Canada.

Results

Sixty three percent of respondents answered two (or more) out of four questions on physical development correctly. Fifteen percent of respondents answered two (or more) out of three questions on cognitive development correctly. Seven percent of respondents answered three (or more) out of five questions on social development correctly. Two percent of respondents answered three (or more) out of five questions on emotional development correctly. Parents and females were better able to identify physical developmental milestones compared to non-parents and males. 81% of adults correctly responded that a child's experience in the first year of life has an important impact on later school performance, 70% correctly responded that a child's ability to learn is not set from birth, 50% of adults correctly responded that children learn more from hearing someone speak than from television, and 45% recognized that parents' emotional closeness with a baby influences later achievement. Parents were most likely to use doctors/paediatricians, books, and nurses as resources. Among parents, there was no relationship between knowledge and parenting morale.

Conclusions

The majority of adults were unable to correctly answer questions related to when children under six years of age typically achieve developmental milestones. Knowledge of physical development exceeded knowledge about cognitive, emotional and social development. Adults were aware of the importance of positive experiences in influencing children's development. Strategies to improve awareness of developmental milestones combined with information on how to support optimal development may improve child development outcomes. Given that parents seek information about child development from health care providers there is an opportunity to ensure that providers are well informed about child development.
Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma
Authors: Tsuchiya Masato , Parker Joel S. , Kono Hiroshi , Matsuda Masanori , Fujii Hideki , Rusyn Ivan
Published: April 2010

Background

The goal of this study was to understand gene expression signatures of hepatocellular carcinoma (HCC) recurrence in subjects with hepatitis C virus (HCV) infection. Recurrence-free survival (RFS) following curative resection of HCC in subjects with HCV is highly variable. Traditional clinico-pathological endpoints are recognized as weak predictors of RFS. It has been suggested that gene expression profiling of HCC and nontumoral liver tissue may improve prediction of RFS, aid in understanding of the underlying liver disease, and guide individualized patient management. Frozen samples of the tumors and nontumoral liver were obtained from 47 subjects with HCV-associated HCC. Additional nontumoral liver samples were obtained from HCV-free subjects with metastatic liver tumors. Gene expression profiling data was used to determine the molecular signature of HCV-associated HCC and to develop a predictor of RFS.

Results

The molecular profile of the HCV-associated HCC confirmed central roles for MYC and TGFβ1 in liver tumor development. Gene expression in tumors was found to have poor predictive power with regards to RFS, but analysis of nontumoral tissues yielded a strong predictor for RFS in late-recurring (>1 year) subjects. Importantly, nontumoral tissue-derived gene expression predictor of RFS was highly significant in both univariable and multivariable Cox proportional hazard model analyses.

Conclusions

Microarray analysis of the nontumoral tissues from subjects with HCV-associated HCC delivers novel molecular signatures of RFS, especially among the late-recurrence subjects. The gene expression predictor may hold important insights into the pathobiology of HCC recurrence andde novotumor formation in cirrhotic patients.
Methodological constraints in interpreting serum paraoxonase-1 activity measurements: an example from a study in HIV-infected patients
Authors: Parra Sandra , Marsillach Judit , Aragonès Gerard , Rull Anna , Beltrán-Debón Raúl , Alonso-Villaverde Carlos , Joven Jorge , Camps Jordi
Published: April 2010

Background

Paraoxonase-1 (PON1) is an antioxidant enzyme that attenuates the production of the monocyte chemoattractant protein-1 (MCP-1) in vitro. Although oxidation and inflammation are closely related processes, the association between PON1 and MCP-1 has not been completely characterised due, probably, to that the current use of synthetic substrates for PON1 measurement limits the interpretation of the data. In the present study, we explored the relationships between the circulating levels of PON1 and MCP-1 in human immunodeficiency virus-infected patients in relation to the multifunctional capabilities of PON1.

Methods

We measured selected variables in 227 patients and in a control group of 409 participants. Serum PON1 esterase and lactonase activities were measured as the rates of hydrolysis of paraoxon and of 5-(thiobutyl)-butyrolactone, respectively. Oxidised LDL and MCP-1 concentrations were determined by enzyme-linked immunosorbent assay. High-density lipoproteins cholesterol, apolipoprotein A-I, and C-reactive protein concentrations were measured by standard automated methods.

Results

There were significant relationships between PON1 activity and several indices of oxidation and inflammation in control subjects and in infected patients. However, these relationships varied not only with disease status but also on the type of substrate used for PON1 measurement.

