bluuebunny/crossref_metadata_2025 huggingface dataset:
In Favor of Clear Thinking: Incorporating Moral Rules Into a Wise Cost-Benefit Analysis—Commentary on Bennis, Medin, & Bartels (2010)
Authors: Bazerman Max H. , D. Greene Joshua
Published: March 2010

Bennis, Medin, and Bartels (2010, this issue) have contributed an interesting article on the comparative benefit of moral rules versus cost-benefit analysis (CBA). Many of their specific comments are accurate, useful, and insightful. At the same time, we believe they have misrepresented CBA and have reached a set of conclusions that are misguided and, if adopted wholesale, potentially dangerous. Overall, they offer wise suggestions for making CBA more effective, rather than eliminating CBA as a decision-making tool.
Sera from patients with Crohn’s disease break bacterial lipopolysaccharide tolerance of human intestinal epithelial cells via MD-2 activity
Authors: Seksik Philippe , Sokol Harry , Grondin Virginie , Adrie Christophe , Duboc Henri , Pigneur Benedicte , Thomas Ginette , Beaugerie Laurent , Trugnan Germain , Masliah Joelle , Bachelet Maria
Published: March 2010

Myeloid differentiation (MD)-2 is linked to the cell surface as a Toll-like receptor (TLR) 4-bound protein though may also function as a soluble receptor to enable the lipopolysaccharide (LPS)-driven response. We recently demonstrated the importance of MD-2 either as a cell-associated or as a soluble receptor in the control of intestinal epithelial cell response toward LPS. High levels of circulating MD-2 were recently proposed as a risk factor for infectious/ inflammatory diseases as septic shock. We hypothesized that MD-2 might be present in sera from patients with inflammatory bowel disease and have pathogenic consequences. We analysed MD-2 activity in sera from patients with inflammatory bowel disease or from healthy subjects. We measured MD-2 activity as the capacity to mediate LPS-driven stimulation of intestinal epithelial cells (HT29). We found that sera from patients with inflammatory bowel disease, particularly Crohn’s disease, endowed HT29 cells with a markedly higher LPS-dependent stimulating capacity as compared to sera from healthy subjects. The effect of sera was specific for LPS activation and was reduced in the presence of anti-MD-2, and anti-TLR4 antibodies. We conclude that sera from patients with inflammatory bowel disease might contain increased MD-2. This might result in higher local availability of the protein leading to a loss of tolerance toward gut microbiota.
Review: The intersection of surfactant homeostasis and innate host defense of the lung: lessons from newborn infants
Authors: Whitsett Jeffrey A.
Published: March 2010

The study of pulmonary surfactant, directed towards prevention and treatment of respiratory distress syndrome in preterm infants, led to the identification of novel proteins/genes that determine the synthesis, packaging, secretion, function, and catabolism of alveolar surfactant. The surfactant proteins, SP-A, SP-B, SP-C, and SP-D, and the surfactant lipid associated transporter, ABCA3, play critical roles in surfactant homeostasis. The study of their structure and function provided insight into a system that integrates the biophysical need to reduce surface tension in the alveoli and the innate host defenses required to maintain pulmonary structure and function after birth. Alveolar homeostasis depends on the intrinsic, multifunctional structures of the surfactant-associated proteins and the shared transcriptional regulatory modules that determine both the expression of genes involved in surfactant production as well as those critical for host defense. Identification of the surfactant proteins and the elucidation of the genetic networks regulating alveolar homeostasis have provided the basis for understanding and diagnosing rare and common pulmonary disorders, including respiratory distress syndrome, inherited disorders of surfactant homeostasis, and pulmonary alveolar proteinosis.
A Review of Arthroscopic Bone Marrow Stimulation Techniques of the Talus
Authors: Murawski Christopher D. , Foo Li Foong , Kennedy John G.
Published: March 2010