Conclusion

The present study is a cautionary tale highlighting that results of clinical studies on PON1 may vary depending on the methods used as well as the disease studied. Until more specific methods using physiologically-akin substrates are developed for PON1 measurement, we suggest the simultaneous employment of at least two different substrates in order to improve the reliability of the results obtained.
Quality prevails over identity in the sexually selected vocalisations of an ageing mammal
Authors: Briefer Elodie , Vannoni Elisabetta , McElligott Alan G
Published: April 2010

Background

Male sexually selected vocalisations generally contain both individuality and quality cues that are crucial in intra- as well as inter-sexual communication. As individuality is a fixed feature whereas male phenotypic quality changes with age, individuality and quality cues may be subjected to different selection pressures over time. Individuality (for example, morphology of the vocal apparatus) and quality (for example, body size and dominance status) can both affect the vocal production mechanism, inducing the same components of vocalisations to convey both kinds of information. In this case, do quality-related changes to the acoustic structure of calls induce a modification of vocal cues to identity from year to year? We investigated this question in fallow deer (Dama dama), in which some acoustic parameters of vocalisations (groans) code for both individuality and quality.

Results

We carried out a longitudinal analysis of groan individuality, examining the effects of age and dominance rank on the acoustic structure of groans of the same males recorded during consecutive years. We found both age- and rank-related changes to groans; the minimum values of the highest formant frequencies and the fundamental frequency increased with the age of males and they decreased when males became more dominant. Both age- and rank-related acoustic parameters contributed to individuality. Male quality changed with age, inducing a change in quality-related parameters and thus, a modification of vocal cues to male individuality between years.

Conclusions

The encoding of individuality and quality information in the same components of vocalisations induces a tradeoff between these two kinds of signals over time. Fallow deer vocalisations are honest signals of quality that are not fixed over time but are modified dynamically according to male quality. As they are more reliable cues to quality than to individuality, they may not be used by conspecifics to recognize a given male from one year to another, but potentially used by both sexes to assess male quality during each breeding season.
Limelight on two HIV/SIV accessory proteins in macrophage infection: Is Vpx overshadowing Vpr?
Authors: Ayinde Diana , Maudet Claire , Transy Catherine , Margottin-Goguet Florence
Published: April 2010

HIV viruses encode a set of accessory proteins, which are important determinants of virulence due to their ability to manipulate the host cell physiology for the benefit of the virus. Although these viral proteins are dispensable for viral growth in manyin vitrocell culture systems, they influence the efficiency of viral replication in certain cell types. Macrophages are early targets of HIV infection which play a major role in viral dissemination and persistence in the organism. This review focuses on two HIV accessory proteins whose functions might be more specifically related to macrophage infection: Vpr, which is conserved across primate lentiviruses including HIV-1 and HIV-2, and Vpx, a protein genetically related to Vpr, which is unique to HIV-2 and a subset of simian lentiviruses. Recent studies suggest that both Vpr and Vpx exploit the host ubiquitination machinery in order to inactivate specific cellular proteins. We review here why it remains difficult to decipher the role of Vpr in macrophage infection by HIV-1 and how recent data underscore the ability of Vpx to antagonize a restriction factor which counteracts synthesis of viral DNA in monocytic cells.
Circulating omentin concentration increases after weight loss
Authors: Moreno-Navarrete José María , Catalán Victoria , Ortega Francisco , Gómez-Ambrosi Javier , Ricart Wifredo , Frühbeck Gema , Fernández-Real José Manuel
Published: April 2010

Background

Omentin-1 is a novel adipokine expressed in visceral adipose tissue and negatively associated with insulin resistance and obesity. We aimed to study the effects of weight loss-induced improved insulin sensitivity on circulating omentin concentrations.

Methods

Circulating omentin-1 (ELISA) concentration in association with metabolic variables was measured in 35 obese subjects (18 men, 17 women) before and after hypocaloric weight loss.

Results

Baseline circulating omentin-1 concentrations correlated negatively with BMI (r = -0.58, p < 0.001), body weight (r = -0.35, p = 0.045), fat mass (r = -0.67, p < 0.001), circulating leptin (r = -0.7, p < 0.001) and fasting insulin (r = -0.37, p = 0.03). Circulating omentin-1 concentration increased significantly after weight loss (from 44.9 ± 9.02 to 53.41 ± 8.8 ng/ml, p < 0.001). This increase in circulating omentin after weight loss was associated with improved insulin sensitivity (negatively associated with HOMA value and fasting insulin, r = -0.42, p = 0.02 and r = -0.45, p = 0.01, respectively) and decreased BMI (r = -0.54, p = 0.001).

Conclusion

As previously described with adiponectin, circulating omentin-1 concentrations increase after weight loss-induced improvement of insulin sensitivity.
Spinal Microglial Motility is Independent of Neuronal Activity and Plasticity in Adult Mice
Authors: Chen Tao , Koga Kohei , Li Xiang-Yao , Zhuo Min
Published: April 2010

Microglia are the resident macrophages in the central nervous system. In the spinal cord dorsal horn, microglia stay in resting condition during physiological sensory processing, and are activated under pathological conditions such as peripheral nerve injury. In cases such as this, the nearby resting microglia increase their motility and accumulate at the site of injury. However, direct evidence to support that nerve activity can enhance the motility of microglia has not yet to be reported. In this study we investigated whether the activation of spinal microglia under in vivo nerve injury may be mimicked by neuronal activity in the spinal cord slice preparation. We found that local application of spinal excitatory neurotransmitters, such as glutamate and substance P did not cause any change in the motility of microglial cells in the spinal cord dorsal horn. The motility of microglial cells is unlikely modulated by other transmitters, neuromodulators and chemokines, because similar applications such as GABA, serotonin, noradrenaline, carbachol, fractalkine or interleukin did not produce any obvious effect. Furthermore, low or high frequency stimulation of spinal dorsal root fibers at noxious intensities failed to cause any enhanced extension or retraction of the microglia processes. By contrast, focal application of ATP triggered rapid and robust activation of microglial cells in the spinal dorsal horn. Our results provide the first evidence that the activation of microglia in the spinal cord after nerve injury is unlikely due solely to neuronal activity, non-neuronal factors are likely responsible for the activation of nerve injury-related microglial cells in the spinal dorsal horn.
Type-specific incidence, clearance and predictors of cervical human papillomavirus infections (HPV) among young women: a prospective study in Uganda
Authors: Banura Cecily , Sandin Sven , van Doorn Leen-Jan , Quint Wim , Kleter Bernhard , Wabwire-Mangen Fred , Mbidde Edward K , Weiderpass Elisabete
Published: April 2010

Background

While infections with human papillomavirus (HPV) are highly prevalent among sexually active young women in Uganda, information on incidence, clearance and their associated risk factors is sparse. To estimate the incidence, prevalence and determinants of HPV infections, we conducted a prospective follow-up study among 1,275 women aged 12-24 years at the time of recruitment. Women answered a questionnaire and underwent a pelvic examination at each visit to collect exfoliated cervical cells. The presence of 42 HPV types was evaluated in exfoliated cervical cells by a polymerase chain based (PCR) assay (SPF10-DEIA LiPA).

Results

Three hundred and eighty (380) of 1,275 (29.8%) women were followed up for a median time of 18.5 months (inter-quartile range 9.7-26.6). Sixty-nine (69) women had incident HPV infections during 226 person-years of follow-up reflecting an incidence rate of 30.5 per 100 person-years. Incident HPV infections were marginally associated with HIV positivity (RR = 2.8, 95% CI: 0.9 - 8.3). Clearance for HPV type-specific infections was frequent ranging between 42.3% and 100.0% for high- and 50% and 100% for low-risk types. Only 31.2% of women cleared all their infections. Clearance was associated with HIV negativity (Adjusted clearance = 0.2, 95% CI: 0.1 - 0.7) but not with age at study entry, lifetime number of sexual partners and multiplicity of infections. The prevalence of low-grade squamous intraepithelial lesions (LSILs) was 53/365 (14.5%). None of the women had a high-grade cervical lesion (HSIL) or cancer. Twenty-two (22) of 150 (14.7%) HPV negative women at baseline developed incident LSIL during follow-up. The risk for LSIL appeared to be elevated among women with HPV 18-related types compared to women not infected with those types (RR = 3.5, 95% CI: 1.0 - 11.8).

Conclusions

Incident HPV infections and type-specific HPV clearance were frequent among our study population of young women. These results underscore the need to vaccinate pre-adolescent girls before initiation of sexual activity.
Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes
Authors: Rosengren Sanna , Corr Maripat , Boyle David L
Published: April 2010

Introduction

The objective of this study was to model the effects of transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast-like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1β, tumor necrosis factor-alpha (TNFα)) challenge.