Osteochondral lesions of the talus are common injuries following acute and chronic ankle sprains. Numerous surgical treatment strategies have been employed for treating these lesions; arthroscopic bone marrow stimulation is recognized as the first-line technique to provide fibrocartilage infill of the defect site. While the short- and medium-term outcomes of this technique are good, the long-term outcomes are not yet known. An increasing number of studies, however, show a cause for concern in employing this technique, including declining outcome scores over time. The current authors have therefore developed a treatment strategy based on previously established guidelines in addition to morphological cartilage-sensitive fast spin echo techniques and quantitative T2 mapping magnetic resonance imaging (MRI). Accordingly, the authors advocate arthroscopic bone marrow stimulation in lesion sizes up to 8 mm in diameter and osteochondral autograft transplant (OATS) in lesion sizes greater than 8 mm in diameter. In the absence of long-term studies, confining the use of arthroscopic bone marrow stimulation to smaller lesions may support prolonged joint life by decreasing the rate at which the fibrocartilage ultimately degenerates over time. Employing the OATS procedure in larger lesions has the advantage of replacing “like with like.” The current review examines the role of arthroscopic bone marrow stimulation techniques of the talus.
Augmentation Strategies following the Microfracture Technique for Repair of Focal Chondral Defects
Authors: Strauss Eric J. , Barker Joseph U. , Kercher James S. , Cole Brian J. , Mithoefer Kai
Published: March 2010

The operative management of focal chondral lesions continues to be problematic for the treating orthopedic surgeon secondary to the limited regenerative capacity of articular cartilage. Although many treatment options are currently available, none fulfills the criteria for an ideal repair solution, including a hyaline repair tissue that completely fills the defect and integrates well with the surrounding normal cartilage. The microfracture technique is an often-utilized, first-line treatment modality for chondral lesions within the knee, resulting in the formation of a fibrocartilaginous repair tissue with inferior biochemical and biomechanical properties compared to normal hyaline cartilage. Although symptomatic improvement has been shown in the short term, concerns about the durability and longevity of the fibrocartilaginous repair have been raised. In response, a number of strategies and techniques for augmentation of the first-generation microfracture procedure have been introduced in an effort to improve repair tissue characteristics and reduce long-term deterioration. Recent experimental approaches utilize modern tissue-engineering technologies including local supplementation of chondrogenic growth factors, hyaluronic acid, or cytokine modulation. Other second-generation microfracture-based techniques use different types of scaffold-guided in situ chondroinduction. The current article presents a comprehensive overview of both the experimental and early clinical results of these developing microfracture augmentation techniques.
Microfracture
Authors: McIlwraith C. Wayne , Frisbie David D.
Published: March 2010

The therapeutic value of microfracture has been demonstrated in clinical patients. The rationale is that focal penetration of the dense subchondral plate exposes cartilage defects to the benefits of cellular and growth factor influx in addition to improving anchorage of the new tissue to the underlying subchondral bone and, to some extent, the surrounding cartilage. While functional outcomes have been reported, there is a paucity of data on the histological, biochemical, and molecular changes in human patients. This paper reviews 4 basic science studies of microfracture using an equine chondral defect model that gave some insight into possible mechanisms of action and also how the microfracture response could be augmented. In study I, microfracture of full-thickness chondral defects in exercised horses significantly increased the repair tissue volume in the defects at both 4 and 12 months. No adverse effects were seen. In study II, an investigation of the healing of full-thickness chondral defects during the first 8 weeks with or without microfracture demonstrated that microfracture significantly increased type II collagen expression as early as 8 weeks after treatment compared to controls; aggrecan expression was progressively increased during the first 8 weeks but was not significantly enhanced by microfracture. In study III, it was demonstrated that removal of the calcified cartilage layer provided optimal amount and attachment of repair tissue, emphasizing that careful removal of calcified layer is critical during debridement prior to microfracture. Study IV assessed the ability of IL-1ra/IGF-1 combination gene therapy to further modulate repair of microfractured chondral defects. The repair tissue in gene therapy–treated joints demonstrated increased proteoglycan and type II collagen content compared to microfracture alone.
A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE
Authors: Schneppenheim Reinhard , Michiels Jan Jacques , Obser Tobias , Oyen Florian , Pieconka Antje , Schneppenheim Sonja , Will Kerstin , Zieger Barbara , Budde Ulrich
Published: March 2010

Among the different phenotypes of von Willebrand disease (VWD) type 2A, we identified a particular subgroup with a high frequency of 29%, characterized by a relative decrease of large von Willebrand factor (VWF) multimers and decreased A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13)–mediated proteolysis previously described in a single family as VWD type IIE (VWD2A/IIE). Phenotype and genotype of 57 patients from 38 unrelated families displaying a particular multimer pattern resembling the original VWD2A/IIE were studied. Pathogenicity of candidate mutations was confirmed by expression studies and phenotypic characterization of recombinant mutants. Specific mutations were identified in all patients. Twenty-two different mutations, most of them affecting cysteine residues, 17 of them being novel, are clustering mainly in the VWF D3 domain and correlate with the VWD2A/IIE phenotype. An intracellular retention of most mutants and/or a defect of multimerization seem to be the main pathogenic molecular mechanisms. ADAMTS13 proteolysis of mutant VWF was not different from wild-type VWF in a static assay, suggesting that reduced in vivo proteolysis is not an intrinsic property of mutant VWF. Our study identified a distinct VWD subtype with a common molecular background which contributes significantly to the heterogeneous spectrum of VWD.
IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production
Authors: Maeda Kenichiro , Mehta Harshini , Drevets Douglas A. , Coggeshall K. Mark
Published: March 2010