Methods

Gene and protein expression by fibroblast-like synoviocytesin vitrowas studied by quantitative Polymerase Chain Reaction (qPCR), ELISA and multiplex bead cytokine assays. Intracellular signaling pathway activation was determined by Western blot for phospho-kinases and the use of specific inhibitors.

Results

In combination, TGF-β and PDGF (2GF) synergistically augmented TNFα- or IL1β-induced matrix metalloproteinase 3 (MMP3), IL6, IL8, and macrophage inflammatory protein 1 alpha (MIP1α) secretion by FLS. Other FLS-derived mediators remained unaffected. Individually, neither growth factor significantly potentiated TNFα or IL1β-induced MMP3 secretion, and only slightly enhanced IL6. The effect of 2GF on TNFα-induced gene expression was transcriptionally mediated; blocked by imatinib mesylate; and occurred even if 2GF was added as much as four hours prior to TNFα. In addition, a 15-minute pulse of 2GF four hours prior to TNFα stimulation yielded a synergistic response. The extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling pathways were induced for at least four hours by 2GF, as demonstrated by persistently upregulated levels of phospho-Akt and phospho-ERK. However, pharmacologic inhibitor studies demonstrated that the potentiating action of 2GF was dependent on PI3 kinase only, and not on ERK.

Conclusions

The combination of PDGF and TGF-β dramatically potentiates FLS response to cytokines in a receptor-mediated and PI3 kinase-dependent fashion. These data suggest that 2GF contribute to synovitis by directing synovial fibroblasts toward a more aggressive phenotype in response to TNFα. Therefore, inhibition of growth factor signaling may constitute a complementary therapeutic approach to cytokine-targeted treatments for RA.
Nicotine withdrawal and agitation in ventilated critically ill patients
Authors: Lucidarme Olivier , Seguin Amélie , Daubin Cédric , Ramakers Michel , Terzi Nicolas , Beck Patrice , Charbonneau Pierre , du Cheyron Damien
Published: April 2010

Introduction

Smoking is highly addictive, and nicotine abstinence is associated with withdrawal syndrome in hospitalized patients. In this study, we aimed to evaluate the impact of sudden nicotine abstinence on the development of agitation and delirium, and on morbidities and outcomes in critically ill patients who required respiratory support, either noninvasive ventilation or intubation, and mechanical ventilation.

Methods

We conducted a prospective, observational study in two intensive care units (ICUs). The 144 consecutive patients admitted to ICUs and requiring mechanical ventilation for >48 hours were included. Smoking status was assessed at ICU admission by using the Fagerström Test of Nicotine Dependence (FTND). Agitation, with the Sedation-Agitation Scale (SAS), and delirium, with the Intensive Care Delirium Screening Checklist (ICDSC), were tested twice daily during the ICU stay. Agitation and delirium were defined by SAS >4 and ICDSC >4, respectively. Nosocomial complications and outcomes were evaluated.

Results

Smokers (n = 44) were younger and more frequently male and were more likely to have a history of alcoholism and to have septic shock as the reason for ICU admission than were nonsmokers. The incidence of agitation, but not delirium, increased significantly in the smoker group (64% versus 32%; P = 0.0005). Nicotine abstinence was associated with higher incidences of self-removal of tubes and catheters, and with more interventions, including the need for supplemental sedatives, analgesics, neuroleptics, and physical restraints. Sedation-free days, ventilator-free days, length of stay, and mortality in ICUs did not differ between groups. Multivariate analysis identified active smoking (OR, 3.13; 95% CI, 1.45-6.74; P = 0.003) as an independent risk factor for agitation. Based on a subgroup of 56 patients, analysis of 28 pairs of patients (smokers and nonsmokers in a 1:1 ratio) matched for age, gender, and alcoholism status found similar results regarding the role of nicotine withdrawal in increasing the risk of agitation during an ICU stay.

Conclusions

Nicotine withdrawal was associated with agitation and higher morbidities in critically ill patients. These results suggest the need to look specifically at those patients with tobacco dependency by using the FTND in ICU settings. Identifying patients at risk of behavioral disorders may lead to earlier interventions in routine clinical practice.
Fluid substitution in rocks saturated with viscoelastic fluids
Authors: Makarynska Dina , Gurevich Boris , Behura Jyoti , Batzle Mike
Published: April 2010

Heavy oils have high densities and extremely high viscosities, and they exhibit viscoelastic behavior. Traditional rock physics based on Gassmann theory does not apply to materials saturated with viscoelastic fluids. We use an effective-medium approach known as coherent potential approximation (CPA) as an alternative fluid-substitution scheme for rocks saturated with viscoelastic fluids. Such rocks are modeled as solids with elliptical fluid inclusions when fluid concentration is small and as suspensions of solid particles in the fluid when the solid concentration is small. This approach is consistent with concepts of percolation and critical porosity, and it allows one to model sandstones and unconsolidated sands.We model the viscoelastic properties of a heavy-oil-saturated rock sample using CPA and a measured frequency-dependent complex shear modulus of the heavy oil. Comparison of modeled results with measured properties of the heavy-oil rock reveals a large discrepancy over a range of frequencies and temperatures. We modify the CPA scheme to account for the effect of binary pore structure by introducing a compliant porosity term. This dramatically improves the predictions. The predicted values of the effective shear modulus of the rock are in good agreement with laboratory data for the range of frequencies and temperatures. This confirms that our scheme realistically estimates the frequency- and temperature-dependent properties of heavy-oil rocks and can be used as an approximate fluid-substitution approach for rocks saturated with viscoelastic fluids.
Interferometric ground-roll removal: Attenuation of scattered surface waves in single-sensor data
Authors: Halliday David F. , Curtis Andrew , Vermeer Peter , Strobbia Claudio , Glushchenko Anna , van Manen Dirk-Jan , Robertsson Johan O.
Published: April 2010

Land seismic data are contaminated by surface waves (or ground roll). These surface waves are a form of source-generated noise and can be strongly scattered by near-surface heterogeneities. The resulting scattered ground roll can be particularly difficult to separate from the desired reflection data, especially when this scattered ground roll propagates in the crossline direction. We have used seismic interferometry to estimate scattered surface waves, recorded during an exploration seismic survey, between pairs of receiver locations. Where sources and receivers coincide, these interreceiver surface-wave estimates were adaptively subtracted from the data. This predictive-subtraction process can successfully attenuate scattered surface waves while preserving the valuable reflected arrivals, forming a new method of scattered ground-roll attenuation. We refer to this as interferometric ground-roll removal.
Insufficient Luteinizing Hormone-Induced Intracellular Signaling Disrupts Ovulation in Preovulatory Follicles Lacking Estrogen Receptor-β
Authors: Rodriguez Karina F. , Couse John F. , Jayes Friederike L. , Hamilton Katherine J. , Burns Katherine A. , Taniguchi Fuminori , Korach Kenneth S.
Published: April 2010

Gonadotropin-stimulated estrogen receptor-β (ERβ)-null preovulatory follicles exhibit submaximal estradiol production, insufficient acquisition of LH receptor, and attenuated expression of essential ovulatory genes. These observations lead to low ovulatory rates compared with wild-type (WT) follicles. We hypothesize that insufficient LH receptor results in reduced cAMP production after an ovulatory stimulus. Individual preantral follicles were cultured with FSH for 4 d and then induced to ovulate with a single dose of human chorionic gonadotropin (hCG). cAMP levels 1 h after hCG were 50% lower in ERβ-null than WT follicles. To determine whether the lack of LH receptor, and resulting lack of cAMP, could be bypassed by direct activation of adenylyl cyclase, WT and ERβ-null follicles were induced to ovulate with forskolin. Ten micromolar forskolin doubled the ovulatory rate of ERβ-null follicles compared with treatment with hCG (∼50 vs. 25%, respectively). In WT follicles, 10 μm forskolin reduced the ovulation rate compared with hCG (14 vs. 83%, respectively), indicating that high doses of forskolin inhibited WT ovulation. A 10 μm concentration of forskolin induced cAMP levels in ERβ-null follicles that were comparable to levels produced in WT follicles after hCG and either partially or completely rescued the attenuated expression of LH-responsive genes. These data indicate that direct activation of adenylyl cyclase, resulting in increased production of cAMP, partially rescues the ovulatory response of ERβ-null follicles, suggesting that insufficient LH receptor and low cAMP levels contribute to their poor ovulatory rates. We also determined that ERβ-null ovaries exhibit an alteration in the activation of ERK1/2. Our evaluation of the ERβ-null ovarian phenotype indicates that ERβ plays a role in facilitating folliculogenesis. We show that expression of ERβ in preovulatory follicles is required for adequate cAMP production and propose that an optimal level of cAMP is required for hCG-stimulated ovulation.
Do stigma and other perceived barriers to mental health care differ across Armed Forces?
Authors: Gould Matthew , Adler Amy , Zamorski Mark , Castro Carl , Hanily Natalie , Steele Nicole , Kearney Steve , Greenberg Neil
Published: April 2010