Src homology 2 domain-containing inositol 5-phosphatase (SHIP−/−) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of macrophages, and requires a stimulus present in vivo. The IL-6–rich peritoneal cavity of SHIP−/− mice shows more than 700-fold more immunoglobulin G (IgG) than wild-type, approximately 20% of which is aggregated or in an immune complex and contains B220+ cells that secrete IgG. The SHIP-deficient peritoneal macrophages show evidence of IgG receptor stimulation. Animals lacking both the signal-transducing γ-chain of IgG receptors and SHIP or Ig and SHIP produce less IL-6. The data indicate a feed-forward process in which peripheral macrophages, responding through IgG receptors to secreted IgG, produce IL-6, to support further B-cell production of IgG. Because of the proinflammatory phenotype of SHIP−/− animals, these findings emphasize the importance of IL-6–neutralizing strategies in autoimmune and proinflammatory diseases.
Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool
Authors: Shahani Tina , Lavend'homme Renaud , Luttun Aernout , Saint-Remy Jean-Marie , Peerlinck Kathelijne , Jacquemin Marc
Published: March 2010

Although the liver is known to be the main site of factor VIII (FVIII) production, other organs are probably also important for the regulation of FVIII secretion. However, the study of the regulation of extrahepatic FVIII production has been hampered by the lack of definitive identification of human tissues able to secrete FVIII. Recent studies have shown that lung endothelial cells can synthesize FVIII. We therefore studied the production of FVIII by endothelial cells purified from other vascular beds. Because physiologic stress results in a rapid elevation of FVIII, we also investigated whether endothelial cells can store FVIII and secrete it after treatment with agonists. Microvascular endothelial cells from lung, heart, intestine, and skin as well as endothelial cells from pulmonary artery constitutively secreted FVIII and released it after treatment with phorbol-myristate acetate and epinephrine. By contrast, endothelial cells from the aorta, umbilical artery and umbilical vein did not constitutively secrete FVIII or release it after treatment with agonists, probably because of a lack of FVIII synthesis. Extrahepatic endothelial cells from certain vascular beds therefore appear to be an important FVIII production and storage site with the potential to regulate FVIII secretion in chronic and acute conditions.
Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma
Authors: Kikuchi Jiro , Wada Taeko , Shimizu Rumi , Izumi Tohru , Akutsu Miyuki , Mitsunaga Kanae , Noborio-Hatano Kaoru , Nobuyoshi Masaharu , Ozawa Keiya , Kano Yasuhiko , Furukawa Yusuke
Published: March 2010

Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-κB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8–dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Authors: Krawczyk Connie M. , Holowka Thomas , Sun Jie , Blagih Julianna , Amiel Eyal , DeBerardinis Ralph J. , Cross Justin R. , Jung Euihye , Thompson Craig B. , Jones Russell G. , Pearce Edward J.
Published: March 2010

Dendritic cells (DCs) are key regulators of innate and acquired immunity. The maturation of DCs is directed by signal transduction events downstream of toll-like receptors (TLRs) and other pattern recognition receptors. Here, we demonstrate that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells. This metabolic switch depends on the phosphatidyl inositol 3′-kinase/Akt pathway, is antagonized by the adenosine monophosphate (AMP)–activated protein kinase (AMPK), and is required for DC maturation. The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10. Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses.
An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells
Authors: Kang Jinjoo , Yoo Jaehyuk , Lee Sunju , Tang Wanli , Aguilar Berenice , Ramu Swapnika , Choi Inho , Otu Hasan H. , Shin Jay W. , Dotto G. Paolo , Koh Chester J. , Detmar Michael , Hong Young-Kwon
Published: March 2010

Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may coreside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.
Long-acting β2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD
Authors: de Vries F. , Setakis E. , Zhang B. , van Staa T.P.
Published: March 2010

The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting β2-agonists (LABA), short-acting β2-agonists (SABA) or inhaled corticosteroids (ICS) in general practice.