Summary

Objectives

Military organizations are keen to address barriers to mental health care yet stigma and barriers to care remain little understood, especially potential cultural differences between Armed Forces. The aim of this study was to compare data collected by the US, UK, Australian, New Zealand and Canadian militaries using Hoge et al.'s perceived stigma and barriers to care measure (Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. New Engl J Med 2004;351:13–22).

Design

Each member country identified data sources that had enquired about Hoge et al.'s perceived stigma and perceived barriers to care items in the re-deployment or immediate post-deployment period. Five relevant statements were included in the study.

Setting

US, UK Australian, New Zealand and Canadian Armed Forces.

Results

Concerns about stigma and barriers to care tended to be more prominent among personnel who met criteria for a mental health problem. The pattern of reported stigma and barriers to care was similar across the Armed Forces of all five nations.

Conclusions

Barriers to care continue to be a major issue for service personnel within Western military forces. Although there are policy, procedural and cultural differences between Armed Forces, the nations studied appear to share some similarities in terms of perceived stigma and barriers to psychological care. Further research to understand patterns of reporting and subgroup differences is required.
Multicriterion Market Segmentation: A New Model, Implementation, and Evaluation
Authors: Liu Ying , Ram Sudha , Lusch Robert F. , Brusco Michael
Published: April 2010

Market segmentation is inherently a multicriterion problem even though it has often been modeled as a single-criterion problem in the traditional marketing literature and in practice. This paper discusses the multicriterion nature of market segmentation and develops a new mathematical model that addresses this issue. A new method for market segmentation based on multiobjective evolutionary algorithms, called MMSEA, is developed. It complements existing segmentation methods by optimizing multiple objectives simultaneously, searching for globally optimal solutions, and approximating a set of Pareto-optimal solutions. We have applied and evaluated this method in two empirical studies for two firms from distinct industries: descriptive segmentation of the cell phone service market from a dual-value creation perspective and predictive segmentation of retail customers based on profit and customer sociodemographic attributes. The results provide decision makers with compelling alternatives and enhanced flexibility currently missing in existing market segmentation methods.
Circulating Immunoreactive Cardiac Troponin Forms Determined by Gel Filtration Chromatography after Acute Myocardial Infarction
Authors: Bates Katharine J , Hall Elizabeth M , Fahie-Wilson Michael N , Kindler Heiko , Bailey Clare , Lythall David , Lamb Edmund J
Published: April 2010

Background: Cardiac troponin I (cTnI) and cTnT measurements are used in the diagnosis of acute myocardial infarction (AMI). Together with troponin C (TnC), the cTnI and cTnT forms make up the ternary cTnT-cTnI-TnC (TIC) complex found within myocardium. Whether cTn occurs in the circulation after AMI as ternary TIC, binary cTnI-TnC (IC) complexes, or free troponin forms has not been thoroughly investigated.

Methods: Blood samples from 10 AMI patients were collected at hospital admission and then at 12, 24, and 48 h after onset of chest pain. Serum was subjected to gel filtration chromatography and cTnT (Roche cTnT) and cTnI (Siemens Centaur UltraTnI and Beckman Access AccuTnI) concentrations were measured in the gel filtration chromatography fractions.

Results: cTnT was present predominantly as free cTnT and cTnI as binary IC complex. These 2 forms were present at every time point. Lesser quantities of TIC complex (6%–32% of total cTnT and <50% of total cTnI) were detected in 4 patients at varying times. Minor quantities of a high molecular mass form of cTnI were detected occasionally. No free cTnI was found. Both cTnI assays identified a similar pattern of cTnI forms.