The study population included β2-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure.

Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.
Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction
Authors: Heijink I.H. , van Oosterhout A. , Kapus A.
Published: March 2010

Impaired airway epithelial barrier function has emerged as a key factor in the pathogenesis of allergic asthma. We aimed to discern the involvement of the epidermal growth factor receptor (EGFR) in allergen-induced epithelial barrier impairment, as we previously observed that house dust mite (HDM) signals through EGFR.

We investigated the junctional integrity of human bronchial epithelial cells using electric cell-substrate impedance sensing and immunofluorescent staining.

HDM induced a rapid, transient fall in epithelial resistance, concomitant with delocalisation of E-cadherin and zona occludens (ZO)-1, and proteolytic cleavage of the latter. EGFR inhibition by AG1478 reduced the HDM-triggered decrease in epithelial resistance and improved restoration of epithelial junctions. Similarly, AG1478 increased epithelial barrier recovery upon electroporation-induced injury, although it delayed the migration phase of the wound healing response. HDM-promoted redistribution of E-cadherin was mediatedviaEGFR-dependent activation of protease-activated receptor (PAR)-2, while the concomitant ZO-1 degradation was PAR-2/EGFR-independent. Importantly, the fibrogenic cytokine transforming growth factor (TGF)-β prolonged HDM-induced EGFR phosphorylation and inhibited ligand-induced EGFR internalisation/degradation, which resulted in sustained E-cadherin and ZO-1 redistribution.

Thus, allergen-induced, PAR-2/EGFR-mediated signalling decreases epithelial resistance and promotes junction disassembly. The TGF-β-enhanced EGFR signalling may be an important contributor to barrier dysfunction and increased epithelial vulnerability in response to HDM.
The occupational contribution to severe exacerbation of asthma
Authors: Henneberger P.K. , Mirabelli M.C. , Kogevinas M. , Antó J.M. , Plana E. , Dahlman-Höglund A. , Jarvis D.L. , Kromhout H. , Lillienberg L. , Norbäck D. , Olivieri M. , Radon K. , Torén K. , Urrutia I. , Villani S. , Zock J.P.
Published: March 2010

The goal of this study was to identify occupational risk factors for severe exacerbation of asthma and estimate the extent to which occupation contributes to these events.

The 966 participants were working adults with current asthma who participated in the follow-up phase of the European Community Respiratory Health Survey. Severe exacerbation of asthma was defined as self-reported unplanned care for asthma in the past 12 months. Occupations held in the same period were combined with a general population job-exposure matrix to assess occupational exposures.

74 participants reported having had at least one severe exacerbation event, for a 1-yr cumulative incidence of 7.7%. From regression models that controlled for confounders, the relative risk (RR) was statistically significant for low (RR 1.7, 95% CI 1.1–2.6) and high (RR 3.6, 95% CI 2.2–5.8) biological dust exposure, high mineral dust exposure (RR 1.8, 95% CI 1.02–3.2), and high gas and fumes exposure (RR 2.5, 95% CI 1.2–5.5). The summary category of high dust, gas, or fumes exposure had RR 3.1 (95% CI 1.9–5.1). Based on this RR, the population attributable risk was 14.7% among workers with current asthma.

These results suggest occupation contributes to approximately one in seven cases of severe exacerbation of asthma in a working population, and various agents play a role.
Predicting outcomes and drug resistance with standardised treatment of active tuberculosis
Authors: Oxlade O. , Schwartzman K. , Pai M. , Heymann J. , Benedetti A. , Royce S. , Menzies D.
Published: March 2010

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment.

A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance.

Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48–86 fewer persons will require retreatment, and 3–12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50–94% of failures and 3–56% of relapses will have multidrug-resistant TB.

We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.
Exposure to volatile organic compounds and loss of pulmonary function in the elderly
Authors: Yoon H.I. , Hong Y-C. , Cho S-H. , Kim H. , Kim Y.H. , Sohn J.R. , Kwon M. , Park S-H. , Cho M-H. , Cheong H-K.
Published: March 2010

Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population.

A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2′-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests.

We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow at 25–75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters.

This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.
The role of per cent predicted 6-min walk distance in pulmonary arterial hypertension
Authors: Lee W-T.N. , Peacock A.J. , Johnson M.K.
Published: March 2010

Absolute 6-min walk distance (6MWD) predicts mortality in pulmonary arterial hypertension (PAH), but varies greatly between normal individuals due to physiological factors such as age, sex, height and weight. The % predicted 6MWD adjusts for these factors and may predict mortality more reliably. The aim of the study was to compare the strength of mortality prediction by absolute and % predicted 6MWD in PAH at baseline and on treatment.

% predicted 6MWD was calculated using four different reference equations in 137 PAH patients (idiopathic and connective tissue disease associated) diagnosed between November 2000 and November 2009. Cox proportional hazards and receiver-operating characteristic (ROC) analyses were used to compare the prognostic strength of absolute and % predicted 6MWD.

% predicted 6MWD was predictive of all-cause mortality at baseline (hazard ratio 0.74–0.83 per 10% increase; p<0.05) and on treatment (0.67–0.75 per 10% increase; p<0.01), but each respective area under the ROC curve was not different from that of absolute 6MWD for predicting 2-yr mortality at baseline (absoluteversus% predicted: 0.74versus0.71–0.75) or on treatment (0.77versus0.72–0.78).

In conclusion, % predicted 6MWD may help clinicians interpret the 6-min walk test, but its prognostic value is not superior to that of absolute 6MWD.
Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study
Authors: Quanjer P.H. , Stanojevic S. , Stocks J. , Hall G.L. , Prasad K.V.V. , Cole T.J. , Rosenthal M. , Perez-Padilla R. , Hankinson J.L. , Falaschetti E. , Golshan M. , Brunekreef B. , Al-Rawas O. , Kühr J. , Trabelsi Y. , Ip M.S.M.
Published: March 2010

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide.

Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4–20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH.

In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age.

When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.
Deposition and metabolism of inhaled ciclesonide in the human lung
Authors: Nave R. , Watz H. , Hoffmann H. , Boss H. , Magnussen H.
Published: March 2010

Ciclesonide is an inhaled corticosteroid, administered as a prodrugviaa metered-dose inhaler. Following deposition in the lung, ciclesonide is hydrolysed by esterases to form the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Formation of des-CIC, as well as reversible esterification of des-CIC with fatty acids, has been demonstratedin vitro. The aim of this study was to investigate thein vivometabolism of ciclesonide in the human lung.

This single-dose, open-label, nonrandomised study was performed in 20 patients undergoing planned lung surgery for treatment of malignant pulmonary lesions. Patients inhaled a single dose of 1,280 μg ciclesonide at various time-points between 2 and 24 h prior to lung tissue resection. The concentration of ciclesonide, des-CIC and fatty acid conjugates of des-CIC in tissue samples was determined. Serum samples for pharmacokinetic analysis were taken at several time-points after inhalation.

The pharmacokinetics in serum indicated that the inhalation by the patients was adequate. Metabolites (des-CIC, des-CIC oleate and des-CIC palmitate) were detected in the resected central and peripheral lung tissues. A substantial portion of ciclesonide was already activated to des-CIC at the first time-point of tissue analysis.

Activation of ciclesonide and formation of des-CIC fatty acid conjugates was confirmedin vivoin the human lung.
Obesity and risk of subsequent hospitalisation with pneumonia
Authors: Kornum J.B. , Nørgaard M. , Dethlefsen C. , Due K.M. , Thomsen R.W. , Tjønneland A. , Sørensen H.T. , Overvad K.
Published: March 2010

Obesity may be associated with increased risk of pneumonia, but available data on this relationship are sparse and inconsistent.

We followed a prospective cohort of 22,578 males and 25,973 females from the Danish Diet, Cancer and Health Study, aged 50–64 yrs and free from major chronic diseases at baseline (1993–1997), for first-time hospitalisation with pneumonia (median follow-up 12 yrs).

Compared with males of normal weight, adjusted hazard ratios (HRs) for pneumonia were 1.4 (95% CI 1.2–1.7) for males with moderate obesity (body mass index (BMI) 30.0–34.9 kg·m−2), and 2.0 (95% CI 1.4–2.8) for males with severe obesity (BMI ≥35.0 kg·m−2), controlling for lifestyle and educational variables. Among females the associations were weaker, with adjusted HRs of 0.8 (95% CI 0.6–1.0) for moderate obesity, and 1.2 (95% CI 0.8–1.6) for severe obesity. Adjustment for major chronic diseases diagnosed during follow-up eliminated the associations between obesity and pneumonia risk.