Conclusions: After AMI, cTnI is present in serum as TIC and IC complexes. cTnT may be present as a combination of TIC and free cTnT or exclusively as free cTnT.
Robust MicroRNA Stability in Degraded RNA Preparations from Human Tissue and Cell Samples
Authors: Jung Monika , Schaefer Annika , Steiner Isabel , Kempkensteffen Carsten , Stephan Carsten , Erbersdobler Andreas , Jung Klaus
Published: April 2010

Background: RNA integrity is the essential factor that determines the accuracy of mRNA transcript measurements obtained with quantitative real-time reverse-transcription PCR (RT-qPCR), but evidence is clearly lacking on whether this conclusion also applies to microRNAs (miRNAs). We evaluated this issue by comparative analysis of the dependence of miRNA and mRNA measurements on RNA integrity in renal and prostate samples, under both model and clinical conditions.

Methods: Samples of total RNA isolated from human renal tissue and Caki-2 cells, as well as from prostate tissue and LNCaP cells, were incubated at 80 °C for 5–240 min. We subsequently determined the RNA integrity number (RIN) and used RT-qPCR to measure various miRNAs (miR-141, miR-155, miR-200c, and miR-210 in renal samples, and miR-96, miR-130b, miR-149, miR-205, and miR-222 in prostate samples). We similarly measured mRNAs encoded by CDH16 (cadherin 16, KSP-cadherin), PPIA [peptidylprolyl isomerase A (cycophilin A)], and TBP (TATA box binding protein) in renal samples, and HIF1A [hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)], HPRT1 (hypoxanthine phosphoribosyltransferase 1), and KLK3 (kallikrein-related peptidase 3; also known as PSA) in prostate samples. Additionally, we quantified selected miRNAs and mRNAs in samples of RNAs with different RIN values that we isolated from clinical samples. The effect of RIN on the miRNA and mRNA data was assessed by linear regression analysis and group comparison.

Results: The heat-incubation experiments of cell line and tissue RNAs showed that RIN values had negligible or no effect on miRNA results, whereas all mRNAs gradually decreased with decreasing RIN values. These findings were corroborated by our findings with clinical samples.

Conclusions: Our results suggest the stability of miRNAs to be generally robust, which makes feasible accurate miRNA measurements with RT-qPCR, even in degraded RNA preparations for which reliable mRNA analyses are commonly inapplicable.
Autism, Music, and the Therapeutic Potential of Music in Alexithymia
Authors: Allen Rory , Heaton Pamela
Published: April 2010

IT HAS BEEN ARGUED, IN VIEW OF THE SOCIAL evolutionary origins of music and the social deficits found in autism, that individuals with autism will be emotionally unresponsive to music. However, a recent study of high-functioning adults with autism has shown that they appear to have a range of responses to music similar to typically developing people, including the deliberate use of music for mood management. In examining why these responses appear unaffected in autism, we explore possible mechanisms for musical mood induction in listeners, hypothesizing that the simulation theory of empathy may illuminate current controversies over the nature of emotion in music. Drawing on these ideas, we put forward suggestions for using a simple associative learning process between musically induced emotions and their cognitive correlates for the clinical treatment of alexithymia, a disorder that is common in autism and characterized by an absence of cognitive insight into one's emotions.
Music-Supported Training is More Efficient than Functional Motor Training for Recovery of Fine Motor Skills in Stroke Patients
Authors: Schneider Sabine , Münte Thomas , Rodriguez-Fornells Antoni , Sailer Michael , Altenmüller Eckart
Published: April 2010

MOTOR IMPAIRMENTS ARE COMMON AFTER STROKE but efficacious therapies for these dysfunctions are scarce. Extending an earlier study on the effects of music-supported training (MST), behavioral indices of motor function were obtained before and after a series of training sessions to assess whether this new treatment leads to improved motor functions. Furthermore, music-supported training was contrasted to functional motor training according to the principles of constraint-induced therapy (CIT). In addition to conventional physiotherapy, 32 stroke patients with moderately impaired motor function and no previous musical experience received 15 sessions of MST over a period of three weeks, using a manualized, step-bystep approach. A control group consisting of 15 patients received 15 sessions of CIT in addition to conventional physiotherapy. A third group of 30 patients received exclusively conventional physiotherapy and served as a control group for the other three groups. Fine as well as gross motor skills were trained by using either a MIDI-piano or electronic drum pads programmed to emit piano tones. Motor functions were assessed by an extensive test battery. MST yielded significant improvement in fine as well as gross motor skills with respect to speed, precision, and smoothness of movements. These improvements were greater than after CIT or conventional physiotherapy. In conclusion, with equal treatment intensity, MST leads to more pronounced improvements of motor functions after stroke than CIT.