Obesity is associated with higher risk of hospitalisation with pneumonia among males but not among females, which is apparently explained by occurrence of other chronic diseases.
Ovarian cancer classification based on dimensionality reduction for SELDI-TOF data
Authors: Tang Kai-Lin , Li Tong-Hua , Xiong Wen-Wei , Chen Kai
Published: March 2010

Background

Recent advances in proteomics technologies such as SELDI-TOF mass spectrometry has shown promise in the detection of early stage cancers. However, dimensionality reduction and classification are considerable challenges in statistical machine learning. We therefore propose a novel approach for dimensionality reduction and tested it using published high-resolution SELDI-TOF data for ovarian cancer.

Results

We propose a method based on statistical moments to reduce feature dimensions. After refining and t-testing, SELDI-TOF data are divided into several intervals. Four statistical moments (mean, variance, skewness and kurtosis) are calculated for each interval and are used as representative variables. The high dimensionality of the data can thus be rapidly reduced. To improve efficiency and classification performance, the data are further used in kernel PLS models. The method achieved average sensitivity of 0.9950, specificity of 0.9916, accuracy of 0.9935 and a correlation coefficient of 0.9869 for 100 five-fold cross validations. Furthermore, only one control was misclassified in leave-one-out cross validation.

Conclusion

The proposed method is suitable for analyzing high-throughput proteomics data.
Molecular evidence for a diverse green algal community growing in the hair of sloths and a specific association with Trichophilus welckeri(Chlorophyta, Ulvophyceae)
Authors: Suutari Milla , Majaneva Markus , Fewer David P , Voirin Bryson , Aiello Annette , Friedl Thomas , Chiarello Adriano G , Blomster Jaanika
Published: March 2010

Background

Sloths are slow-moving arboreal mammals inhabiting tropical rainforests in Central and South America. The six living species of sloths are occasionally reported to display a greenish discoloration of their pelage. Trichophilus welckeri, a green algal species first described more than a century ago, is widely believed to discolor the animals fur and provide the sloth with effective camouflage. However, this phenomenon has not been explored in any detail and there is little evidence to substantiate this widely held opinion.

Results

Here we investigate the genetic diversity of the eukaryotic community present in fur of all six extant species of sloth. Analysis of 71 sloth hair samples yielding 426 partial 18S rRNA gene sequences demonstrates a diverse eukaryotic microbial assemblage. Phylogenetic analysis reveals that sloth fur hosts a number of green algal species and suggests that acquisition of these organisms from the surrounding rainforest plays an important role in the discoloration of sloth fur. However, an alga corresponding to the morphological description of Trichophilus welckeri was found to be frequent and abundant on sloth fur. Phylogenetic analysis demonstrated the retention of this alga on the fur of sloths independent of geographic location.

Conclusions

These results demonstrate a unique diverse microbial eukaryotic community in the fur of sloths from Central and South America. Our analysis streghtens the case for symbiosis between sloths and Trichophilus welckeri.
Transcriptome analysis of reproductive tissue and intrauterine developmental stages of the tsetse fly (Glossina morsitans morsitans)
Authors: Attardo Geoffrey M , Ribeiro José MC , Wu Yineng , Berriman Matthew , Aksoy Serap
Published: March 2010

Background

Tsetse flies, vectors of African trypanosomes, undergo viviparous reproduction (the deposition of live offspring). This reproductive strategy results in a large maternal investment and the deposition of a small number of progeny during a female's lifespan. The reproductive biology of tsetse has been studied on a physiological level; however the molecular analysis of tsetse reproduction requires deeper investigation. To build a foundation from which to base molecular studies of tsetse reproduction, a cDNA library was generated from female tsetse (Glossina morsitans morsitans) reproductive tissues and the intrauterine developmental stages. 3438 expressed sequence tags were sequenced and analyzed.

Results

Analysis of a nonredundant catalogue of 1391 contigs resulted in 520 predicted proteins. 475 of these proteins were full length. We predict that 412 of these represent cytoplasmic proteins while 57 are secreted. Comparison of these proteins with other tissue specific tsetse cDNA libraries (salivary gland, fat body/milk gland, and midgut) identified 51 that are unique to the reproductive/immature cDNA library. 11 unique proteins were homologus to uncharacterized putative proteins within the NR database suggesting the identification of novel genes associated with reproductive functions in other insects (hypothetical conserved). The analysis also yielded seven putative proteins without significant homology to sequences present in the public database (unknown genes). These proteins may represent unique functions associated with tsetse's viviparous reproductive cycle. RT-PCR analysis of hypothetical conserved and unknown contigs was performed to determine basic tissue and stage specificity of the expression of these genes.

Conclusion

This paper identifies 51 putative proteins specific to a tsetse reproductive/immature EST library. 11 of these proteins correspond to hypothetical conserved genes and 7 proteins are tsetse specific.
Discovery of global genomic re-organization based on comparison of two newly sequenced rice mitochondrial genomes with cytoplasmic male sterility-related genes
Authors: Fujii Sota , Kazama Tomohiko , Yamada Mari , Toriyama Kinya
Published: March 2010

Background

Plant mitochondrial genomes are known for their complexity, and there is abundant evidence demonstrating that this organelle is important for plant sexual reproduction. Cytoplasmic male sterility (CMS) is a phenomenon caused by incompatibility between the nucleus and mitochondria that has been discovered in various plant species. As the exact sequence of steps leading to CMS has not yet been revealed, efforts should be made to elucidate the factors underlying the mechanism of this important trait for crop breeding.

Results

Two CMS mitochondrial genomes, LD-CMS, derived from Oryza sativa L. ssp. indica (434,735 bp), and CW-CMS, derived from Oryza rufipogon Griff. (559,045 bp), were newly sequenced in this study. Compared to the previously sequenced Nipponbare (Oryza sativa L. ssp. japonica) mitochondrial genome, the presence of 54 out of 56 protein-encoding genes (including pseudo-genes), 22 tRNA genes (including pseudo-tRNAs), and three rRNA genes was conserved. Two other genes were not present in the CW-CMS mitochondrial genome, and one of them was present as part of the newly identified chimeric ORF, CW-orf307. At least 12 genomic recombination events were predicted between the LD-CMS mitochondrial genome and Nipponbare, and 15 between the CW-CMS genome and Nipponbare, and novel genetic structures were formed by these genomic rearrangements in the two CMS lines. At least one of the genomic rearrangements was completely unique to each CMS line and not present in 69 rice cultivars or 9 accessions of O. rufipogon.

Conclusion

Our results demonstrate novel mitochondrial genomic rearrangements that are unique in CMS cytoplasm, and one of the genes that is unique in the CW mitochondrial genome, CW-orf307, appeared to be the candidate most likely responsible for the CW-CMS event. Genomic rearrangements were dynamic in the CMS lines in comparison with those of rice cultivars, suggesting that 'death' and possible 'birth' processes of the CMS genes occurred during the breeding history of rice.
A/C magnetic hyperthermia of melanoma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: a mouse study
Authors: Balivada Sivasai , Rachakatla Raja Shekar , Wang Hongwang , Samarakoon Thilani N , Dani Raj Kumar , Pyle Marla , Kroh Franklin O , Walker Brandon , Leaym Xiaoxuan , Koper Olga B , Tamura Masaaki , Chikan Viktor , Bossmann Stefan H , Troyer Deryl L
Published: March 2010

Background

There is renewed interest in magnetic hyperthermia as a treatment modality for cancer, especially when it is combined with other more traditional therapeutic approaches, such as the co-delivery of anticancer drugs or photodynamic therapy.

Methods

The influence of bimagnetic nanoparticles (MNPs) combined with short external alternating magnetic field (AMF) exposure on the growth of subcutaneous mouse melanomas (B16-F10) was evaluated. Bimagnetic Fe/Fe3O4 core/shell nanoparticles were designed for cancer targeting after intratumoral or intravenous administration. Their inorganic center was protected against rapid biocorrosion by organic dopamine-oligoethylene glycol ligands. TCPP (4-tetracarboxyphenyl porphyrin) units were attached to the dopamine-oligoethylene glycol ligands.

Results

The magnetic hyperthermia results obtained after intratumoral injection indicated that micromolar concentrations of iron given within the modified core-shell Fe/Fe3O4 nanoparticles caused a significant anti-tumor effect on murine B16-F10 melanoma with three short 10-minute AMF exposures. We also observed a decrease in tumor size after intravenous administration of the MNPs followed by three consecutive days of AMF exposure 24 hrs after the MNPs injection.

Conclusions

These results indicate that intratumoral administration of surface modified MNPs can attenuate mouse melanoma after AMF exposure. Moreover, we have found that after intravenous administration of micromolar concentrations, these MNPs are capable of causing an anti-tumor effect in a mouse melanoma model after only a short AMF exposure time. This is a clear improvement to state of the art.
Are the elderly more vulnerable to psychological impact of natural disaster? A population-based survey of adult survivors of the 2008 Sichuan earthquake
Authors: Jia Zhaobao , Tian Wenhua , Liu Weizhi , Cao Yang , Yan Jin , Shun Zhisheng
Published: March 2010

Background

The association between ages and psychological impact of natural disasters has not been well characterized. A population-based study was conducted 15 months after the 2008 Sichuan earthquake to assess whether elderly survivors were more likely to develop posttraumatic stress disorder (PTSD) and general psychiatric morbidity.

Methods

A population-based survey of 327 survivors (152 elders, 175 younger adults) was conducted in severely affected areas by the earthquake, using a multi-stage systematic sampling design.

Results

Compared with the younger adult survivors, the elderly were more likely to have symptoms of PTSD (22.5% vs. 8.0%, p = 0.001) and general psychiatric morbidity (42.0% vs. 25.4%, p = 0.003). Risk factors, such as being elderly, having been in serious danger, having lost family members, and having felt guilt concerning one's death or injury were significantly associated with developing PTSD; being elderly, having family members or friends seriously injured, and having felt guilt concerning one's death or injury were significantly associated with developing general psychiatric morbidity. Utilization of mental health services is strongly associated with the decreased risk for developing both of the symptoms.

Conclusion

Compared with the younger adults, the elderly survivors were more likely to develop PTSD and general psychiatric morbidity. More mental health services should be distributed to the elderly and groups at particular risk, to ensure their smooth mental health reconstruction after the earthquake.
What the hyena's laugh tells: Sex, age, dominance and individual signature in the giggling call of Crocuta crocuta
Authors: Mathevon Nicolas , Koralek Aaron , Weldele Mary , Glickman Stephen E , Theunissen Frédéric E
Published: March 2010

Background

Among mammals living in social groups, individuals form communication networks where they signal their identity and social status, facilitating social interaction. In spite of its importance for understanding of mammalian societies, the coding of individual-related information in the vocal signals of non-primate mammals has been relatively neglected. The present study focuses on the spotted hyenaCrocuta crocuta, a social carnivore known for its complex female-dominated society. We investigate if and how the well-known hyena's laugh, also known as the giggle call, encodes information about the emitter.

Results

By analyzing acoustic structure in both temporal and frequency domains, we show that the hyena's laugh can encode information about age, individual identity and dominant/subordinate status, providing cues to receivers that could enable assessment of the social position of an emitting individual.

Conclusions

The range of messages encoded in the hyena's laugh is likely to play a role during social interactions. This call, together with other vocalizations and other sensory channels, should ensure an array of communication signals that support the complex social system of the spotted hyena. Experimental studies are now needed to decipher precisely the communication network of this species.
The epidemiology of hospitalized influenza in children, a two year population-based study in the People's Republic of China
Authors: Ji Wei , Zhang Tao , Zhang Xuelan , Jiang Lufang , Ding Yunfang , Hao Chuangli , Ju Liwen , Wang Yuqing , Jiang Qingwu , Steinhoff Mark , Black Steven , Zhao Genming
Published: March 2010

Background

The epidemiology and disease burden of annual influenza in children in mainland People's Republic of China have not been reported in detail. To understand the incidence and epidemiology of laboratory-proven influenza hospitalization in children in China, a review of available laboratory and hospital admission data was undertaken.

Methods

We conducted a retrospective population-based study in Suzhou and the surrounding area of Jiangsu province, China for hospitalized cases of respiratory illness at Suzhou Children's Hospital. Cases of pneumonia or respiratory illness were identified from hospital computer data bases. Routine virological testing by fluorescent monoclonal antibody assay of all hospitalized children identified influenza and other viruses. We calculated incidence rates using census population denominators.

Results

Of 7,789 specimens obtained during 2007 and 2008, 85 were positive for influenza A and 25 for influenza B. There were 282 specimens with parainfluenza virus and 1392 with RSV. Influenza occurred throughout the year, with peaks in the winter, and in August/September. Overall estimated annual incidence of laboratory-proven influenza hospitalization was 23-27/100,000 children 0-4 years old, and 60/100,000 in infants 0-6 months, with an average hospitalization of 9 days.

Conclusions

Influenza disease in young children in this part of China is a relatively common cause of hospitalization, and occurs throughout the year. The use of influenza vaccine in Chinese children has the potential to reduce the effect of influenza in the children, as well as in their communities. Studies are needed to further assess the burden of influenza, and to develop and refine effective strategies of immunization of young children in China.